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InternalMed_Harrison. platelet aggregation/adhesion. Hyperuricemia is present. Hyperlipidemia includes elevation of triglycerides, low-density lipoproteins, and phospholipids. Type Ib patients have additional findings of neutropenia and impaired neutrophil function, which result in recurrent bacterial infections and oral and intestinal mucosal ulceration. GSD I patients may experience intermittent diarrhea, which can worsen with age. In GSD Ib, diarrhea is largely due to loss of mucosal barrier function caused by inflammation.


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InternalMed_Harrison. long-term CompliCations Gout usually becomes symptomatic at puberty as a result of long-term hyperuricemia. Puberty is often delayed. Nearly all female patients have ultrasound findings consistent with polycystic ovaries; however, the other clinical features of polycystic ovary syndrome, such as acne and hirsutism, are not seen. Several reports of successful pregnancy in women with GSD I suggest that fertility is not affected. Increased bleeding during menstrual cycles, including life-threatening menorrhagia, has been reported. Secondary to lipid abnormalities, there is an increased risk of pancreatitis. Patients with GSD I may be at increased risk for cardiovascular disease. In adult patients, frequent fractures can occur and radiographic evidence of osteopenia/ osteoporosis can be found; in prepubertal patients, radial bone mineral content is significantly reduced. Pulmonary hypertension—although rare—has been reported. By the second or third decade of life, many patients with type


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InternalMed_Harrison. in prepubertal patients, radial bone mineral content is significantly reduced. Pulmonary hypertension—although rare—has been reported. By the second or third decade of life, many patients with type I GSD develop hepatic adenomas that can hemorrhage and, in some cases, become malignant. Renal disease is a serious late complication. Almost all patients older than 20 years have proteinuria, and many have hypertension, kidney stones, nephrocalcinosis, and altered creatinine clearance. Laboratory findings include abnormally high levels of blood lactate, triglycerides, cholesterol, and uric acid. In some patients, renal function deteriorates and progresses to complete failure, requiring dialysis or transplantation.


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InternalMed_Harrison. diagnosis Clinical presentation and abnormal plasma lactate and lipid values suggest that a patient may have GSD I, but gene-based mutation analysis provides a noninvasive means of reaching a definitive diagnosis for most patients with types Ia and Ib disease. Before the glucose-6-phosphatase and glucose-6-phosphate translocase genes were cloned, a definitive diagnosis required a liver biopsy to demonstrate a deficiency. Type III GSD (Debrancher Deficiency, Limit Dextrinosis) Type III GSD is an autosomal recessive disorder caused by a deficiency of glycogen debranching enzyme. Debranching and phosphorylase enzymes are responsible for complete degradation of glycogen. When the debranching enzyme is defective, glycogen breakdown is incomplete. Abnormal glycogen accumulates with short outer chains and resembles dextrin.


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InternalMed_Harrison. CliniCal and laboratory findings Deficiency of glycogen debranching enzyme causes hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy, and cardiomyopathy. The disorder usually involves both liver and muscle and, in such cases, is termed type IIIa GSD. However, in ~15% of patients, the disease appears to involve only the liver and is classified as type IIIb. Hypoglycemia and hyperlipidemia occur in children. In type III disease (as opposed to type I disease), fasting ketosis can be prominent, aminotransferase levels are elevated, and blood lactate and uric acid concentrations are usually normal. Serum creatine kinase (CK) levels can sometimes be used to identify patients with muscle involvement, but normal levels do not rule out muscle enzyme deficiency. In most patients with type III disease, hepatomegaly improves with age; however, liver cirrhosis and hepatocellular carcinoma may occur in late adulthood. Hepatic adenomas may occur, although less commonly than in GSD


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InternalMed_Harrison. type III disease, hepatomegaly improves with age; however, liver cirrhosis and hepatocellular carcinoma may occur in late adulthood. Hepatic adenomas may occur, although less commonly than in GSD I. Left ventricular hypertrophy and life-threatening arrhythmias have been reported. Patients with type IIIa disease may experience muscle weakness in childhood that can become severe after the third or fourth decade of life. Polycystic ovaries are common in GSD III, and some patients develop features of polycystic ovarian syndrome, such as hirsutism and irregular menstrual cycles. Reports of successful pregnancy in women with GSD III suggest that fertility is normal.


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InternalMed_Harrison. diagnosis In type IIIa GSD, deficient debranching enzyme activity can be demonstrated in liver, skeletal muscle, and heart. In contrast, patients with type IIIb have debranching enzyme deficiency in the liver but not in muscle. The liver has distended hepatocytes due to glycogen buildup; areas of fibrosis are also noted very early in the disease course. In the past, definitive assignment of subtype required enzyme assays in both liver and muscle. DNA-based analyses now provide a noninvasive way of subtyping these disorders in most patients. However, the large size of the gene and the distribution of private mutations across it pose challenges in DNA-based analysis. CHAPTER 433e Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism


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InternalMed_Harrison. Type IX GSD (Liver Phosphorylase Kinase Deficiency) Defects of PhK cause a heterogeneous group of glycogenoses. The PhK enzyme complex consists of four subunits (α, β, γ, and δ). Each subunit is encoded by different genes (X chromosome as well as autosomes) that are differentially expressed in various tissues. PhK deficiency can be divided into several subtypes on the basis of the gene/subunit involved, the tissues primarily affected, and the mode of inheritance. The most common subtype is X-linked liver PhK deficiency, which is also one of the most common liver glycogenoses. PhK activity may also be deficient in erythrocytes and leukocytes but is normal in muscle. Typically, a child between the ages of 1 year and 5 years presents with growth retardation and hepatomegaly. Children tend eventually to exhibit normal growth patterns initiated by a delayed growth spurt during puberty. Liver fibrosis has been identified in some patients, including children. Levels of cholesterol,


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InternalMed_Harrison. tend eventually to exhibit normal growth patterns initiated by a delayed growth spurt during puberty. Liver fibrosis has been identified in some patients, including children. Levels of cholesterol, triglycerides, and liver enzymes are mildly elevated. Fasting ketosis is another feature of the disease. Lactic and uric acid levels are usually normal. Hypoglycemia is typically mild; however, phenotypic variability is being increasingly recognized, with significant involvement in some cases of the X-linked form. The accumulated glycogen in liver (β particles, rosette form) has a frayed or burst appearance and is less compact than the glycogen seen in type I or type III GSD. Hepatomegaly and abnormal blood chemistries gradually return to normal with age. Most adults reach a normal final height and are practically asymptomatic, despite persistent PhK deficiency. The prognosis is usually good, and adult patients have minimal hepatomegaly. Some patients have significant ketosis and


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InternalMed_Harrison. height and are practically asymptomatic, despite persistent PhK deficiency. The prognosis is usually good, and adult patients have minimal hepatomegaly. Some patients have significant ketosis and progressive liver disease that can advance to fibrosis and liver failure. It is recommended that adult patients be monitored for hepatic complications with regular CT or MRI scans.


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InternalMed_Harrison. Treatment is symptom based. A high-carbohydrate diet and frequent feedings are effective in preventing hypoglycemia. Some patients require no specific treatment. Recent studies have shown that instituting a treatment regimen of cornstarch and protein feedings early, even in seemingly stable patients, may prevent long-term complications. Blood ketones and glucose should be evaluated during times of stress. Other subtypes of type IX GSD include an autosomal recessive form of liver and muscle PhK deficiency, an autosomal recessive form of liver PhK deficiency that often develops into liver cirrhosis, a muscle-specific PhK deficiency that causes cramps and myoglobinuria with exercise, and a cardiac-specific PhK deficiency that is lethal during infancy because of massive glycogen deposition in the myocardium. The finding of PhK deficiency in the cardiac-specific PhK deficiency may be a secondary phenomenon, as a subset of these patients have mutations in PRKAG2.


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InternalMed_Harrison. Other Liver Glycogenoses with Hepatomegaly and Hypoglycemia These disorders include hepatic phosphorylase deficiency (Hers disease, type VI) and hepatic glycogenosis with renal Fanconi syndrome (type XI). Patients with GSD type VI can have growth retardation, hyperlipidemia, and hyperketosis in addition to hepatomegaly and hypoglycemia. Some patients have a benign clinical course. GSD XI is caused by defects in the facilitative glucose transporter 2 (GLUT-2), which transports glucose and galactose in and out of hepatocytes, pancreatic cells, and the basolateral membranes of intestinal and renal epithelial cells. The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in liver and kidney.


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InternalMed_Harrison. Type V GSD (Muscle Phosphorylase Deficiency, McArdle Disease) Type V GSD is an autosomal recessive disorder caused by deficiency of muscle phosphorylase. McArdle disease is a prototypical muscle-energy disorder as the enzyme deficiency limits ATP generation by glycogenolysis and results in glycogen accumulation.


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InternalMed_Harrison. CliniCal and laboratory findings Usually, symptoms first develop in adulthood and involve exercise intolerance with muscle cramps. Two types of activity tend to cause symptoms: (1) brief exercise of great intensity, such as sprinting or carrying heavy loads; and (2) less intense but sustained activity, such as climbing stairs or walking uphill. Most patients can engage in moderate exercise, such as walking on level ground, for long periods. Patients often exhibit the “second-wind” phenomenon, in which, after a short break from the initiation of strenuous physical effort, they are able to continue the activity without pain. Although most patients experience episodic muscle pain and cramping as a result of exercise, 35% report permanent pain that seriously affects sleep and other activities. About half of patients report burgundy-colored urine after exercise; this coloration results from myoglobinuria secondary to rhabdomyolysis. Intense myoglobinuria after vigorous exercise can lead to


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InternalMed_Harrison. About half of patients report burgundy-colored urine after exercise; this coloration results from myoglobinuria secondary to rhabdomyolysis. Intense myoglobinuria after vigorous exercise can lead to renal failure. Clinical heterogeneity is uncommon; however, there are cases with symptom onset as late as the eighth decade and cases that present early with hypotonia, generalized muscle weakness, and progressive respiratory insufficiency, which is often fatal.


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InternalMed_Harrison. Although cardiac involvement is not usually associated with muscle phosphorylase deficiency, hypertrophic cardiomyopathy has been observed in an adult patient with GSD V. In rare cases, electromyographic findings may suggest inflammatory myopathy, a diagnosis that may be confused with polymyositis. These patients may be at risk for statin-induced myopathy and rhabdomyolysis. During rest, the serum CK level is usually elevated; after exercise, the CK level increases even more. Exercise also increases levels of blood ammonia, inosine, hypoxanthine, and uric acid; these abnormalities reflect residues of accelerated muscle purine nucleotide recycling as a result of insufficient ATP production. NADH is underproduced during physical exertion.


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InternalMed_Harrison. diagnosis Lack of an increase in blood lactate and exaggerated blood ammonia elevations after an ischemic exercise test are indicative of a muscle glycogenosis and suggest a defect in the conversion of glycogen or glucose to lactate. This abnormal exercise response, however, can also occur with other defects in glycogenolysis or glycolysis, such as deficiencies of muscle phosphofructokinase or debranching enzyme (when the test is done after fasting). The cycle test detects the hallmark heart rate observed during the second-wind phenomenon. A definitive diagnosis is made by enzymatic assay in muscle tissue or by mutation analysis of the myophosphorylase gene.


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InternalMed_Harrison. DISORDERS WITH PROGRESSIVE SKELETAL MuSCLE MYOPATHY AND/OR CARDIOMYOPATHY Pompe Disease, Type II GSD (Acid α-1,4 Glucosidase Deficiency) Pompe disease is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4 glucosidase, an enzyme responsible for the degradation of glycogen in the lysosomes. This disease is characterized by the accumulation of glycogen in the lysosomes as opposed to accumulation in cytoplasm (as in the other glycogenoses). CliniCal and laboratory findings The disorder encompasses a range of phenotypes. Each includes myopathy but differs in the age of onset, extent of organ involvement, and clinical severity. The most severe is the infantile form, with cardiomegaly, hypotonia, and death before the age of 1 year. Infants may appear normal at birth but soon develop generalized muscle weakness with feeding difficulties, macroglossia, hepatomegaly, and congestive heart failure due to hypertrophic cardiomyopathy.


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InternalMed_Harrison. The late-onset form (juvenile/late-childhood or adult form) is characterized by skeletal muscle manifestations, usually with minimal or no cardiac involvement, and a more slowly progressive course. The juvenile form typically presents as delayed motor milestones (if age of onset is early enough) and difficulty in walking. With disease progression, patients often develop swallowing difficulties, proximal muscle weakness, and respiratory muscle involvement. Death may occur before the end of the second decade.


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InternalMed_Harrison. Adults typically present between the second and seventh decades with slowly progressive myopathy without overt cardiac involvement. The clinical picture is dominated by slowly progressive proximal limb girdle muscle weakness. The pelvic girdle, paraspinal muscles, and diaphragm are most seriously affected. Respiratory symptoms include somnolence, morning headache, orthopnea, and exertional dyspnea. In rare instances, patients present with respiratory insufficiency as the initial symptom. Basilar artery aneurysms and dilation of the ascending aorta have been observed in patients with Pompe disease. Ptosis, lingual weakness, gastrointestinal dysmotility, and incontinence due to poor sphincter tone are now being recognized as part of the clinical spectrum. Individuals with advanced disease often require some form of ventilation and are dependent on a walking aid or wheelchair.


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InternalMed_Harrison. Laboratory findings include elevated levels of serum CK, aspartate aminotransferase, and lactate dehydrogenase. Levels of urine glucose tetrasaccharide (Hex4), a breakdown product of glycogen, are elevated, especially on the severe end of the disease spectrum. In infants, chest x-ray shows massive cardiomegaly, and electrocardiographic findings include a high-voltage QRS complex and a shortened PR interval. Muscle biopsy shows vacuoles that stain positive for glycogen; the muscle acid phosphatase level is increased, presumably from a compensatory increase of lysosomal enzymes. Electromyography reveals myopathic features, with irritability of muscle fibers and pseudomyotonic discharges. Serum CK is not always elevated in adults, and, depending on the muscle biopsied or tested, muscle histology or electromyography may not be abnormal. The affected muscle should be examined.


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InternalMed_Harrison. diagnosis The confirmatory step for a diagnosis of Pompe disease is enzyme assay demonstrating deficient acid α-glucosidase or a gene sequence with two pathogenic mutations in the GAA gene. Enzyme activity can be measured in muscle, cultured skin fibroblasts, or blood. Deficiency is usually more severe in the infantile form. Early diagnosis is the key to treatment efficacy.


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InternalMed_Harrison. GSD Mimicking Hypertrophic Cardiomyopathy Deficiency of LAMP2— also called Danon’s disease—or of the protein kinase, AMP-activated gamma 2 noncatalytic subunit (PRKAG2), results in the accumulation of glycogen in the heart and skeletal muscle. LAMP2 deficiency is X-linked, whereas PRKAG2 deficiency is autosomal dominant. Clinically, both subsets of patients present primarily with hypertrophic cardiomyopathy. Their electrophysiologic abnormalities, particularly ventricular preexcitation and conduction defects, can distinguish them from patients with hypertrophic cardiomyopathy resulting from defects in sarcomere-protein genes. In patients with LAMP2 deficiency, mental delays are common and the onset of cardiac symptoms, including chest pain, palpitation, syncope, and cardiac arrest, can occur between the ages of 8 and 15 years—i.e., earlier than the average age of 33 years for patients with PRKAG2 deficiency. Patients as young as 9 years old have presented with PRKAG2 deficiency. A


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InternalMed_Harrison. occur between the ages of 8 and 15 years—i.e., earlier than the average age of 33 years for patients with PRKAG2 deficiency. Patients as young as 9 years old have presented with PRKAG2 deficiency. A rapidly fatal congenital form of PRKAG2 presents in early infancy with severe hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome. In these patients, levels of PhK have been found to be low. The prognosis for LAMP2 deficiency is poor, with progressive end-stage heart failure early in adulthood. By contrast, except in the fatal congenital form, long-term survival is possible for patients with cardiomyopathy due to PRKAG2 mutations. Some patients may require the implantation of a pacemaker and aggressive control of arrhythmias. Congestive heart failure has been documented in patients with PRKAG2 deficiency.


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InternalMed_Harrison. Heart transplantation has been suggested as a preventive measure for LAMP2 deficiency and noncongenital PRKAG2 deficiency. “Classic” galactosemia is caused by galactose 1-phosphate uridyltransferase (GALT) deficiency. It is a serious disease with an incidence of 1 in 60,000 and an early onset of symptoms. The newborn infant normally receives up to 40% of caloric intake as lactose (glucose + galactose). Without the transferase, the infant is unable to metabolize galactose 1-phosphate (Fig. 433e-1), which consequently accumulates, resulting in injury to parenchymal cells of the kidney, liver, and brain. After the first feeding, infants can present with vomiting, diarrhea, hypotonia, jaundice, and hepatomegaly. Patients with galactosemia are at increased risk for Escherichia coli neonatal sepsis; the onset of sepsis often precedes the diagnosis of galactosemia.


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InternalMed_Harrison. Widespread newborn screening for galactosemia has identified 433e-5 these infants early and allowed them to be placed on dietary restriction. Elimination of galactose from the diet reverses growth failure as well as renal and hepatic dysfunction, improving the prognosis. However, on long-term follow-up, some patients still have ovarian failure manifesting as primary or secondary amenorrhea as well as developmental delays and learning disabilities that increase in severity with age. Of women with classic galactosemia, 80–90% or more report hypergonadotropic hypogonadism. While most female patients are infertile when they reach childbearing age, a few have given birth. Several mutations appear to be protective, particularly the p.Ser135Leu mutation, which is more common in the African-American population. Methods for fertility preservation, such as cryopreservation, are still in the experimental stages. In addition, most patients have speech disorders, and a smaller proportion


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InternalMed_Harrison. population. Methods for fertility preservation, such as cryopreservation, are still in the experimental stages. In addition, most patients have speech disorders, and a smaller proportion demonstrate poor growth and impaired motor function and balance (with or without overt ataxia). Adults on dairy-free diets have developed cataracts, tremors, and low bone density. The treatment of galactosemia to prevent long-term complications remains a challenge.


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InternalMed_Harrison. Deficiency of galactokinase (Fig. 433e-1) causes cataracts. Deficiency of uridine diphosphate galactose 4-epimerase can be benign when the enzyme deficiency is limited to blood cells but can be as severe as classic galactosemia when the enzyme deficiency is generalized. Fructokinase deficiency, or essential fructosemia (Fig. 433e-1), causes a benign condition that is usually an incidental finding made through the detection of fructose as a reducing substance in the urine.


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InternalMed_Harrison. Deficiency of fructose 1,6-bisphosphate aldolase (aldolase B; hereditary fructose intolerance) is a serious disease in infants. These patients are healthy and asymptomatic until fructose or sucrose (table sugar) is ingested (usually from fruit, sweetened cereal, or sucrose-containing formula). Clinical manifestations may include jaundice, hepatomegaly, vomiting, lethargy, irritability, and convulsions. The incidence of celiac disease is higher among patients with hereditary fructose intolerance (>10%) than in the general population (1–3%). Laboratory findings show prolonged clotting time, hypoalbuminemia, elevation of bilirubin and aminotransferase levels, and proximal renal tubular dysfunction. If the disease is not diagnosed and intake of the noxious sugar continues, hypoglycemic episodes recur, and liver and kidney failure progresses, eventually leading to death. Treatment requires the elimination of all sources of sucrose, fructose, and sorbitol from the diet. Through this


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InternalMed_Harrison. episodes recur, and liver and kidney failure progresses, eventually leading to death. Treatment requires the elimination of all sources of sucrose, fructose, and sorbitol from the diet. Through this treatment, liver and kidney dysfunction improve, and catch-up growth is common; intellectual development is usually unimpaired. Over time, the patient’s symptoms become milder, even after fructose ingestion, and the long-term prognosis is good.


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InternalMed_Harrison. Fructose 1,6-diphosphatase deficiency is characterized by childhood life-threatening episodes of acidosis, hypoglycemia, hyperventilation, convulsions, and coma. These episodes are triggered by febrile infections and gastroenteritis when oral food intake decreases. Laboratory findings show low blood glucose levels, high lactate and uric acid levels, and metabolic acidosis. Unlike hereditary fructose intolerance, this deficiency usually is not associated with an aversion to sweets, and renal tubular and liver functions are normal. Treatment of acute attacks requires the correction of hypoglycemia and acidosis by IV infusion. Later, avoidance of fasting and elimination of fructose and sucrose from the diet prevent further episodes. A slowly released carbohydrate such as cornstarch is useful for the long-term prevention of hypoglycemia. The prognosis is good, as patients who survive childhood develop normally.


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InternalMed_Harrison. CHAPTER 433e Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism The GSDs and other inherited disorders of carbohydrate metabolism, although rare, have been reported in most ethnic populations. The prevalent genetic mutations for each disease may vary in different ethnic populations, but clinical symptoms are remarkably similar and treatment guidelines apply to all populations. The practice of newborn screening should be considered worldwide to intercept the rapid progression of many of these disorders.


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InternalMed_Harrison. Inherited Disorders of Amino Acid Metabolism in Adults Nicola Longo Amino acids are not only the building blocks of proteins but also serve as neurotransmitters (glycine, glutamate, γ-aminobutyric acid) or as 434e precursors of hormones, coenzymes, pigments, purines, or pyrimidines. Eight amino acids, referred to as essential, cannot be synthesized by humans and must be obtained from dietary sources. The others are formed endogenously. Each amino acid has a unique degradative pathway by which its nitrogen and carbon components are used for the synthesis of other amino acids, carbohydrates, and lipids. Disorders of amino acid metabolism and transport (Chap. 435e) are individually rare—the incidences range from 1 in 10,000 for cystinuria or phenylketonuria to 1 in 200,000 for homocystinuria or alkaptonuria—but collectively, they affect perhaps 1 in 1000 newborns. Almost all are transmitted as autosomal recessive traits.


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InternalMed_Harrison. The features of inherited disorders of amino acid catabolism are summarized in Table 434e-1. In general, these disorders are named for the compound that accumulates to highest concentration in blood (-emias) or urine (-urias). In the aminoacidopathies, the parent amino acid is found in excess, whereas products in the catabolic pathway accumulate in organic acidemias. Which compound(s) accumulates depends on the site of the enzymatic block, the reversibility of the reactions proximal to the lesion, and the availability of alternative pathways of metabolic “runoff.” Biochemical and genetic heterogeneity are common. Five distinct forms of hyperphenylalaninemia, nine forms of homocystinuria, and methylmalonic acidemia are recognized. Such heterogeneity reflects the presence of a large array of molecular defects.


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InternalMed_Harrison. The manifestations of these conditions differ widely (Table 434e-1). Some, such as sarcosinemia, produce no clinical consequences. At the other extreme, complete deficiency of ornithine transcarbamylase is lethal in the untreated neonate. Central nervous system (CNS) dysfunction, in the form of developmental retardation, seizures, alterations in sensorium, or behavioral disturbances, is present in more than half the disorders. Protein-induced vomiting, neurologic dysfunction, and hyperammonemia occur in many disorders of urea cycle intermediates. Metabolic ketoacidosis, often accompanied by hyperammonemia, is a frequent presenting finding in disorders of branched-chain amino acid metabolism. Some disorders produce focal tissue or organ involvement such as liver disease, renal failure, cutaneous abnormalities, or ocular lesions.


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InternalMed_Harrison. The analysis of plasma amino acids (by ion-exchange chromatography), urine organic acids (by gas chromatography/mass spectrometry), and plasma acylcarnitine profile (by tandem mass spectrometry) is commonly used to diagnose and monitor most of these disorders. The diagnosis is confirmed by enzyme assay on cells or tissues from the patients or by DNA testing. The clinical manifestations in many of these conditions can be prevented or mitigated if a diagnosis is achieved early and appropriate treatment (e.g., dietary protein or amino acid restriction or vitamin supplementation) is instituted promptly. For this reason, newborn screening programs seek to identify several of these disorders. Infants with a positive screening test need additional metabolic testing (usually suggested by the newborn screening program) to confirm or exclude the diagnosis. Confirmed cases should be referred to a metabolic center for initiation of therapy. The parents need to be counseled about the recurrence


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InternalMed_Harrison. screening program) to confirm or exclude the diagnosis. Confirmed cases should be referred to a metabolic center for initiation of therapy. The parents need to be counseled about the recurrence risk of the disease in future pregnancies. In some cases, parents need testing to exclude metabolic alterations seen in carriers for some of these disorders (such as some forms of homocystinuria) or because they might have a disorder themselves (such as glutaric acidemia type 1, methylcrotonyl coenzyme A carboxylase deficiency, or fatty acid oxidation defects). Some metabolic disorders can remain asymptomatic until adult age, presenting only when fasting or severe stress require full activity of affected metabolic pathways to provide energy.


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InternalMed_Harrison. Selected disorders that illustrate the principles, properties, and 434e-1 problems presented by the disorders of amino acid metabolism are discussed in this chapter.


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InternalMed_Harrison. The hyperphenylalaninemias (Table 434e-1) result from impaired conversion of phenylalanine to tyrosine. The most common and clinically important is phenylketonuria (frequency 1:10,000), which is an autosomal recessive disorder characterized by an increased concentration of phenylalanine and its by-products in body fluids and by severe mental retardation if untreated in infancy. It results from reduced activity of phenylalanine hydroxylase. The accumulation of phenylalanine inhibits the transport of other amino acids required for protein or neurotransmitter synthesis, reduces synthesis and increases degradation of myelin, and leads to inadequate formation of norepinephrine and serotonin. Phenylalanine is a competitive inhibitor of tyrosinase, a key enzyme in the pathway of melanin synthesis, and accounts for the hypopigmentation of hair and skin. Untreated children with classic phenylketonuria are normal at birth but fail to attain early developmental milestones, develop microcephaly,


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InternalMed_Harrison. and accounts for the hypopigmentation of hair and skin. Untreated children with classic phenylketonuria are normal at birth but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, seizures, and severe intellectual disability are major clinical problems later in life. Electroencephalographic abnormalities; “mousy” odor of skin, hair, and urine (due to phenylacetate accumulation); and a tendency to develop hypopigmentation and eczema complete the devastating clinical picture. In contrast, affected children who are detected and treated at birth show none of these abnormalities.


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InternalMed_Harrison. To prevent intellectual disability, diagnosis and initiation of dietary treatment of classic phenylketonuria must occur before the child is 2 weeks of age. For this reason, most newborns in North America, Australia, and Europe are screened by determinations of blood phenylalanine levels. Abnormal values are confirmed using quantitative analysis of plasma amino acids. Dietary phenylalanine restriction is usually instituted if blood phenylalanine levels are >360 μmol/L (6 mg/dL). Treatment consists of a special diet low in phenylalanine and supplemented with tyrosine, since tyrosine becomes an essential amino acid in phenylalanine hydroxylase deficiency. With therapy, plasma phenylalanine concentrations should be maintained between 120 and 360 μmol/L (2 and 6 mg/dL). Dietary restriction should be continued and monitored indefinitely. Some patients with milder forms of phenylketonuria (phenylalanine <1200 μm at presentation) show increased tolerance to dietary proteins and improved


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InternalMed_Harrison. should be continued and monitored indefinitely. Some patients with milder forms of phenylketonuria (phenylalanine <1200 μm at presentation) show increased tolerance to dietary proteins and improved metabolic control when treated with tetrahydrobiopterin (5–20 mg/ kg per day), an essential cofactor of phenylalanine hydroxylase.


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InternalMed_Harrison. A number of women with phenylketonuria who have been treated since infancy will reach adulthood and become pregnant. If maternal phenylalanine levels are not strictly controlled before and during pregnancy, their offspring are at increased risk for congenital defects and microcephaly (maternal phenylketonuria). After birth, these children have severe intellectual disability and growth retardation. Pregnancy risks can be minimized by continuing lifelong phenylalanine-restricted diets and assuring strict phenylalanine restriction 2 months prior to conception and throughout gestation. CHAPTER 434e Inherited Disorders of Amino Acid Metabolism in Adults The homocystinurias are nine biochemically and clinically distinct disorders (Table 434e-1) characterized by increased concentration of the sulfur-containing amino acid homocystine in blood and urine.


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InternalMed_Harrison. Classic homocystinuria, the most common (frequency 1:200,000), results from reduced activity of cystathionine β-synthase (Fig. 434e-1), the pyridoxal phosphate–dependent enzyme that condenses homocysteine with serine to form cystathionine. Most patients present between CHAPTER 434e Inherited Disorders of Amino Acid Metabolism in Adults Abbreviations: AD, autosomal dominant; AR, autosomal recessive; Cbl, cobalamin; DOPA, dihydroxyphenylalanine; GABA, γ-aminobutyric acid; GTP, guanosine 5′-triphosphate; XL, X-linked.


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InternalMed_Harrison. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; Cbl, cobalamin; DOPA, dihydroxyphenylalanine; GABA, γ-aminobutyric acid; GTP, guanosine 5′-triphosphate; XL, X-linked. 5,10-Methylene THF Methylene Tetrahydro Folate Reductase (MTHFR) N5-methyl THF Methyl-cobalamin Cobalamin (B12) cbl C, D, F, J, X Glycine Serine TetraHydro Folate (THF) Remethylation Methionine Synthase Reductase (cblE) Methionine Synthase (cblG) Methionine Betaine Dimethylglycine Betaine homocysteine methyltransferase Homocysteine Serine Glycine Creatine AMPCystathionine Homoserine Cysteine Cystathionine ˜synthase (B6) Cystathionase (B6) Adenosine Trans-sulfuration Methyl transfer ATP Methionine adenosyl transferase (MAT) S-adenosyl methionine Methyltransferases N-methylglycine (Sarcosine) Glycine N-methyltransferase CH3 S-adenosyl homocysteine S-adenosyl homocysteine hydrolase CH3-S-(CH2)2-CH-COOH NH2 Guanidinoacetate Guanidinoacetate methyltransferase Adenosine kinase


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InternalMed_Harrison. FIgURE 434e-1 Pathways, enzymes, and coenzymes involved in the homocystinurias. Methionine transfers a methyl group during its conversion to homocysteine. Defects in methyl transfer or in the subsequent metabolism of homocysteine by the pyridoxal phosphate (vitamin B6)dependent cystathionine β-synthase increase plasma methionine levels. Homocysteine is transformed into methionine via remethylation. This occurs through methionine synthase, a reaction requiring methylcobalamin and folic acid. Deficiencies in these enzymes or lack of cofactors is associated with decreased or normal methionine levels. In an alternative pathway, homocysteine can be remethylated by betaine:homocysteine methyl transferase. 3 and 5 years of age with dislocated optic lenses and intellectual disability (in about half of cases). Some patients develop a marfanoid habitus and radiologic evidence of osteoporosis.


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InternalMed_Harrison. Life-threatening vascular complications (affecting coronary, renal, and cerebral arteries) can occur during the first decade of life and are the major cause of morbidity and mortality. Classic homocystinuria can be diagnosed with analysis of plasma amino acids, showing elevated methionine and presence of free homocystine. Total plasma homocysteine is also extremely elevated (usually >100 μM). Treatment consists of a special diet restricted in protein and methionine and supplemented with cystine. In approximately half of patients, oral pyridoxine (25–500 mg/d) produces a fall in plasma methionine and homocystine concentration in body fluids. Folate and vitamin B12 deficiency should be prevented by adequate supplementation. Betaine is also effective in reducing homocystine levels in pyridoxineunresponsive patients.


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InternalMed_Harrison. The other forms of homocystinuria are the result of impaired remethylation of homocysteine to methionine. This can be caused by defective methionine synthase or reduced availability of two essential cofactors, 5-methyltetrahydrofolate and methylcobalamin (methylvitamin B12).


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InternalMed_Harrison. Hyperhomocysteinemia refers to increased total plasma concentration of homocysteine with or without an increase in free homocystine (disulfide form). Hyperhomocysteinemia, in the absence of significant homocystinuria, is found in some heterozygotes for the genetic defects noted above or in homozygotes for milder variants. Changes of homocysteine levels are also observed with increasing age; with smoking; in postmenopausal women; in patients with renal failure, hypothyroidism, leukemias, inflammatory bowel disease, or psoriasis; and during therapy with drugs such as methotrexate, nitrous oxide, isoniazid, and some antiepileptic agents. Homocysteine acts as an atherogenic and thrombophilic agent. An increase in total plasma homocysteine is an independent risk factor for coronary, cerebrovascular, and peripheral arterial disease as well as for deep vein thrombosis (Chap. 291e). Homocysteine is synergistic with hypertension and smoking, and it is additive with other risk factors that


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InternalMed_Harrison. and peripheral arterial disease as well as for deep vein thrombosis (Chap. 291e). Homocysteine is synergistic with hypertension and smoking, and it is additive with other risk factors that predispose to peripheral arterial disease. In addition, hyperhomocysteinemia and folate and vitamin deficiency have been associated with an increased risk of neural tube defects in pregnant women. Vitamin supplements are effective in reducing plasma homocysteine levels in these cases, although there are limited effects on cardiovascular disease.


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InternalMed_Harrison. Alkaptonuria is a rare (frequency 1:200,000) disorder of tyrosine catabolism in which deficiency of homogentisate 1,2-dioxygenase (also known as homogentisic acid oxidase) leads to excretion of large amounts of homogentisic acid in urine and accumulation of oxidized homogentisic acid pigment in connective tissues (ochronosis). Alkaptonuria may go unrecognized until middle life, when degenerative joint disease develops. Prior to this time, about half of patients might be diagnosed for the presence of dark urine. Foci of gray-brown scleral pigment and generalized darkening of the concha, anthelix, and, finally, helix of the ear usually develop after age 30. Low back pain usually starts between 30 and 40 years of age. Ochronotic arthritis is heralded by pain, stiffness, and some limitation of motion of the hips, knees, and shoulders. Acute arthritis may resemble rheumatoid arthritis, but small joints are usually spared. Pigmentation of heart valves, larynx, tympanic membranes, and skin


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InternalMed_Harrison. of motion of the hips, knees, and shoulders. Acute arthritis may resemble rheumatoid arthritis, but small joints are usually spared. Pigmentation of heart valves, larynx, tympanic membranes, and skin occurs, and occasional patients develop pigmented renal or prostatic calculi. Pigment deposition in the heart and blood vessels leads to aortic stenosis necessitating valve replacement, especially after 60 years of age. The diagnosis should be suspected in a patient whose urine darkens to blackness. Homogentisic acid in urine is identified by urine organic acid analysis. Ochronotic arthritis is treated symptomatically with pain medications, spinal surgery, and arthroplasty (Chap. 394). Ascorbic acid and protein restriction are not effective in reducing homogentisic acid production. By contrast, nitisone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione), a drug used in tyrosinemia type I, reduces urinary excretion of homogentisic acid and, in conjunction with a low-protein diet,


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InternalMed_Harrison. nitisone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione), a drug used in tyrosinemia type I, reduces urinary excretion of homogentisic acid and, in conjunction with a low-protein diet, might prevent the long-term complications of alkaptonuria.


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InternalMed_Harrison. Excess ammonia generated from protein nitrogen is removed by the urea cycle, a process mediated by several enzymes and transporters (Table 434e-1). Complete absence of any of these enzymes usually causes severe hyperammonemia in newborns, while milder variants can be seen in adults. The accumulation of ammonia and glutamine leads to brain edema and direct neuronal toxicity. Deficiencies in urea cycle enzymes are individually rare, but as a group, they affect about 1:25,000 individuals. They are all transmitted as autosomal recessive traits, with the exception of ornithine transcarbamylase deficiency, which is X-linked. Hepatocytes of females with ornithine transcarbamylase deficiency express either the normal or the mutant allele due to random X-inactivation and may be unable to remove excess ammonia if mutant cells are predominant.


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InternalMed_Harrison. Infants with classic urea cycle defects present at 1–4 days of life with refusal to eat and lethargy progressing to coma and death. Milder enzyme deficiencies present with protein avoidance, recurrent vomiting, migraine, mood swings, chronic fatigue, irritability, and disorientation that can progress to coma. Females with ornithine transcarbamylase deficiency can present at time of childbirth due to the combination of involuntary fasting and stress that favors catabolism. The diagnosis requires measurement of plasma ammonia, plasma amino acids, and urine orotic acid, useful for differentiating ornithine transcarbamylase deficiency from carbamyl phosphate synthase-1 and N-acetylglutamate synthase deficiency. Hyperammonemia can also be 434e-5 caused by liver disease from any cause and several organic acidemias and fatty acid oxidation defects (the latter two excluded by the analysis of urine organic acids and plasma acylcarnitine profile).


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InternalMed_Harrison. Therapy is aimed at stopping catabolism and ammonia production by providing adequate calories (as IV glucose and lipids in the comatose patient) and, if needed, insulin. Excess nitrogen is removed by IV phenylacetate and benzoate (0.25 g/kg for the priming dose and subsequently as an infusion over 24 h) that conjugate with glutamine and glycine, respectively, to form phenylacetylglutamine and hippuric acid, water-soluble molecules efficiently excreted in urine. Arginine (200 mg/kg per day) becomes an essential amino acid (except in arginase deficiency) and should be provided intravenously to resume protein synthesis. If these measures fail to reduce ammonia, hemodialysis should be initiated promptly. Chronic therapy consists of a protein-restricted diet, phenylbutyrate, glycerol phenylbutyrate (a liquid drug better tolerated by most patients), arginine, or citrulline supplements, depending on the specific diagnosis. Liver transplantation should be considered in patients with severe


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InternalMed_Harrison. (a liquid drug better tolerated by most patients), arginine, or citrulline supplements, depending on the specific diagnosis. Liver transplantation should be considered in patients with severe urea cycle defects that are difficult to control medically.


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InternalMed_Harrison. Hyperammonemia due to a functional deficiency of glutamine synthase can occur in patients receiving chemotherapy for different malignancies or undergoing solid organ transplants. It can also be seen with hepatic cirrhosis. Several of these patients have been successfully rescued from hyperammonemia using the protocol described above for urea cycle defects. CHAPTER 434e Inherited Disorders of Amino Acid Metabolism in Adults


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InternalMed_Harrison. Inherited Defects of Membrane Transport Nicola Longo Specific membrane transporters mediate the passage of a wide variety of substances across cellular membranes. Classes of substrates include amino acids, sugars, cations, anions, vitamins, and water. The number 435e of inherited disorders of membrane transport continues to increase with the identification of new transporters on the plasma membrane or intracellular organelles and the clarification of the molecular basis of diseases with previously unknown pathophysiology. The first transport disorders identified affected the gut or the kidney, but transport processes are now proving essential for the normal function of every organ. Mutations in transporter molecules cause disorders of the heart, muscle, brain, and endocrine and sensory organs (Table 435e-1). Inherited defects impairing the transport of selected amino acids that can present in adults are discussed here as examples of the abnormalities encountered; others are considered


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InternalMed_Harrison. (Table 435e-1). Inherited defects impairing the transport of selected amino acids that can present in adults are discussed here as examples of the abnormalities encountered; others are considered elsewhere in this text.


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InternalMed_Harrison. Cystinuria (frequency of 1 in 10,000 to 1 in 15,000) is an autosomal recessive disorder caused by defective transporters in the apical brush border of proximal renal tubule and small intestinal cells. It is characterized by impaired reabsorption and excessive urinary excretion of the dibasic amino acids lysine, arginine, ornithine, and cystine. Because cystine is poorly soluble, its excess excretion predisposes to the formation of renal, ureteral, and bladder stones. Such stones are responsible for the signs and symptoms of the disorder. There are two variants of cystinuria. Homozygotes for both variants have high urinary excretion of cystine, lysine, arginine, and ornithine. Type I heterozygotes usually have normal urinary amino acid excretion, whereas most non–type I (formerly type II and type


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InternalMed_Harrison. III) heterozygotes have moderately increased urinary excretion of each of the four amino acids. The gene for type I cystinuria (SLC3A1, chromosome 2p16.3) encodes a membrane glycoprotein. Non–type I cystinuria is caused by mutations in SLC7A9 (chromosome 19q13) that encodes the b0,+ amino acid transporter. The glycoprotein encoded by SLC3A1 favors the correct processing of the b0,+ membrane transporter and explains why mutations in two different genes cause a similar disease. Class of Substance Individual Tissues Manifesting and Disorder Substrates Transport Defect Molecular Defect Major Clinical Manifestations Inheritance CHAPTER 435e Inherited Defects of Membrane Transport


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InternalMed_Harrison. CHAPTER 435e Inherited Defects of Membrane Transport Cystine stones account for 1–2% of all urinary tract calculi but are the most common cause of stones in children. Cystinuria homozygotes regularly excrete 2400–7200 μmol (600–1800 mg) of cystine daily. Since the maximum solubility of cystine in the physiologic urinary pH range of 4.5–7.0 is about 1200 μmol/L (300 mg/L), cystine needs to be diluted to 2.5–7 L of water to prevent crystalluria. Stone formation usually manifests in the second or third decade but may occur in the first year of life. Symptoms and signs are those typical of urolithiasis: hematuria, flank pain, renal colic, obstructive uropathy, and infection (Chap. 342). Recurrent urolithiasis may lead to progressive renal insufficiency.


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InternalMed_Harrison. Cystinuria is suspected after observing typical hexagonal crystals in the sediment of acidified, concentrated, chilled urine or after performing a urinary nitroprusside test. Quantitative urine amino acid analysis confirms the diagnosis of cystinuria by showing selective overexcretion of cystine, lysine, arginine, and ornithine. Quantitative measurements are important for differentiating heterozygotes from homozygotes and for following free cystine excretion during therapy.


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InternalMed_Harrison. Management is aimed at preventing cystine crystal formation by increasing urinary volume and by maintaining an alkaline urine pH. Fluid ingestion in excess of 4 L/d is essential, and 5–7 L/d is optimal. Urinary cystine concentration should be <1000 μmol/L (250 mg/L). The daily fluid ingestion necessary to maintain this dilution of excreted cystine should be spaced over 24 h, with one-third of the total volume ingested between bedtime and 3 A.M. Cystine solubility rises sharply above pH 7.5, and urinary alkalinization (with bicarbonate or potassium citrate) can be therapeutic. Penicillamine (1–3 g/d) and tiopronin (α-mercaptopropionylglycine, 800–1200 mg/d in four divided doses) undergo sulfhydryl-disulfide exchange with cystine to form mixed disulfides. Because these disulfides are much more soluble than cystine, pharmacologic therapy can prevent and promote dissolution of calculi. Penicillamine can have significant side effects and should be reserved for patients who fail to respond


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InternalMed_Harrison. soluble than cystine, pharmacologic therapy can prevent and promote dissolution of calculi. Penicillamine can have significant side effects and should be reserved for patients who fail to respond to hydration alone or who are in a high-risk category (e.g., one remaining kidney, renal insufficiency). When medical management fails, shock wave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy are effective for most stones. Open urologic surgery is considered for complex staghorn stones or when the patient has concomitant renal or ureteral abnormalities. Occasional patients progress to renal failure and require kidney transplantation.


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InternalMed_Harrison. This disorder is characterized by a defect in renal tubular reabsorption of the three dibasic amino acids lysine, arginine, and ornithine but not cystine (lysinuric protein intolerance). Homozygotes show defective intestinal transport of dibasic amino acids as well as exaggerated renal losses. Lysinuric protein intolerance is most common in Finland (1 in 60,000), southern Italy, and Japan, but is rare elsewhere. The transport defect affects basolateral rather than luminal membrane transport and is associated with impairment of the urea cycle. The defective gene (SLC7A7, chromosome 14q11.2) encodes the y+LAT membrane transporter, which associates with the cell-surface glycoprotein 4F2 heavy chain to form the complete sodium-independent transporter y+L.


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InternalMed_Harrison. Manifestations are related to impairment of the urea cycle and to immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping. Affected patients present in childhood with hepatosplenomegaly, protein intolerance, and episodic ammonia intoxication. Older patients may present with severe osteoporosis, impairment of kidney function, pulmonary alveolar proteinosis, various autoimmune disorders, and an incompletely characterized immune deficiency. Plasma concentrations of lysine, arginine, and ornithine are reduced, whereas urinary excretion of lysine and orotic acid are increased. Hyperammonemia may develop after the ingestion of protein loads or with infections, probably because of insufficient amounts of arginine and ornithine to maintain proper function of the urea cycle. Therapy consists of dietary protein restriction and supplementation of citrulline (2–8 g/d), a neutral amino acid that fuels the urea cycle when metabolized


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InternalMed_Harrison. proper function of the urea cycle. Therapy consists of dietary protein restriction and supplementation of citrulline (2–8 g/d), a neutral amino acid that fuels the urea cycle when metabolized to arginine and ornithine. Pulmonary disease responds to glucocorticoids or bronchoalveolar lavage in some patients. Women with lysinuric protein intolerance who become pregnant have an increased risk of anemia, toxemia, and bleeding complications during delivery. These can be minimized by aggressive nutritional therapy and control of blood pressure. Their infants can have intrauterine growth restriction but have normal neurologic function


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InternalMed_Harrison. Citrullinemia type 2 is a recessive condition caused by deficiency of the mitochondrial aspartate-glutamate carrier AGC2 (citrin). A defect in this transporter reduces the availability of cytoplasmic aspartate to combine with citrulline, impairing the urea cycle and decreasing the transfer of reducing equivalents from the cytosol to the mitochondria through the malate–aspartate NADH shuttle. Mutations in the SLC25A13 gene on chromosome 7q21.3 that encodes for this transporter are rare in Caucasians, but affect about 1:20,000 people with ancestry from Japan, China, and Southeast Asia with variable penetrance.


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InternalMed_Harrison. The disease usually presents with sudden onset between 20 and 50 years of age with recurring episodes of hyperammonemia with associated neuropsychiatric symptoms such as altered mental status, irritability, seizures, or coma resembling hepatic encephalopathy. Some patients might come to medical attention for hypertriglyceridemia, pancreatitis, hepatoma, or fatty liver histologically similar to nonalcoholic steatohepatitis. Without therapy, most patients die with cerebral edema within a few years of onset. Episodes are usually triggered by medications (such as acetaminophen), surgery, alcohol consumption or high sugar intake, the latter conditions causing excess NADH production. NADH is not generated by the metabolism of proteins or fats, and many individuals with citrullinemia type 2 spontaneously prefer foods such as meat, eggs, and fish, and avoid carbohydrates.


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InternalMed_Harrison. Laboratory studies during an acute attack include elevated ammonia, citrulline, and arginine with low or normal levels of glutamine (the latter is usually increased in classic urea cycle defects). The diagnosis is confirmed by demonstrating mutations in the SLC25A13 gene. Liver transplantation prevents progression of the disease and normalizes biochemical parameters. A diet high in fats and proteins and low in carbohydrates with supplements of arginine and pyruvate is also effective in preventing further episodes, at least in the short term.


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InternalMed_Harrison. Hartnup disease (frequency 1 in 24,000) is an autosomal recessive disorder characterized by pellagra-like skin lesions, variable neurologic manifestations, and neutral and aromatic aminoaciduria. Alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, glutamine, asparagine, and histidine are excreted in urine in quantities 5–10 times greater than normal, and intestinal transport of these same amino acids is defective. The defective neutral amino acid transporter, B°AT1 encoded by the SLC6A19 gene on chromosome 5p15, requires either collectrin or angiotensin-converting enzyme 2 for surface expression in the kidney and intestine, respectively.


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InternalMed_Harrison. The clinical manifestations result from nutritional deficiency of the essential amino acid tryptophan, caused by its intestinal and renal malabsorption, and of niacin, which derives in part from tryptophan metabolism. Only a small fraction of patients with the chemical findings of this disorder develop a pellagra-like syndrome, implying that manifestations depend on other factors in addition to the transport defect. The diagnosis of Hartnup disease should be suspected in any patient with clinical features of pellagra who does not have a history of dietary niacin deficiency (Chap. 96e). The neurologic and psychiatric manifestations range from attacks of cerebellar ataxia to mild emotional lability to frank delirium, and they are usually accompanied by exacerbations of the erythematous, eczematoid skin rash. Fever, sunlight, stress, and sulfonamide therapy provoke clinical relapses. Diagnosis is made by detection of the neutral aminoaciduria, which does not occur in dietary niacin


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InternalMed_Harrison. eczematoid skin rash. Fever, sunlight, stress, and sulfonamide therapy provoke clinical relapses. Diagnosis is made by detection of the neutral aminoaciduria, which does not occur in dietary niacin deficiency. Treatment is directed at niacin repletion and includes a high-protein diet and daily nicotinamide supplementation (50–250 mg).


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InternalMed_Harrison. Atlas of Clinical Manifestations of Metabolic Diseases J. Larry Jameson The term metabolism is derived from the Greek metabol, meaning “to 436e change.” This term encompasses the broad array of chemical pathways that are necessary for normal development and homeostasis. In practice, clinicians generally use the term metabolism in reference to energy utilization for anabolism or catabolism. Alternatively, intermediary metabolism describes the myriad cellular pathways that convert energy sources from one form to another (e.g., the citric acid cycle). The emerging field of metabolomics is based on the premise that the identification and measurement of metabolic products will enhance our understanding of physiology and disease.


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InternalMed_Harrison. Over the years, the classification of metabolic diseases has extended beyond traditional pathways involved in fuel metabolism to include disorders such as lysosomal storage diseases and connective tissue diseases. Thus, metabolic diseases really reflect disorders of cell biology, and many have a well-defined genetic basis. For example, lysosomal storage diseases (Chap. 432e) result from a variety of genetic defects, usually in a lysosomal enzyme, causing accumulation of a substrate within the lysosome. Certain lipodystrophies and cardiomyopathies can be caused by mutations in lamin A, a structural protein in the nuclear envelope. Membrane defects (Chap. 435e), usually involving transporters of amino acids, sugars, or ions, cause disorders such as cystinuria, Hartnup’s disease, or Wilson’s disease (Chap. 429). Connective tissue diseases (Chap. 427) frequently involve defects in collagen synthesis or structure (osteogenesis imperfecta, Ehlers-Danlos syndrome, Alport’s syndrome) or in


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InternalMed_Harrison. disease (Chap. 429). Connective tissue diseases (Chap. 427) frequently involve defects in collagen synthesis or structure (osteogenesis imperfecta, Ehlers-Danlos syndrome, Alport’s syndrome) or in other extracellular matrix structural proteins such as fibrillin (Marfan syndrome). Many metabolic disorders originate from defects in enzymes involved in the synthesis or degradation of amino acids, carbohydrates, lipids, purines, or pyrimidines (Chaps. 431e, 433e, and 434e). Lipoprotein disorders (Chap. 421) are caused by defects in a wide array of cellular pathways including membrane receptors (the low-density lipoprotein receptor), enzyme defects (lipoprotein lipase), carrier proteins (apolipoprotein B100), or transporters (ATPbinding cassette transporter ABCA1). In some instances, metabolic abnormalities induce compensatory physiologic responses that reflect the interactions of multiple metabolic pathways. For example, the metabolic syndrome (Chap. 422), which includes a constellation


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InternalMed_Harrison. abnormalities induce compensatory physiologic responses that reflect the interactions of multiple metabolic pathways. For example, the metabolic syndrome (Chap. 422), which includes a constellation of clinical features (central obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperglycemia, and hypertension), likely has multiple genetic and environmental origins. Cushing’s syndrome reflects the metabolic effects of excess cortisol on multiple tissues (Chap. 406).


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InternalMed_Harrison. This broader definition results in a plethora of metabolic diseases, numbering in the thousands. Fortunately, comprehensive reference sources exist, such as the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID) (http://www.ommbid.com/) and the Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi .nlm.nih.gov/entrez/query.fcgi?db=OMIM). The study of metabolic diseases has been invaluable for advancing our understanding of human genetics by providing insight into principles such as patterns of inheritance, variable expressivity, phenotypic variation, and novel approaches to therapy, including screening programs, blood and organ transplantation, gene therapy, and enzyme replacement (Chap. 82).


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InternalMed_Harrison. This atlas provides a visual survey of selected metabolic disorders 436e-1 with references to the topics elsewhere in the text. The author encourages submission of additional illustrations that might facilitate learning among our peers and thereby enhance the recognition and care of patients with these disorders. Figure 436e-1 “Gauntlet” of pellagra (niacin deficiency). Note indurated, lichenified, pigmented, and scaly skin on the dorsa of the hands. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 96e. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases


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InternalMed_Harrison. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases Figure 436e-2 Scurvy (vitamin C deficiency). Note perifollicular hemorrhage on the leg. The follicles are often plugged by keratin (perifollicular hyperkeratosis). This eruption occurred in a 46-year-old alcoholic, homeless man who also had bleeding gums and loose teeth. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 96e. Figure 436e-3 Podagra with gouty inflammation of the left first metatarsophalangeal joint. Note swelling and erythema. (From KJ Knoop et al: The Atlas of Emergency Medicine, 2nd ed. New York, McGraw-Hill, 2002. Courtesy of Kevin J. Knoop, MD, MS; with permission.) See Chaps. 395 and 431e. Figure 436e-4 Large tophi of gout located in and around the right knee. (Courtesy of Daniel L. Savitt, MD; with permission.) See Chaps. 395 and 431e.


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InternalMed_Harrison. Figure 436e-4 Large tophi of gout located in and around the right knee. (Courtesy of Daniel L. Savitt, MD; with permission.) See Chaps. 395 and 431e. Figure 436e-5 Gouty arthritis of the finger. The finger is an unusual site for gouty arthritis. Examination of the synovial fluid confirmed the diagnosis. (Courtesy of Alan B. Storrow, MD; with permission.) See Chaps. 395 and 431e. Figure 436e-6 Cushing’s syndrome. Note plethoric moon facies with erythema and telangiectases of cheek and forehead. The face and neck show increased deposition of fat, which was also seen in the supraclavicular areas (not depicted here). (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 406.


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InternalMed_Harrison. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 406. Figure 436e-7 Necrobiosis lipoidica diabeticorum. A large symmetric plaque with active tan-pink, well-demarcated, raised, firm borders and a yellow center in the pretibial regions of a 28-year-old diabetic woman is shown. The central parts of the lesion are depressed with atrophic changes of epidermal thinning and telangiectasis against a yellow background. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 417. Figure 436e-8 Patient with multiple endocrine neoplasia 2B syn-drome. Note the multiple neuromas on the lips and tongue and the marfanoid facies. (Source: DG Gardner, D Shoback, eds: Greenspan’s Basic & Clinical Endocrinology, 8th ed. New York, McGraw-Hill, 2006, www .accessmedicine.com.) See Chap. 408.


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InternalMed_Harrison. Figure 436e-10 Bone scan of a patient with severe Paget’s disease of the skull, ribs, spine, pelvis, right femur, and acetabulum. Note localization of bone-seeking isotope (99mTc-labeled bisphosphonate) in these areas. (Source: DG Gardner, D Shoback, eds: Greenspan’s Basic & Clinical Endocrinology, 8th ed. New York, McGraw-Hill, 2006, www.access medicine.com.) See Chap. 426e. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases Figure 436e-9 Early and late radiographs of Paget’s disease of the tibia of a male patient, taken at 45 (A) and 65 years of age (B). (Source: HB Skinner: Current Diagnosis & Treatment in Orthopedics, 4th ed. New York, McGraw-Hill, 2007, www.accessmedicine.com.) See Chap. 426e. Figure 436e-11 Tendinous xanthomas. Large subcutaneous tumors adherent to the Achilles tendons. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 421.


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InternalMed_Harrison. AB Figure 436e-12 Papular eruptive xanthomas. A. Multiple, discrete, red-to-yellow papules becoming confluent on the elbow of a white individual with uncontrolled diabetes mellitus; lesions were present on both elbows and buttocks. B. Papular eruptive xanthomas on the elbows and lower arms of an African-American patient. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 421. Figure 436e-13 Forms of xanthomas and other lipid deposits frequently seen in familial hypercholesterolemia homozygotes. A. Arcus corneae. B, E, and F. Cutaneous planar xanthomas, which usually have a bright orange hue. C, D, and G. Tuberous xanthomas on the elbows.


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InternalMed_Harrison. (Source for panels C and D: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www.ommbid.com.) H. Tendon and tuberous xanthomas. (Panel H reproduced through the courtesy of Dr. A. Khachadurian; with permission.) See Chap. 421. Figure 436e-14 Examples of xanthomas in type III hyperlipo-proteinemic patients. A. Tuberoeruptive xanthomas of the elbows. B. Tuberous xanthomas of the digits and xanthomas of the palmar creases (xanthoma striata palmaris) (arrows). (Courtesy of Dr. Thomas P. Bersot; with permission.) See Chap. 421. Figure 436e-15 A 17-year-old patient with abetalipoproteinemia, with generalized weakness, kyphoscoliosis, and lordosis. (Courtesy of Drs. Peter Herbert, Gerd Assmann, Antonio M. Gotto, Jr., and Donald Fredrickson; with permission.) See Chap. 421.


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InternalMed_Harrison. Figure 436e-16 Porphyria cutanea tarda. Periorbital and malar violaceous coloration, hyperpigmentation, and hypertrichosis on the face; bullae, crusts, and scars on the dorsa of the hands. (Source: K Wolff et al: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) See Chap. 430. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases


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InternalMed_Harrison. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases Figure 436e-17 Mucopolysaccharidosis type IH (Hurler’s syndrome) in a 4-year-old boy. The diagnosis was made at the age of 15 months, at which time he had developmental delay, hepatomegaly, and skeletal involvement. At the time of the picture, the patient had short stature, an enlarged tongue, persistent nasal discharge, stiff joints, and hydrocephalus. Verbal language skills consisted of four or five words. The patient had a severe hearing loss and wore hearing aids. (Source: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www.ommbid .com.) See Chap. 432e.


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InternalMed_Harrison. Figure 436e-18 Growth and development of two patients with type Ia glycogen storage disease. A. Patient at age 7 years and at age 39 years. B. Another patient at age 10 years and at age 33 years. Both patients survive despite inadequate treatment of their disease. Note that the abdomen is less protuberant with age. Hypoglycemia also improves with age. In adulthood, however, both patients continue to be short, and both have gout, multiple liver adenomas, and progressive renal disease. (Source: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www.ommbid.com.) See Chap. 433e.


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InternalMed_Harrison. Figure 436e-19 Progressive myopathy in a patient with type IIIa glycogen storage disease. The patient has a debrancher deficiency in both liver and muscle (subtype IIIa). As a child, he had hepatomegaly, hypoglycemia, and growth retardation. After puberty, he no longer had hepatomegaly, and his final height is normal. Note the muscle wasting in the lower legs and both hands at age 44 years of age (left panel); this condition progressed to pronounced muscle atrophy at age 53 years (two right panels). (Source: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www.ommbid.com.) See Chap. 433e.


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InternalMed_Harrison. Figure 436e-20 Skeletal features of Marfan’s syndrome in a 16-year-old girl. Note the long limbs (associated with disproportion-ately tall stature), long fingers, scoliosis, and genu valgum. (Source: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www.ommbid.com.) See Chap. 427. Figure 436e-21 Marfan’s syndrome. A. Long, narrow face. B. Arachnodactyly and positive wrist sign. C. High-arched palate. D. Ectopia lentis associated with aortic aneurysm and severe aortic regurgitation in a teenage girl. (Source: V Fuster et al [eds]: Hurst’s The Heart, 11th ed. New York, McGraw-Hill, 2004, www.accessmedicine.com.) See Chap. 427. Figure 436e-22 Ochronotic pigmentation of the femur of a 56-year-old alkaptonuric patient. (Courtesy of Dr. H. W. Edmonds of the Washington Hospital Center, Washington, DC; with permission.) See Chap. 434e.


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InternalMed_Harrison. Figure 436e-24 Two patients with type B Niemann-Pick disease (NPD). A. A 4.7-year-old patient. (From DS Fredrickson, HR Sloan, in JB Stanbury et al: The Metabolic Basis of Inherited Disease, 3rd ed. New York, McGraw-Hill, 1972. Used by permission.) B. A 44-year-old patient. See Chap. 432e. Figure 436e-23 Clusters of angiokeratomas (telangiectases) on the buttocks (A) and in the umbilical area (B) of a hemizygote with Fabry disease. (Source: CR Scriver et al [eds]: The Metabolic and Molecular Bases of Inherited Disease online, 8th ed. New York, McGraw-Hill, www .ommbid.com.) See Chap. 432e. Figure 436e-25 “Cherry red” spot in the eye of a Tay-Sachs patient. (From http://www.nei.nih.gov/resources/eyegene.asp.) See Chap. 432e. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases


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InternalMed_Harrison. CHAPTER 436e Atlas of Clinical Manifestations of Metabolic Diseases Figure 436e-26 Kayser-Fleischer ring. This manifestation develops in Wilson’s disease from copper deposition in Descemet’s membrane, which produces brownish discoloration of the peripheral cornea. It should not be confused with the yellow-white lipid ring of arcus senilis, which is common in the elderly and occasionally signifies hyperlipidemia, especially when it appears at a young age. (Courtesy of Jonathan C. Horton, MD, PhD; with permission.) See Chap. 429.


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InternalMed_Harrison. Figure 436e-27 Anterior view of patients with different forms of lipodystrophy. A. Congenital generalized lipodystrophy: a 16-year-old girl with generalized loss of fat, acromegaloid features, severe acanthosis nigricans affecting the axillae and abdomen, and umbilical hernia. (From A Garg et al: J Clin Endocrinol Metab 84:3390, 1999; with permission.) B. Familial partial lipodystrophy, Dunnigan variety: a 43-year-old woman with marked loss of subcutaneous fat from both the limbs and the trunk and excess fat deposition in the face, chin, supraclavicular area, and labia majora. (From JM Peters et al: Nat Genet 18;292, 1998; with permission.) C. Acquired generalized lipodystrophy: a 10-year-old boy who developed generalized loss of fat that also affected the palms and soles after panniculitis at the age of 3 months. D. Acquired partial lipodystrophy: a 30-year-old woman with onset of lipodystrophy at age 14 years. Note loss of fat from the face, neck, upper limbs, trunk, and anterior


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InternalMed_Harrison. at the age of 3 months. D. Acquired partial lipodystrophy: a 30-year-old woman with onset of lipodystrophy at age 14 years. Note loss of fat from the face, neck, upper limbs, trunk, and anterior thighs. There is accumulation of excess fat in the hips and other regions of the lower limbs.


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InternalMed_Harrison. 2535 approach to the patient with Neurologic Disease Daniel H. Lowenstein, Joseph B. Martin, Stephen L. Hauser Neurologic diseases are common and costly. According to estimates by the World Health Organization, neurologic disorders affect over 1 bil-lion people worldwide, constitute 12% of the global burden of disease, and cause 14% of global deaths (Table 437-1). These numbers are only expected to increase as the world’s population ages. Most patients with neurologic symptoms seek care from internists and other generalists rather than from neurologists. Because therapies now exist for many neurologic disorders, a skillful approach to diagnosis is essential. Errors commonly result from an overreliance on costly neuroimaging procedures and laboratory tests, which, while useful, do not substitute for an adequate history and examination. The proper approach to the patient with a neurologic illness begins with the patient and focuses the clinical problem first in anatomic and then in


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InternalMed_Harrison. substitute for an adequate history and examination. The proper approach to the patient with a neurologic illness begins with the patient and focuses the clinical problem first in anatomic and then in pathophysiologic terms; only then should a specific diagnosis be entertained. This method ensures that technology is judiciously applied, a correct diagnosis is established in an efficient manner, and treatment is promptly initiated. THE NEUROLOGIC METHOD 437 part 17: Neurologic Disorders seCtioN 1 DiaGNosis of NeuroLoGiC DisorDers


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InternalMed_Harrison. Approach to the Patient with Neurologic Disease The first priority is to identify the region of the nervous system that is likely to be responsible for the symptoms. Can the disorder be mapped to one specific location, is it multifocal, or is a diffuse process present? Are the symptoms restricted to the nervous system, or do they arise in the context of a systemic illness? Is the problem in the central nervous system (CNS), the peripheral nervous system (PNS), or both? If in the CNS, is the cerebral cortex, basal ganglia, brainstem, cerebellum, or spinal cord responsible? Are the pain-sensitive meninges involved? If in the PNS, could the disorder be located in peripheral nerves and, if so, are motor or sensory nerves primarily affected, or is a lesion in the neuromuscular junction or muscle more likely?


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InternalMed_Harrison. The first clues to defining the anatomic area of involvement appear in the history, and the examination is then directed to confirm or rule out these impressions and to clarify uncertainties. A more detailed examination of a particular region of the CNS or PNS is often indicated. For example, the examination of a patient who presents with a history of ascending paresthesias and weakness should be directed toward deciding, among other things, if the location of the lesion is in the spinal cord or peripheral nerves. Focal back pain, a spinal cord sensory level, and incontinence suggest a spinal cord origin, whereas a stocking-glove pattern of sensory loss suggests peripheral nerve disease; areflexia usually indicates peripheral neuropathy but may also be present with spinal shock in acute spinal cord disorders.


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InternalMed_Harrison. Deciding “where the lesion is” accomplishes the task of limiting the possible etiologies to a manageable, finite number. In addition, this strategy safeguards against making serious errors. Symptoms of recurrent vertigo, diplopia, and nystagmus should not trigger “multiple sclerosis” as an answer (etiology) but “brainstem” or “pons” (location); then a diagnosis of brainstem arteriovenous malformation will not be missed for lack of consideration. Similarly, the combination of optic neuritis and spastic ataxic paraparesis suggests optic nerve and spinal cord disease; multiple sclerosis (MS), CNS syphilis, and vitamin B12 deficiency are treatable disorders that can produce this syndrome. Once the question, “Where is the lesion?” is answered, then the question, “What is the lesion?” can be addressed.


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InternalMed_Harrison. Clues to the pathophysiology of the disease process may also be present in the history. Primary neuronal (gray matter) disorders may present as early cognitive disturbances, movement disorders, or seizures, whereas white matter involvement produces predominantly “long tract” disorders of motor, sensory, visual, and cerebellar pathways. Progressive and symmetric symptoms often have a metabolic or degenerative origin; in such cases lesions are usually not sharply circumscribed. Thus, a patient with paraparesis and a clear spinal cord sensory level is unlikely to have vitamin B12 deficiency as the explanation. A Lhermitte symptom (electric shock–like sensations evoked by neck flexion) is due to ectopic impulse generation in white matter pathways and occurs with demyelination in the cervical spinal cord; among many possible causes, this symptom may indicate MS in a young adult or compressive cervical spondylosis in an older person. Symptoms that worsen after exposure to heat or exercise


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InternalMed_Harrison. spinal cord; among many possible causes, this symptom may indicate MS in a young adult or compressive cervical spondylosis in an older person. Symptoms that worsen after exposure to heat or exercise may indicate conduction block in demyelinated axons, as occurs in MS. A patient with recurrent episodes of diplopia and dysarthria associated with exercise or fatigue may have a disorder of neuromuscular transmission such as myasthenia gravis. Slowly advancing visual scotoma with luminous edges, termed fortification spectra, indicates spreading cortical depression, typically with migraine.


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InternalMed_Harrison. Attention to the description of the symptoms experienced by the patient and substantiated by family members and others often permits an accurate localization and determination of the probable cause of the complaints, even before the neurologic examination is performed. The history also helps to bring a focus to the neurologic examination that follows. Each complaint should be pursued as far as possible to elucidate the location of the lesion, the likely underlying pathophysiology, and potential etiologies. For example, a patient complains of weakness of the right arm. What are the associated features? Does the patient have difficulty with brushing hair or reaching upward (proximal) or buttoning buttons or opening a twist-top bottle (distal)? Negative associations may also be crucial. A patient with a right hemiparesis without a language deficit likely has a lesion (internal capsule, brainstem, or spinal cord) different from that of a patient with a right hemiparesis and aphasia (left


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InternalMed_Harrison. with a right hemiparesis without a language deficit likely has a lesion (internal capsule, brainstem, or spinal cord) different from that of a patient with a right hemiparesis and aphasia (left hemisphere). Other pertinent features of the history include the following: 2536 1. Temporal course of the illness. It is important to determine the precise time of appearance and rate of progression of the symptoms experienced by the patient. The rapid onset of a neurologic complaint, occurring within seconds or minutes, usually indicates a vascular event, a seizure, or migraine. The onset of sensory symptoms located in one extremity that spread over a few seconds to adjacent portions of that extremity and then to the other regions of the body suggests a seizure. A more gradual onset and less well-localized symptoms point to the possibility of a transient ischemic attack (TIA). A similar but slower temporal march of symptoms accompanied by headache, nausea, or visual disturbance suggests


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InternalMed_Harrison. well-localized symptoms point to the possibility of a transient ischemic attack (TIA). A similar but slower temporal march of symptoms accompanied by headache, nausea, or visual disturbance suggests migraine. The presence of “positive” sensory symptoms (e.g., tingling or sensations that are difficult to describe) or involuntary motor movements suggests a seizure; in contrast, transient loss of function (negative symptoms) suggests a TIA. A stuttering onset where symptoms appear, stabilize, and then progress over hours or days also suggests cerebrovascular disease; an additional history of transient remission or regression indicates that the process is more likely due to ischemia rather than hemorrhage. A gradual evolution of symptoms over hours or days suggests a toxic, metabolic, infectious, or inflammatory process. Progressing symptoms associated with the systemic manifestations of fever, stiff neck, and altered level of consciousness imply an infectious process. Relapsing and


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InternalMed_Harrison. or inflammatory process. Progressing symptoms associated with the systemic manifestations of fever, stiff neck, and altered level of consciousness imply an infectious process. Relapsing and remitting symptoms involving different levels of the nervous system suggest MS or other inflammatory processes. Slowly progressive symptoms without remissions are characteristic of neurodegenerative disorders, chronic infections, gradual intoxications, and neoplasms.


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InternalMed_Harrison. 2. Patients’ descriptions of the complaint. The same words often mean different things to different patients. “Dizziness” may imply impending syncope, a sense of disequilibrium, or true spinning vertigo. “Numbness” may mean a complete loss of feeling, a positive sensation such as tingling, or even weakness. “Blurred vision” may be used to describe unilateral visual loss, as in transient monocular blindness, or diplopia. The interpretation of the true meaning of the words used by patients to describe symptoms obviously becomes even more complex when there are differences in primary languages and cultures. 3.


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InternalMed_Harrison. 3. Corroboration of the history by others. It is almost always helpful to obtain additional information from family, friends, or other observers to corroborate or expand the patient’s description. Memory loss, aphasia, loss of insight, intoxication, and other factors may impair the patient’s capacity to communicate normally with the examiner or prevent openness about factors that have contributed to the illness. Episodes of loss of consciousness necessitate that details be sought from observers to ascertain precisely what has happened during the event. 4.


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InternalMed_Harrison. 4. Family history. Many neurologic disorders have an underlying genetic component. The presence of a Mendelian disorder, such as Huntington’s disease or Charcot-Marie-Tooth neuropathy, is often obvious if family data are available. More detailed questions about family history are often necessary in polygenic disorders such as MS, migraine, and many types of epilepsy. It is important to elicit family history about all illnesses, in addition to neurologic and psychiatric disorders. A familial propensity to hypertension or heart disease is relevant in a patient who presents with a stroke. There are numerous inherited neurologic diseases that are associated with multisystem manifestations that may provide clues to the correct diagnosis (e.g., neurofibromatosis, Wilson’s disease, mitochondrial disorders). 5.


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InternalMed_Harrison. Medical illnesses. Many neurologic diseases occur in the context of systemic disorders. Diabetes mellitus, hypertension, and abnormalities of blood lipids predispose to cerebrovascular disease. A solitary mass lesion in the brain may be an abscess in a patient with valvular heart disease, a primary hemorrhage in a patient with a coagulopathy, a lymphoma or toxoplasmosis in a patient with AIDS, or a metastasis in a patient with underlying cancer. Patients with malignancy may also present with a neurologic paraneoplastic syndrome (Chap. 122) or complications from chemotherapy or radiotherapy. Marfan’s syndrome and related collagen disorders predispose to dissection of the cranial arteries and aneurysmal subarachnoid hemorrhage; the latter may also occur with polycystic kidney disease. Various neurologic disorders occur with dysthyroid states or other endocrinopathies. It is especially important to look for the presence of systemic diseases in patients with peripheral neuropathy. Most


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InternalMed_Harrison. neurologic disorders occur with dysthyroid states or other endocrinopathies. It is especially important to look for the presence of systemic diseases in patients with peripheral neuropathy. Most patients with coma in a hospital setting have a metabolic, toxic, or infectious cause.


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InternalMed_Harrison. 6.


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InternalMed_Harrison. Drug use and abuse and toxin exposure. It is essential to inquire about the history of drug use, both prescribed and illicit. Sedatives, antidepressants, and other psychoactive medications are frequently associated with acute confusional states, especially in the elderly. Aminoglycoside antibiotics may exacerbate symptoms of weakness in patients with disorders of neuromuscular transmission, such as myasthenia gravis, and may cause dizziness secondary to ototoxicity. Vincristine and other antineoplastic drugs can cause peripheral neuropathy, and immunosuppressive agents such as cyclosporine can produce encephalopathy. Excessive vitamin ingestion can lead to disease; examples include vitamin A and pseudotumor cerebri or pyridoxine and peripheral neuropathy. Many patients are unaware that over-the-counter sleeping pills, cold preparations, and diet pills are actually drugs. Alcohol, the most prevalent neurotoxin, is often not recognized as such by patients, and other drugs of abuse such


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InternalMed_Harrison. sleeping pills, cold preparations, and diet pills are actually drugs. Alcohol, the most prevalent neurotoxin, is often not recognized as such by patients, and other drugs of abuse such as cocaine and heroin can cause a wide range of neurologic abnormalities. A history of environmental or industrial exposure to neurotoxins may provide an essential clue; consultation with the patient’s coworkers or employer may be required.


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InternalMed_Harrison. 7. Formulating an impression of the patient. Use the opportunity while taking the history to form an impression of the patient. Is the information forthcoming, or does it take a circuitous course? Is there evidence of anxiety, depression, or hypochondriasis? Are there any clues to problems with language, memory, insight, comportment, or behavior? The neurologic assessment begins as soon as the patient comes into the room and the first introduction is made.


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InternalMed_Harrison. The neurologic examination is challenging and complex; it has many components and includes a number of skills that can be mastered only through repeated use of the same techniques on a large number of individuals with and without neurologic disease. Mastery of the complete neurologic examination is usually important only for physicians in neurology and associated specialties. However, knowledge of the basics of the examination, especially those components that are effective in screening for neurologic dysfunction, is essential for all clinicians, especially generalists.


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InternalMed_Harrison. There is no single, universally accepted sequence of the examination that must be followed, but most clinicians begin with assessment of mental status followed by the cranial nerves, motor system, reflexes, sensory system, coordination, and gait. Whether the examination is basic or comprehensive, it is essential that it be performed in an orderly and systematic fashion to avoid errors and serious omissions. Thus, the best way to learn and gain expertise in the examination is to choose one’s own approach and practice it frequently and do it in the same exact sequence each time.


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InternalMed_Harrison. The detailed description that follows describes the more commonly used parts of the neurologic examination, with a particular emphasis on the components that are considered most helpful for the assessment of common neurologic problems. Each section also includes a brief description of the minimal examination necessary to adequately screen for abnormalities in a patient who has no symptoms suggesting neurologic dysfunction. A screening examination done in this way can be completed in 3–5 min.


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InternalMed_Harrison. Several additional points about the examination are worth noting. First, in recording observations, it is important to describe what is found rather than to apply a poorly defined medical term (e.g., “patient groans to sternal rub” rather than “obtunded”). Second, subtle CNS abnormalities are best detected by carefully comparing a patient’s performance on tasks that require simultaneous activation of both cerebral hemispheres (e.g., eliciting a pronator drift of an outstretched arm with the eyes closed; extinction on one side of bilaterally applied light touch, also with eyes closed; or decreased arm swing or a slight asymmetry when walking). Third, if the patient’s complaint is brought on by some activity, reproduce the activity in the office. If the complaint is of dizziness when the head is turned in one direction, have the patient do this and also look for associated signs on examination (e.g., nystagmus or dysmetria). If pain occurs after walking two blocks, have the patient


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InternalMed_Harrison. head is turned in one direction, have the patient do this and also look for associated signs on examination (e.g., nystagmus or dysmetria). If pain occurs after walking two blocks, have the patient leave the office and walk this distance and immediately return, and repeat the relevant parts of the examination. Finally, the use of tests that are individually tailored to the patient’s problem can be of value in assessing changes over time. Tests of walking a 7.5-m (25ft) distance (normal, 5–6 s; note assistance, if any), repetitive finger or toe tapping (normal, 20–25 taps in 5 s), or handwriting are examples.


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InternalMed_Harrison. • The bare minimum: During the interview, look for difficulties with communication and determine whether the patient has recall and insight into recent and past events. The mental status examination is under way as soon as the physician begins observing and speaking with the patient. If the history raises any concern for abnormalities of higher cortical function or if cognitive problems are observed during the interview, then detailed testing of the mental status is indicated. The patient’s ability to understand the language used for the examination, cultural background, educational experience, sensory or motor problems, or comorbid conditions need to be factored into the applicability of the tests and interpretation of results.


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InternalMed_Harrison. The Folstein mini-mental status examination (MMSE) is a standardized screening examination of cognitive function that is extremely easy to administer and takes <10 min to complete. Using age-adjusted values for defining normal performance, the test is ~85% sensitive and 85% specific for making the diagnosis of dementia that is moderate or severe, especially in educated patients. When there is sufficient time available, the MMSE is one of the best methods for documenting the current mental status of the patient, and this is especially useful as a baseline assessment to which future scores of the MMSE can be compared. Individual elements of the mental status examination can be subdivided into level of consciousness, orientation, speech and language, memory, fund of information, insight and judgment, abstract thought, and calculations.


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InternalMed_Harrison. Level of consciousness is the patient’s relative state of awareness of the self and the environment, and ranges from fully awake to comatose. When the patient is not fully awake, the examiner should describe the responses to the minimum stimulus necessary to elicit a reaction, ranging from verbal commands to a brief, painful stimulus such as a squeeze of the trapezius muscle. Responses that are directed toward the stimulus and signify some degree of intact cerebral function (e.g., opening the eyes and looking at the examiner or reaching to push away a painful stimulus) must be distinguished from reflex responses of a spinal origin (e.g., triple flexion response—flexion at the ankle, knee, and hip in response to a painful stimulus to the foot). Orientation is tested by asking the person to state his or her name, location, and time (day of the week and date); time is usually the first to be affected in a variety of conditions.


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InternalMed_Harrison. Orientation is tested by asking the person to state his or her name, location, and time (day of the week and date); time is usually the first to be affected in a variety of conditions. Speech is assessed by observing articulation, rate, rhythm, and prosody (i.e., the changes in pitch and accentuation of syllables and words). Language is assessed by observing the content of the patient’s verbal and written output, response to spoken commands, and ability to read. A typical testing sequence is to ask the patient to name successively more detailed components of clothing, a watch, or a pen; repeat the phrase “No ifs, ands, or buts”; follow a three-step, verbal command; write a sentence; and read and respond to a written command.


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InternalMed_Harrison. Memory should be analyzed according to three main time scales: (1) immediate memory is assessed by saying a list of three items and having the patient repeat the list immediately; (2) short-term memory is tested by asking the patient to recall the same three items 5 and 15 min later; and (3) long-term memory is evaluated by determining how well the patient is able to provide a coherent chronologic history of his or her illness or personal events. Fund of information is assessed by asking questions about major historic or current events, with special attention to educational level and life experiences. Abnormalities of insight and judgment are usually detected during 2537 the patient interview; a more detailed assessment can be elicited by asking the patient to describe how he or she would respond to situations having a variety of potential outcomes (e.g., “What would you do if you found a wallet on the sidewalk?”).


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InternalMed_Harrison. Abstract thought can be tested by asking the patient to describe similarities between various objects or concepts (e.g., apple and orange, desk and chair, poetry and sculpture) or to list items having the same attributes (e.g., a list of four-legged animals). Calculation ability is assessed by having the patient carry out a computation that is appropriate to the patient’s age and education (e.g., serial subtraction of 7 from 100 or 3 from 20; or word problems involving simple arithmetic). • The bare minimum: Check the fundi, visual fields, pupil size and reactivity, extraocular movements, and facial movements. The cranial nerves (CN) are best examined in numerical order, except for grouping together CN III, IV, and VI because of their similar function.


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InternalMed_Harrison. The cranial nerves (CN) are best examined in numerical order, except for grouping together CN III, IV, and VI because of their similar function. CN I (Olfactory) Testing is often omitted unless there is suspicion for inferior frontal lobe disease (e.g., meningioma). With eyes closed, ask the patient to sniff a mild stimulus such as toothpaste or coffee and identify the odorant.