Neurology_Adams

Neurology_Adams. Homocysteine is elevated in the blood and CSF, and homocystine in the urine. This is because of an inherited cystathionine synthase deficiency that results in an inadequacy of cystathionine formation, a substance essential to many tissues including the brain. This may be the explanation of the developmental delay. Plasma methionine levels are also elevated. The infarcts in the brain are clearly related to thrombotic and embolic arterial occlusions. The administration of large doses (50 to 500 mg) of pyridoxine (a cystathionine synthase coenzyme), folate 5 mg daily and cobalamin (vitamin B12) 1,000 µg daily, reduces the excretion of homocystine. If vascular lesions have occurred, anticoagulants probably prevent further occlusions.


Neurology_Adams

Neurology_Adams. Homocysteinemia and homocystinuria may also be expressions of 5,10-methylenetetrahydrofolate reductase deficiency. Again, the clinical manifestations consist of multiple cerebrovascular lesions, dementia, epilepsy, and polyneuropathy. The last is believed to be caused by a coincidental folic acid deficiency, but in some cases it may have been caused by chronic phenytoin administration (Nishimura et al). Much milder elevations of serum homocystine have been recognized as contributing to the risk of coronary disease and stroke in otherwise normal individuals. Fabry Disease (Anderson-Fabry Disease, GLA Mutation) (See Also Chaps. 33 and 43)


Neurology_Adams

Neurology_Adams. Fabry Disease (Anderson-Fabry Disease, GLA Mutation) (See Also Chaps. 33 and 43) This disease, also known as angiokeratoma corporis diffusum, is inherited as an X-linked recessive trait. It occurs in complete form in males and in incomplete form in female carriers. The primary deficit is in the enzyme alpha-galactosidase A, the result of which is the accumulation of ceramide trihexoside in endothelial, perithelial, and smooth muscle cells of blood vessels as well as in renal tubular and glomerular cells and other viscera and in nerve cells in many parts of the nervous system (hypothalamic and amygdaloid nuclei, substantia nigra, reticular and other nuclei of the brainstem, anterior and intermediolateral horns of the spinal cord, sympathetic and dorsal root ganglia).


Neurology_Adams

Neurology_Adams. The disease becomes manifest clinically in childhood or adolescence, with intermittent lancinating pains and dysesthesias of the extremities. A notable feature of these pains is their evocation by fever, hot weather, and vigorous exercise. Usually there is no sensory loss, but autonomic disturbances have been recorded in a series of our cases. Many years later there is a diffuse vascular involvement that leads to hypertension, renal damage, cardiomegaly, and myocardial ischemia. Thrombotic infarctions occur in the brain during early adult years. Occasional cases are discovered in adulthood with confluent cerebral white matter changes on MRI and progressive problems such as dysarthria.


Neurology_Adams

Neurology_Adams. The characteristic angiokeratomas tend to be most prominent periumbilically and resemble small angiomas that obliterate slightly with pressure. Desnick and colleagues have reviewed the neurologic, neuropathologic, and biochemical findings in this disease, and Cable and colleagues have written informatively on the autonomic aspects. Treatment Enzyme replacement, given by infusion, is now available. The two main trials of this treatment, summarized in an editorial by Pastores and Thadhani, were each conducted quite differently. Both showed an improvement in kidney and other organ function but only one demonstrated a reduction in neuropathic pain, and neither studied the risk of stroke. Like enzyme replacement therapy for Gaucher disease, prolonged treatment is expensive; but some evidence from the trials cited above indicates that certain aspects of the disease are reversible.


Neurology_Adams

Neurology_Adams. The painful neuropathic features that have brought several cases to our attention are discussed with the polyneuropathies, in Chap. 43. This disorder was discussed briefly with the neonatal metabolic disorders. The occurrence of stroke as a complication of this disorder was placed on record by our colleagues Shih et al (1977). A child 4.5 years of age, whose development had been retarded since birth (seizures and opisthotonos had been present), became hemiplegic. Another unrelated child, supposedly normal until 2 years of age, entered the hospital with fever, confusion, generalized seizures, right hemiplegia, and aphasia (infantile hemiplegia); subluxation of the lenses (upward) was discovered later. There was an increased level of sulfite and thiosulfate and an abnormal amino acid, S-sulfocysteine, in the blood. One child appeared to respond to a low-sulfur–amino-acid diet.


Neurology_Adams

Neurology_Adams. Certain metabolic diseases may be the cause of serious disturbances of cognitive function and behavior, even in the adolescent and early adult period. The diagnosis and management of these metabolic diseases are so unusual that some special remarks are appropriate. When they present later in adolescence and adult life they evolve more slowly than childhood forms. The most obvious and easily detectable of these derangements are in the cognitive sphere, that is, memory, calculation, problem solving, and verbal skills. Impulsivity, loss of self-control, and antisocial behavior are the most troubling behavioral abnormalities. Each of these phenomena has its own cerebral anatomy, as pointed out in Chap. 21, and the state of dementia comprises various degrees and combinations of these abnormalities.


Neurology_Adams

Neurology_Adams. Intellectual functions are difficult to accurately assess in early childhood. Slowness in learning and in acquiring language functions become manifest in school and may then be interpreted loosely as developmental delay. Up until school age, these intellectual functions have not developed sufficiently to allow recognition of their regressive course. Only in late childhood do they become clearly distinguishable and measurable by standardized tests. Far less tangible are subtle changes in personality and behavior.


Neurology_Adams

Neurology_Adams. A useful principle in recognizing those adolescents with a metabolic brain disease is that sooner or later, such a condition will cause a regression in cognitive and intellectual functions. Bipolar disease, sociopathies, and character disorders do not result in the loss of neurologic function. The recognition of a metabolic cause of mental deterioration depends on the demonstration of failing memory, impaired thinking, inability to learn, and loss of verbal and arithmetic abilities, many of which are measured quantitatively by intelligence tests. The appearance of pyramidal signs, aphasia, apraxia, ataxia, or areflexia further sets them apart.


Neurology_Adams

Neurology_Adams. If one reviews all the diseases described in this chapter and selects those that may demonstrate regression of cognitive function in association with personality change and alteration of behavior in an adult—diseases that may for a time be unaccompanied by other neurologic abnormalities—the following metabolic disorders merit special consideration in approximate relative order of importance: 1. Wilson disease 2. Adrenoleukodystrophy 3. Metachromatic leukodystrophy 4. PKAN pigmentary degeneration 5. Late-onset neuronal ceroid-lipofuscinosis (Kufs form) 6. Juvenile and adult Gaucher disease (type III) 7. Some of the mucopolysaccharidoses 8. Adult GM2 gangliosidosis 9. Mucolipidosis I (type I sialidosis) 10. Lafora-body myoclonic epilepsy 11. Nonwilsonian copper disorder (hereditary ceruloplasmin deficiency)


Neurology_Adams

Neurology_Adams. In each of these diseases, dementia and personality disorder may gradually develop and exist for many months, even a year or two, before other neurologic signs appear. One must look carefully for the earliest signs of movement disorders and other neurologic abnormalities, which greatly clarify the diagnostic problem. The common use of neuroleptic drugs, causing tardive dyskinesia and parkinsonian signs, is an obstacle to determining if there are neurologic features in these ostensibly psychiatric conditions. The increasing range and precision of biochemical and cytologic tests have brought to light a number of inherited metabolic diseases that sometimes have their onset in adult life. Such disorders, while uncommon, nevertheless are important because they must be considered in the differential diagnosis of degenerative diseases. Also to be considered in the differential diagnosis is an array of mitochondrial disorders, to be discussed further on in this chapter.


Neurology_Adams

Neurology_Adams. In the last three decades, the authors have personally observed or have otherwise come to know of examples of the following metabolic diseases, the onset of which was in adult life: 1. Metachromatic leukoencephalopathy 2. Adrenoleukodystrophy 3. Globoid body leukodystrophy (Krabbe disease) 4. Kufs form of neuronal ceroid lipofuscinosis 5. GM2 gangliosidosis 6. Wilson disease 7. Gaucher disease 8. Niemann-Pick disease 9. Carnitine palmityl transferase deficiency 10. Mucopolysaccharide encephalopathy 11. Mucolipidosis type I 12. Polyneuropathies (Andrade disease, Fabry disease, porphyria, Refsum disease) 13. Mitochondrial diseases, particularly progressive


Neurology_Adams

Neurology_Adams. In the late encephalopathic forms of the metabolic and mitochondrial diseases, the diagnosis is usually made only after symptoms have been present for months or years, the disease having been mistaken for some other condition, particularly depression or a degenerative dementia. Even a manifest psychosis may have occurred in relation to some of these disorders, but such occurrences are admittedly rare. For example, one of our patients with metachromatic leukodystrophy, a 30-year-old man, began failing in college years and was later unsuccessful in holding a job because of carelessness and mistakes in his work and indifference to criticism, irritability, and stubbornness (clearly traceable to a mild dementia). Only when Babinski signs and loss of tendon reflexes in the legs were detected was the correct diagnosis entertained for the first time. By then he had been ill for nearly 10 years. Bosch and Hart described a patient with the onset of dementia at 62 years of age and drew attention


Neurology_Adams

Neurology_Adams. the correct diagnosis entertained for the first time. By then he had been ill for nearly 10 years. Bosch and Hart described a patient with the onset of dementia at 62 years of age and drew attention to 27 other similar cases of adult-onset metachromatic leukoencephalopathy (see also the 7 cases reported by Turpin and Baumann). Overt signs of neuropathy are usually lacking in these adult-onset cases, but EMG and sural nerve biopsy will disclose the characteristic abnormalities.


Neurology_Adams

Neurology_Adams. One of our adult patients with Wilson disease had been committed to a psychiatric hospital because of paranoid tendencies and fighting with his family; the presence of a tremor and mild rigidity of the limbs had been attributed at first to phenothiazine drugs. In some of Griffin’s cases of adrenomyeloneuropathy, a spastic weakness of the legs and sensory ataxia progressing over several years were the main clinical manifestations; a spinocerebellar degeneration was suspected. One of our patients with Kufs lipid storage disease began to deteriorate mentally in early adult life and only much later showed an increasing rigidity, with athetotic posturing of limbs and difficulty in walking; he succumbed to his disease after more than a decade of symptoms. Another recent patient with Kufs disease presented at age 51 with vague visual difficulty, which was followed by spasticity of the legs, behavioral disinhibition, and dementia spanning 6 years. Josephs and colleagues describe 2 of 5


Neurology_Adams

Neurology_Adams. disease presented at age 51 with vague visual difficulty, which was followed by spasticity of the legs, behavioral disinhibition, and dementia spanning 6 years. Josephs and colleagues describe 2 of 5 patients with adult-onset Niemann-Pick disease type C who had a psychosis beginning at ages 61 and 27, respectively (see also Sevin et al).


Neurology_Adams

Neurology_Adams. We have observed cerebellar ataxia, polymyoclonus, and progressive blindness in adolescents and adults with a variant of GM2 gangliosidosis; cherry-red macular spots provided the clue to diagnosis. Several such cases have been reported in the last decade, particularly among the Japanese (Miyatake et al). Nine cases of a spinocerebellar ataxia with dementia or psychosis of adult onset were described by Wilner and colleagues. Also in our service were 2 adult patients with progressive spinal muscular atrophy who proved to have this same GM2 hexosaminidase deficiency; the process was clinically almost indistinguishable from a very slowly progressive lower motor neuron form of motor neuron disease but they had no macular changes and displayed the additional features of ataxia and an intermittent and atypical psychosis. An asymmetrical corticospinal syndrome with areflexia had advanced so slowly in one of our cases of Krabbe disease that she became disabled only in her sixties.


Neurology_Adams

Neurology_Adams. Another of our patients, an adolescent with severe diffuse myoclonus and seizures and slight intellectual deterioration, was found after several years to have one of the rare variants of Gaucher disease. Another with dementia, rigidity, choreoathetosis, slight cerebellar ataxia, and Babinski signs had a variant of Niemann-Pick disease. Rarely, Gaucher disease may be associated with an early and severe parkinsonian syndrome. Cases of familial adult-onset Leigh disease have been described by Kalimo and colleagues. Adrenoleukodystrophy presenting in adult life as a spinocerebellar or olivopontocerebellar syndrome has already been mentioned.


Neurology_Adams

Neurology_Adams. These rare forms of inherited metabolic disease are notable for their chronicity and for the prominence, eventually, of a particular neurologic symptom or syndrome. Once the disease is established, however, there is nearly always evidence of involvement of multiple neuronal systems, reflected in a subtle or overt dementia, character disorder, or signs referable to corticospinal, cerebellar, extrapyramidal, visual, and peripheral nerve structures. This multiplicity of neuronal system involvement is much more a feature of heritable metabolic disease than of degenerative disease and the finding of such involvement should provoke a search for an inherited metabolic disorder.


Neurology_Adams

Neurology_Adams. To reiterate the clinical aspects, the aforementioned dictum that tract involvement (corticospinal, cerebellar, peduncular, sensory, optic nerve) indicates a leukodystrophy and that “gray matter” signs (seizures, myoclonus, dementia, retinal lesions) indicate a poliodystrophy is useful mainly in the early stages of a disease. Some of the lysosomal storage diseases affect both galactolipids (galactocerebrosides and sulfatides) and gangliosides; hence both white and gray matters are involved. The paper by Turpin and Baumann is of interest when this group of diseases is viewed from the strictly psychiatric point of view. Certain outstanding clinical symptoms that are more often attributable to common diseases of the adult nervous system, such as multiple sclerosis and atherosclerosis, are sometimes the result of an inborn error of metabolism. These infrequent instances are categorized by their main features in Table 36-8, which is adopted from Grey et al.


Neurology_Adams

Neurology_Adams. Viewed from another perspective, patients are sometimes referred for the evaluation of diffuse white matter disease of the cerebrum that has been found with aiming studies. Multiple sclerosis and its variants come to mind immediately as noted by Eldridge et al but, as discussed in Chap. 35, diseases other than MS are more likely to cause diffuse, symmetric, and bilateral changes in the deep hemispheres. These include CADASIL, Susac syndrome, infiltrative tumors such as lymphoma and gliomatosis cerebri, and autoimmune systemic conditions that secondarily affect the white matter, perhaps by a mechanism of microvasculitis. However, the dysmyelinating leukodystrophies discussed in this chapter may manifest late in life and enter into the differential diagnosis of this imaging appearance. As a guide to evaluating such cases, Schiffmann and van der Knaap have provided an extensive listing of diseases and characterized them by the presence of the MRI characteristics, particularly the


Neurology_Adams

Neurology_Adams. As a guide to evaluating such cases, Schiffmann and van der Knaap have provided an extensive listing of diseases and characterized them by the presence of the MRI characteristics, particularly the presence of hypomyelination in which the white matter is hyperintense or isointense to the cortex on T1-weighted MRI images (and usually less T2 hyperintense than in other pathologic changes of white matter). They further divide the group that is not hypomyelinated by the feature of confluence of multifocal distribution. The algorithm they provide may guide the clinician in choosing an appropriate laboratory plan.


Neurology_Adams

Neurology_Adams. In concluding this discussion, which classifies the inherited monogenetic metabolic diseases in accordance with their clinical characteristics, the reader will appreciate its artificiality. Nearly every one of the diseases of each category may present some neurologic abnormality other than the ones we have emphasized, so that the potential number of variations is almost limitless. However, the plan presented here of thinking of these diseases in reference to age periods and syndromes, is of heuristic value and facilitates clinical study of this extremely difficult segment of neurologic medicine.


Neurology_Adams

Neurology_Adams. As with the metabolic disorders of the nervous system, the diseases included under this heading are so varied and may involve so many parts of the nervous system that the clinical entities by which they are identified cannot be easily addressed in any one part of this book. In their overlapping relationships, however, they are unlike the more discrete clinical entities caused by nuclear genetic mutations. Their diversity is evident not only in the details of their clinical presentations but also in the age at which symptoms first become apparent and, what is most intriguing, sometimes in the abrupt onset of their neurologic manifestations. Most of this variability in presentation is understandable from the principles of mitochondrial genetics outlined in the introductory section of this chapter. Of particular importance is the mosaicism of the mitochondria within cells and from cell to cell and the crucial role the organelles play in the oxidative energy metabolism that supports the


Neurology_Adams

Neurology_Adams. chapter. Of particular importance is the mosaicism of the mitochondria within cells and from cell to cell and the crucial role the organelles play in the oxidative energy metabolism that supports the function of cells in all organs. Although a ubiquitous metabolic derangement would seemingly offer an explanation for the dysfunction of several disparate tissues in the mitochondrial disorders, such clarification is not available.


Neurology_Adams

Neurology_Adams. Fortunately for the clinician, the most important of these diseases are expressed in several recognizable core syndromes and in a few variants thereof and they are each monogenic disorders. A number of acronyms derived from the initial letters of the main clinical features are used to designate the major mitochondrial syndromes: MERRF, MELAS, PEO, NARP, etc., as summarized in Table 36-9. The addition of certain subtle dysmorphic features including short stature; endocrinopathies, particularly diabetes; and a number of other systemic abnormalities such as lactic acidosis (discussed further on) aids in diagnosis of this class of disorder.


Neurology_Adams

Neurology_Adams. These diseases are the result of mutations in the mitochondrial genome, a ringed DNA of 16,569 base pairs and 37 genes contained within the organelle, or of mutations in a few nuclear genes that code for a component of the mitochondrion. To date, more than 100 point mutations and 200 deletions, insertions, and rearrangements have been identified. It is estimated that two-thirds of the point mutations affect the transfer RNA of the mitochondrion, one-third affect polypeptide units of the respiratory chain, and a small number affect mitochondrial ribosomal RNA. This corresponds approximately to the proportion of genes devoted to each of these functions. DiMauro and Schon, and Koopman and colleagues have written reviews of mitochondrial genomics and the most relevant diseases, which may be consulted by interested readers.


Neurology_Adams

Neurology_Adams. The first described and best-characterized member of this group of diseases is a symmetrical proximal myopathy that occurs as an isolated illness or in combination with any of the major mitochondrial syndromes. In 1966, Shy and coworkers described the histochemical and electron-microscopic abnormalities of the muscle mitochondria in a childhood myopathy, which they called megaconial (meaning marked enlargement of the mitochondria) or pleoconial (referring to an excessive number of mitochondria). Later this change came to be known as “ragged red fibers,” so named because of the subsarcolemmal and intermyofibrillar collections of membranous (mitochondrial) material in the type 1 (red) muscle fibers as visualized by the Gomori trichrome stain in sections of frozen muscle. This morphologic change may be an asymptomatic accompaniment of the mitochondrial disorders or, conversely, a mitochondrial disease of the CNS may exist without histologic or ultrastructural abnormalities in the muscle.


Neurology_Adams

Neurology_Adams. A second unifying feature of these diseases is an elevation of lactate concentration or of the lactate-to-pyruvate ratio in the blood and CSF; this is the result of the respiratory chain abnormalities. These elevations are most prominent after exercise, infection, fever, or alcohol ingestion and in some conditions are capable of inducing recurrent ketoacidotic coma, which may be the presenting manifestation of a mitochondrial disease. Leigh syndrome and MELAS particularly have a tendency to exhibit elevations of lactate; however, the diagnosis of either cannot be excluded in the presence of normal levels of this substance, even after provocation by exercise (see further on for a description of testing for elevated lactate). Using phosphorus MRI scans, one can compare levels of inorganic phosphate to phosphocreatine levels in muscle; in genetic muscle diseases of several types, this ratio increases, but it is highest in those of mitochondrial origin.


Neurology_Adams

Neurology_Adams. Although the mitochondrial diseases are considered here as a group, individual ones are of necessity mentioned in other chapters because of their outstanding characteristics. Thus the syndrome that combines epilepsy, deafness, and developmental delay with ragged red muscle fibers (myoclonic epilepsy with ragged red fibers, or MERRF) was discussed in Chap. 15, on epilepsy. The syndrome of progressive external ophthalmoplegia (PEO) has been included with other abnormalities of eye movements due to muscular disorders (see Chap. 45); lactic acidosis and stroke-like episodes (MELAS) were considered in Chap. 33, with the cerebrovascular diseases; and Leber hereditary optic neuropathy, with other causes of visual loss (see Chaps. 13 and 38). Leigh syndrome, a symmetrical subacute necrotizing encephalomyelopathy, usually with lactic acidosis, also has a number of complex presentations and is mentioned in the differential diagnosis of several diseases. For each of the aforementioned processes,


Neurology_Adams

Neurology_Adams. usually with lactic acidosis, also has a number of complex presentations and is mentioned in the differential diagnosis of several diseases. For each of the aforementioned processes, wide clinical experience will bring to light an individual or a family in whom some odd syndrome has been linked to a mitochondrial disorder. Furthermore, two major syndromes may coexist in one individual and fragmentary subsyndromes are known to occur, having an onset any time from childhood to early adult life. Consequently, it serves little purpose to catalogue all of these associations. Only the best-characterized entities, listed in Table 36-9, are described here. The most common combinations of mitochondrial syndromes have been of Kearns-Sayre syndrome with MELAS or with MERRF, progressive ophthalmoplegia with MERRF, and MERRF with MELAS.


Neurology_Adams

Neurology_Adams. We prefer to avoid the issue of what defines a “mitochondrial disorder”—its genetic defect, the biochemical disorder, or the clinical syndrome. The clinician assigns this term to the combination of a mutation of mitochondrial DNA and certain clinical features that constitute a recognizable syndrome; the biochemical changes are taken as markers of the disordered energy-producing mechanisms of the mitochondrial machinery. Mitochondrial failure has also become a focus of interest in various degenerative neurologic conditions, such as Alzheimer and Parkinson diseases but none of the currently understood mutations of the mitochondrial genome is clearly implicated in these conditions.


Neurology_Adams

Neurology_Adams. The mildest form of muscle disorder caused by mitochondrial disease is a benign and relatively static proximal weakness that tends to be more severe in the arms. Exercise intolerance alone is reported by more than half of these patients. There are adult-onset cases, but careful questioning usually reveals lifelong symptoms (weakness, poor endurance, discomfort, exertional dyspnea, and tachycardia), which may be so slight and slowly progressive that the patient leads a relatively normal life for decades. Less-frequent patterns of muscle disease include a fascioscapulohumeral or limb-girdle pattern of weakness as well as occasional episodes of exertional myoglobinuria. Some patients develop PEO several years after the limb weakness becomes evident. Several mutations are associated with a pure or predominant myopathic syndrome, the most common one being located at position 3250 of the mitochondrial genome. Rare variants, such as combined skeletal weakness and cardiomyopathy, are


Neurology_Adams

Neurology_Adams. a pure or predominant myopathic syndrome, the most common one being located at position 3250 of the mitochondrial genome. Rare variants, such as combined skeletal weakness and cardiomyopathy, are referable to other loci.


Neurology_Adams

Neurology_Adams. At the opposite end of the spectrum is an infantile myopathy in which weakness and lactic acidosis become evident in the first week of life and are fatal by 1 year. Many of these patients and some members of their families have a history of renal dysfunction combined with weakness of early onset. The muscle tissue shows numerous ragged red fibers, and cytochrome oxidase activity is virtually absent. DiMauro (1983) and others have described a remarkable partly reversible form, which, early on, requires ventilatory support and gastric feeding but improves clinically as the child ages; the lactic acidosis disappears by age 2 or 3 years. In these severe childhood cases, the deficiencies in cytochrome oxidase suggest a defect in mitochondrial genes, but the site has not been found.


Neurology_Adams

Neurology_Adams. As mentioned above, the histologic feature that unites mitochondrial myopathies is the presence of ragged red fibers. This finding points to the diagnosis of a mitochondrial disorder in any case where weakness is coupled with exercise intolerance and elevated serum lactate, particularly if there is a family history of similar problems. Also, the presence of ragged red fibers differentiates the mitochondrial myopathies from the glycogenoses but it bears emphasizing that ragged red fibers are rare in infants and young children, even in those with confirmed mitochondrial disease. Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome (See Also Chap. 45)


Neurology_Adams

Neurology_Adams. The combination of progressive ptosis and symmetrical ophthalmoplegia is a common manifestation of mitochondrial disease. Usually there is no diplopia or strabismus or at most only transient diplopia, despite slightly dysconjugate gaze. Mitochondrial abnormalities are found in the extraocular muscles of these patients. We have been impressed at how long the illness can exist before it brings the patient to a physician. To be differentiated is myasthenia gravis, which is characterized by fatigable weakness and responsiveness to cholinergic medications, neither of which is a feature of mitochondrial disorders. In our experience, nearly all cases of PEO are because of mitochondrial disorders, but rarely the condition may be simulated by one of several genetically determined muscular dystrophies, including oculopharyngeal dystrophy and a type in which there are no other associated weaknesses but is, however, linked to facioscapulohumeral dystrophy (FSH; Chap. 45).


Neurology_Adams

Neurology_Adams. PEO bears a close relationship to the Kearns-Sayre syndrome of retinitis pigmentosa (onset before age 20 years), ataxia, heart block and other conduction defects, and elevated CSF protein; sensorineural deafness, seizures, or pyramidal signs may be added (see Chap. 45 for clinical description). The CNS syndromes of MELAS or MERRF (see further on) may also be combined with PEO.


Neurology_Adams

Neurology_Adams. This is a familial or sporadically occurring mitochondrial disorder with a wide range of clinical manifestations. Only some of the cases display a maternal pattern of inheritance. The onset of neurologic difficulty in more than half of these patients is in the first year of life, mostly before the sixth month; but late-onset forms, with great heterogeneity of presentation as late as early adulthood, are also known. Neurologic symptoms often appear subacutely or abruptly, sometimes precipitated by a febrile illness or a surgical operation. It has seemed to us that this rapid onset is more characteristic of Leigh disease than it is of the other mitochondrial disorders and the disease could reasonably be designated as “acute necrotizing encephalomyelopathy” (ANE), a term applied to a similar entity in Japan and China.


Neurology_Adams

Neurology_Adams. In infants, loss of head control and other recent motor acquisitions, hypotonia, poor sucking, anorexia and vomiting, irritability and continuous crying, generalized seizures, and myoclonic jerks constitute the usual clinical picture. If the onset is in the second year, there is delay in walking, ataxia, dysarthria, psychomotor regression, tonic spasms, characteristic respiratory disturbances (episodic hyperventilation, especially during infections, and periods of apnea, gasping, and quiet sobbing), external ophthalmoplegia, nystagmus, and disorders of gaze (like those of Wernicke disease), paralysis of deglutition, and abnormal movements of the limbs (particularly dystonia but also jerky and choreiform movements). Mild cases, showing mainly developmental delay, have been mistaken for cerebral palsy. Peripheral nerves are involved in some cases (areflexia, weakness, atrophy, and slowed conduction velocities of peripheral nerves); in a few, autonomic failure is the most prominent


Neurology_Adams

Neurology_Adams. cerebral palsy. Peripheral nerves are involved in some cases (areflexia, weakness, atrophy, and slowed conduction velocities of peripheral nerves); in a few, autonomic failure is the most prominent feature. In some children the disease is episodic; in others it is intermittently progressive and quite protracted, with exacerbation of neurologic symptoms in association with nonspecific infections. The CSF is usually normal but the protein content may be increased.


Neurology_Adams

Neurology_Adams. The pathologic changes take the form of bilaterally symmetrical foci of spongy necrosis with myelin degeneration, vascular proliferation, and gliosis in the thalami, midbrain, pons, medulla, and spinal cord. In cases of acute onset there may be minor hemorrhagic change. The basal ganglia are characteristically but not invariably affected. Also, there may be a demyelinative type of peripheral neuropathy. In their distribution and histologic appearance, the CNS lesions resemble those of Wernicke disease (caused by a deficiency of thiamine) except that the lesions of Leigh disease are more extensive—sometimes involving the striatum—and they spare the mammillary bodies. The lesions, particularly those of the lenticular nuclei and brainstem, may be seen in CT and are strikingly demonstrated by MRI. The histochemical appearance of muscle is normal, although electron microscopy may show an increased number of mitochondria.


Neurology_Adams

Neurology_Adams. The clinical boundaries of Leigh disease have not been defined precisely. A familial disorder of infancy and early childhood, referred to as bilateral striatal necrosis and associated with dystonia, visual failure, and other neurologic defects, is probably a variant. The same may be true of an obscure adult-onset syndrome of progressive dementia, caused by thalamic lesions, in the form of necrosis, vascular proliferation, and gliosis. A resemblance to what has recently been termed acute necrotizing encephalomyelopathy, arising in children after an infectious illness, was alluded to earlier.


Neurology_Adams

Neurology_Adams. The mitochondrial 8993 mutation associated with Leigh disease that explains 20 percent of cases is also discussed below in relation to the NARP syndrome. The close relationship between the two processes reemphasizes the point that several mitochondrial mutations rise to the clinical and pathologic picture of a necrotizing encephalopathy. However, it has been recently pointed out that many cases of Leigh disease are associated with nuclear mutations, including in RANBP2 that codes for a component of the nuclear pore. Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome (NARP)


Neurology_Adams

Neurology_Adams. Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome (NARP) As just indicated, Leigh syndrome exemplifies to a remarkable degree the heterogeneity of abnormalities that may be associated with cytochrome oxidase deficiency caused by a single mitochondrial gene mutation. A minor transversion error, the substitution of one nucleotide in the mitochondrial DNA at position 8993, the same site implicated in Leigh syndrome, also gives rise to a maternally inherited syndrome of sensory NARP. The mutation creates a defective ATPase-6 of complex V of the mitochondrial respiratory chain. Included in some cases of NARP are developmental delay, seizures, and proximal muscle weakness. The severity of the NARP syndrome corresponds to the amount of aberrant DNA in the mitochondrial genome; mutations involving more than 90 percent of mitochondrial DNA produce the more severe phenotype of the necrotizing encephalopathy.


Neurology_Adams

Neurology_Adams. Santorelli and colleagues found that 12 of 50 patients with Leigh syndrome from 10 families displayed the 8993 point mutation. Within one kindred, the mitochondrial aberration may vary from a mild developmental delay, to NARP, to the full-blown Leigh syndrome, or early death with lactic acidosis. These differences in severity are thought to result from the mosaicism of mitochondrial genetics and specifically to the protective effect of even small amounts of the normal mitochondrial genome. The first manifestations of disease may not appear until adulthood, although it only rarely begins after age 20 years.


Neurology_Adams

Neurology_Adams. Further confounding the clinical classification of this disease complex is the observation that many patients with the Leigh syndrome have a pyruvate dehydrogenase (usually X-linked) or pyruvate decarboxylase deficiency or a cytochrome oxidase deficiency. These are common to many mitochondrial disorders and inherited usually as an autosomal recessive trait. However, patients with Leigh syndrome and the 8993 mutation tend not to have these enzymatic deficiencies. Bridging these complex cases to the typical ones are instances with cytochrome oxidase deficiency with psychomotor retardation, slowed growth, and lactic acidosis, many without the striatal or brainstem spinal necroses of Leigh syndrome.


Neurology_Adams

Neurology_Adams. Certain types of organic acidemia occurring in early infancy and of unproved genetic etiology have already been mentioned. Here reference is made to those few cases that are associated with deletions of mitochondrial DNA. The syndrome consists of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions with intervening periods of normalcy. Choreoathetosis or progressive ophthalmoplegia have been added in a few cases. Probably most cases of this type are caused by disorders of the mitochondrial respiratory chain, particularly of the pyruvate-decarboxylase complex. Some children are dysmorphic, with a broad nasal bridge, micrognathia, posteriorly rotated ears, short arms and fingers, and other similar but mild dysmorphic features. De Vivo and colleagues have written a synopsis of this disease. Death usually occurs before the third year. The important laboratory findings are acidosis with high lactate levels and hyperalaninemia. The few cases that have been


Neurology_Adams

Neurology_Adams. a synopsis of this disease. Death usually occurs before the third year. The important laboratory findings are acidosis with high lactate levels and hyperalaninemia. The few cases that have been examined postmortem are found to have necrosis and cavitation of the globus pallidus and cerebral white matter, as in subacute necrotizing encephalomyelopathy (SNE). The diagnosis can be made by the finding of ragged red fibers in muscle or by measurement of enzyme activity. The process must be distinguished from the several diseases of infancy that are complicated by lactic acidosis.


Neurology_Adams

Neurology_Adams. This disease presents as progressive myoclonic epilepsy or myoclonic ataxia. As was noted in Chap. 5, these cases must be differentiated from several similar clinical entities, such as juvenile myoclonic epilepsy, Unverricht- Lundborg disease, Lafora-body disease, Baltic myoclonus, and neuronal ceroid-lipofuscinosis, discussed earlier in this chapter. Tsairis and colleagues were the first to describe the connection between familial myoclonic epilepsy and mitochondrial changes in muscle, and numerous variants have been identified since their report.


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Neurology_Adams. Myoclonus in a child or young adult is the most typical feature and is elicited by startle or by voluntary movement of the limbs. The nature of the seizures varies but includes drop attacks, focal epilepsy, or tonic-clonic types, some of which are photosensitive. The ataxia tends to worsen progressively, replacing the myoclonus and seizures in some instances and remaining a minor feature in others. The myopathy usually produces inapparent or mild weakness, but the presence of mitochondrial muscle abnormalities is necessary for clinical diagnosis. To this constellation may be added any of the other elements of the mitochondrial diseases that have already been denoted, including deafness (present in our cases), mental decline, optic atrophy, ophthalmoplegia, cervical lipomas, short stature, or neuropathy.


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Neurology_Adams. Most cases are familial and display maternal inheritance, but the age of onset may vary and affected individuals have been reported with symptoms beginning as late as the sixth decade. Almost always the patients with later onset have the mildest disease, with only myoclonic epilepsy. Conversely, those with onset in the first decade tend to be more severely affected and die before the third decade. As with the other mitochondrial processes, the quantitative burden of mutant DNA bears some relationship to the time of onset and severity of the disease. Eighty percent of patients with MERRF have a point mutation of the mitochondrial genome at locus 8344, which codes for a transfer RNA and, conversely, most patients with this mutation will ultimately manifest some or all the clinical features of MERRF, including those with crossover features of the Leigh syndrome. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)


Neurology_Adams

Neurology_Adams. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Patients with this syndrome have normal early development followed by poor growth, focal or generalized seizures, and recurrent acute episodes that resemble strokes or prolonged transient ischemic attacks. The stroke deficits often improve but in some cases lead to a progressive encephalopathy. Some have hemicranial headaches that cannot be distinguished from migraine, and others suffer repetitive vomiting or episodic lactic acidosis. If there is a characteristic feature it is the unusual clinical pattern of focal seizures, sometimes prolonged, which herald a stroke (see Pavlakis et al) and produce an unusual radiographic pattern of infarction involving the cortex and immediate subcortical white matter. The CT may also show numerous low- density regions that have no clinical correlates. Most patients have ragged red fibers in muscle but only rarely is there weakness or exercise intolerance.


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Neurology_Adams. Approximately 80 percent of MELAS cases are related to a mitochondrial mutation occurring at the 3243 site of the mitochondrial gene or, in a few instances, at an alternative locus that also codes for a segment of transfer RNA. Maternal inheritance is common but sporadic cases are well known. In the survey conducted by Hammans and coworkers, only half of the cases of the 3243 mutation were associated with the MELAS syndrome. The finding of an abnormal mitochondrial genome in the endothelium and smooth muscle of cerebral vessels has been suggested as a basis for the strokes and migraine headaches. The Diagnosis of Mitochondrial Disorders


Neurology_Adams

Neurology_Adams. The characteristic neurologic signs of a mitochondrial disorder fall into certain broad groups: (1) combinations of ataxia, seizures, and myoclonus, typified by the MERRF syndrome; (2) migraine-like headaches, recurrent small strokes, and preceding seizures, represented by the MELAS syndrome; (3) combinations of ophthalmoplegia (progressive external ophthalmoplegia), retinitis pigmentosa, polyneuropathy, or deafness (Kearns-Sayre syndrome); (4) optic atrophy (Leber type); and (5) a myopathy that is slowly progressive or fluctuating in severity. These may be combined with dementia, lactic acidosis, short stature, diabetes, ptosis, and cardiac conduction defects as well as with multiple symmetrical lipomas. Peripheral nerve involvement, although common in these disorders, is usually asymptomatic; autonomic failure may be a rare manifestation. A panoply of visceral dysfunctions are at times associated with the neurologic features including bone marrow changes of sideroblastic anemia,


Neurology_Adams

Neurology_Adams. autonomic failure may be a rare manifestation. A panoply of visceral dysfunctions are at times associated with the neurologic features including bone marrow changes of sideroblastic anemia, renal tubular defects, endocrinopathies (mainly diabetes mellitus, but also hypothyroidism or deficiency of growth hormone), hepatopathy, cardiomyopathy, and recurrent vomiting with intestinal pseudoobstruction. Diabetes has been a marker in several of the early-onset MELAS and MERRF cases that we have seen, but less often when the first manifestations appeared in adulthood.


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Neurology_Adams. The investigation of a suspected case of mitochondrial disease begins with an exploration of the family history for unusual childhood diseases including neonatal death, unexplained seizure disorders, and progressive neurologic deficits of the types already described. Unexplained deafness or diabetes in family members might also raise the level of suspicion of a mitochondrial disorder. The diagnosis should be suspected when a disorder with these characteristics occurs in a pattern that indicates maternal inheritance. However, one encounters families with mendelian patterns of inheritance due to nuclear gene defects as described in the introductory section of this chapter. Commercial tests are available for the more frequent mitochondrial point mutation sites (3243, 8993, and 8344) in leukocytes. Detection of deletions requires analysis of muscle tissue. They are useful for diagnosis but reveal abnormalities in only a modest number, estimated to be approximately 15 percent of cases that


Neurology_Adams

Neurology_Adams. Detection of deletions requires analysis of muscle tissue. They are useful for diagnosis but reveal abnormalities in only a modest number, estimated to be approximately 15 percent of cases that have the index aspect of this group of diseases, ragged red muscle fibers; the frequency is higher in cases with identifiable phenotypes such as MERRF and MELAS. Resting and postexercise lactate and pyruvate determinations are helpful, but this test of aerobic capacity has limitations. The more recent work of Taivassalo and colleagues, although showing a wide range of values, suggests that measurement of the partial pressure of oxygen in venous blood from the forearm after ischemic exercise (ischemic forearm test) may still be useful in distinguishing patients with mitochondrial disease from normal subjects. In the former there is a paradoxical rise in Po2 from an average of 27 to 38 mm Hg, whereas normals show a decline in this value.


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Neurology_Adams. A muscle biopsy will disclose several basic abnormalities; ragged red fibers can be recognized by use of the modified Gomori stain on frozen material, and the absence of succinate dehydrogenase and cytochrome oxidase by appropriate histochemical staining. In cases of suspected Leigh syndrome or MELAS, the CT or MRI may show some of the characteristic cerebral lesions; in the other mitochondrial disorders, there are often focal nondescript hyperintensities on T2-weighted MRI as well as atrophy, lucencies, or calcification. Sampling of chorionic villi for prenatal diagnosis may reveal mutant mitochondrial DNA, but this information is not entirely dependable.


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Neurology_Adams. It should be evident from the foregoing discussion that normal findings in any of these tests, including the muscle biopsy, do not exclude mitochondrial disease. In the final analysis, it is the clinical syndrome, family history, and corroborating evidence of a mitochondrial disorder or its genetic representation that is diagnostic. Jackson and coworkers suggest that isolated phenomena, such as dementia, muscle weakness, epilepsy, nerve deafness, migraine with strokes, small stature, myoclonic epilepsy, and cardiomyopathy, should prompt consideration of a mitochondrial disorder when no other explanation is evident. Adachi M, Torii J, Schneck L, Volk BW: Electron microscopic and enzyme histochemical studies of the cerebellum in spongy degeneration. Acta Neuropathol 20:22, 1972. Aicardi J: Early myoclonic encephalopathy. In: Roger J, Dravet C, Bureau M, et al (eds): Epileptic Syndromes in Infancy, Childhood, and Adolescence. New York, Demos, 1985, pp 13–23.


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Neurology_Adams. Aicardi J: Early myoclonic encephalopathy. In: Roger J, Dravet C, Bureau M, et al (eds): Epileptic Syndromes in Infancy, Childhood, and Adolescence. New York, Demos, 1985, pp 13–23. Aicardi J, Castelein P: Infantile neuroaxonal dystrophy. Brain 102:727, 1979. Allen RJ, Young W, Bonacci J, et al: Neonatal dystonic parkinsonism, a “stiff-baby syndrome,” in biopterin deficiency with hyperprolactinemia detected by newborn screening for hyperphenylalaninemia, and responsiveness to treatment. Ann Neurol 28:434, 1990. Alpers BJ: Diffuse progressive degeneration of cerebral gray matter. Arch Neurol Psychiatry 25:469, 1931. Austin J: Studies in metachromatic leukodystrophy: XII. Multiple sulfatase deficiency. Arch Neurol 28:258, 1973. Banker BQ, Victor M: Spongy degeneration of infancy. In: Goodman RM, Motulsky AG (eds): Genetic Diseases Among Ashkenazi Jews. New York, Raven Press, 1979, pp 210–216.


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Neurology_Adams. Scheinberg IH, Sternlieb I: Wilson’s Disease: Major Problems in Internal Medicine. Vol 23. Philadelphia, Saunders, 1984. Schiffmann R, van der Knaap MS: An MRI-based approach to the diagnosis of white matter disorders. Neurology 72:750, 2009. Schilsky ML, Scheinberg IH, Sternlieb I: Liver transplantation for Wilson’s disease: Indications and outcome. Hepatology 19:583, 2001. Schulz A, Ajayi T, Specchio N, et al: Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med 378:1898, 2018. Scriver CR, Clow CL: Phenylketonuria: Epitome of human biochemical genetics. N Engl J Med 303:1335, 1980. Seitelberger F: Pelizaeus-Merzbacher disease. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 10. Amsterdam, North-Holland, 1970, pp 150–202. Sevin M, Lesca G, Baumann N, et al: The adult for of Niemann-Pick disease type C. Brain I130:120, 2007. Shih VE, Abrams IF, Johnson JL, et al: Sulfite oxidase deficiency. N Engl J Med 297:1022, 1977.


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Neurology_Adams. Shih VE, Abrams IF, Johnson JL, et al: Sulfite oxidase deficiency. N Engl J Med 297:1022, 1977. Shih VE, Safran AP, Ropper AH, Tuchman M: Ornithine carbamoyl transferase deficiency: Unusual clinical findings and novel mutation. J Inherit Metab Dis 22:672, 1999. Shuman RM, Leech RW, Scott CR: The neuropathology of the nonketotic and ketotic hyperglycinemias: Three cases. Neurology 28:139, 1978. Shy GM, Gonatas NK, Perez M: Two childhood myopathies with abnormal mitochondria: I. Megaconial myopathy. II. Pleoconial myopathy. Brain 89:133, 1966. Siemerling E, Creutzfeldt HG: Bronzekrankheit und sklerosierende encephalomyelitis (diffuse sklerose). Arch Psychiatr Nervenkr 68:217, 1923. Sjögren T: Die juvenile amaurotische Idiotie: Klinische und erblichkeitsmedizinische Untersuchungen. Hereditas 14:197, 1931.


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Neurology_Adams. Nervenkr 68:217, 1923. Sjögren T: Die juvenile amaurotische Idiotie: Klinische und erblichkeitsmedizinische Untersuchungen. Hereditas 14:197, 1931. Sly WS, Whyte MP, Sunderam V: Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis with cerebral calcification. N Engl J Med 313:139, 1985. Staba SL, Escolar ML, Poe M, et al: Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med 350:1960, 2004. Starosta-Rubinstein S, Young AB, Kluin K, et al: Clinical assessment of 31 patients with Wilson’s disease. Arch Neurol 44:365, 1987. Swoboda KJ, Saul JP, McKenna CE, et al: Aromatic l-amino acid decarboxylase deficiency. Overview of clinical features and outcomes. Ann Neurol 54(Suppl 6):S49, 2000. Szanto J, Gallyas F: A study of iron metabolism in neuropsychiatric patients: Hallervorden-Spatz disease. Arch Neurol 14:438, 1966.


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Neurology_Adams. Szanto J, Gallyas F: A study of iron metabolism in neuropsychiatric patients: Hallervorden-Spatz disease. Arch Neurol 14:438, 1966. Taivassalo T, Abbott A, Wyrick P, et al: Venous oxygen levels during aerobic exercise: An index of impaired oxidative metabolism in mitochondrial myopathy. Ann Neurol 51:38, 2002. Tassinari CA, Michelucci R, Genton P, et al: Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): A condition unrelated to mitochondrial encephalomyopathies. J Neurol Neurosurg Psychiatry 52:262, 1989. Tellez-Nagel I, Rapin I, Iwamoto T, et al: Mucolipidosis IV. Arch Neurol 33:828, 1976. Tennison MB, Bouldin TW, Whaley RA: Mineralization of the basal ganglia detected by CT in Hallervorden-Spatz syndrome. Neurology 38:155, 1988.


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Neurology_Adams. Tennison MB, Bouldin TW, Whaley RA: Mineralization of the basal ganglia detected by CT in Hallervorden-Spatz syndrome. Neurology 38:155, 1988. Thomas PK, Abrams JD, Swallow D, Stewart G: Sialidosis type I: Cherry-red spot-myoclonus syndrome with sialidase deficiency and altered electrophoretic mobilities of some enzymes known to be glycoproteins. J Neurol Neurosurg Psychiatry 42:873, 1979. Trobe JD, Sharpe JA, Hirsch DK, Gebarski SS: Nystagmus of Pelizaeus-Merzbacher disease: A magnetic search-coil study. Arch Neurol 48:87, 1991. Tsairis P, Engel WK, Kark P: Familial myoclonic epilepsy syndrome associated with skeletal muscle abnormalities. Neurology 23:408, 1973. Tsuji S, Choudary PV, Martin BM, et al: A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher’s disease. N Engl J Med 316:570, 1987.


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Neurology_Adams. Tsuji S, Choudary PV, Martin BM, et al: A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher’s disease. N Engl J Med 316:570, 1987. Tsuji S, Yamada T, Tsutsumi A, Miyatake T: Neuraminidase deficiency and accumulation of sialic acid in lymphocytes in adult type sialidosis with partial b-galactosidase deficiency. Ann Neurol 11:541, 1982. Turpin JC, Baumann N: Manifestations psychiatriques ou cognitves inaugurales dans les neurolipidoses de l’adulte. Rev Neurol 159:637, 2003. Vakili S, Drew AL, von Schuching S, et al: Hallervorden-Spatz syndrome. Arch Neurol 34:729, 1977. van Bogaert L: Contribution clinique et anatomique a l’etude de la paralysie agitante juvenile primitive. Rev Neurol 2:315, 1930. van Bogaert L: Le cadre des xanthomatoses et leurs differents types: Xanthomatoses secondaires. Rev Med (Paris) 17:433, 1962. van Bogaert L, Bertrand I: Sur une idiotie famaliale avec dégénérescence spongieuse du neuraxe. Acta Neurol Belg 49:572, 1949.


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Neurology_Adams. van Bogaert L, Bertrand I: Sur une idiotie famaliale avec dégénérescence spongieuse du neuraxe. Acta Neurol Belg 49:572, 1949. Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 79:1031, 2016. Williams FJB, Walshe JM: Wilson’s disease: An analysis of the cranial computerized tomographic experiences found in 60 patients and the changes in response to treatment with chelating agents. Brain 104:735, 1981. Williams RS, Marshall PC, Lott IT, et al: The cellular pathology of Menkes steely hair syndrome. Neurology 28:575, 1978. Wilner JP, Grabowski GA, Gordon RF, et al: Chronic GM2 gangliosidosis masquerading as atypical Friedreich’s ataxia: Clinical, morphologic, and biochemical studies of nine cases. Neurology 31:787, 1981. Wilson SAK: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34:295, 1912.


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Neurology_Adams. Wilson SAK: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34:295, 1912. Wisniewski KE, Zhong N, Phillipart M: Pheno/genotypic correlations of neuronal ceroid lipofuscinosis. Neurology 57:576, 2001. Yang Y, Muzni DM, Reid JG, et al: Clinical and whole-exome sequencing for the diagnosis of medelian disorders. New Engl J Med 369:1502, 2013. Yokoi S, Nakayama H, Negeshi T: Biochemical studies on tissues from a patient with Lafora disease. Clin Chim Acta 62:415, 1975. Young RR, Kleinman G, Ojemann RG, et al: Compressive myelopathy in Maroteaux-Lamy syndrome: Clinical and pathological findings. Ann Neurol 8:336, 1980. Zeman W, Donahue S, Dyken P, Green J: The neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome). In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 10. Amsterdam, North-Holland, 1970, pp 588–679.


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Neurology_Adams. Figure 36-1. Retinal cherry-red spot in a patient with Tay-Sachs disease. The whitish ring surrounds the dark macula. In this dark-skinned child, the macular spot is dark rather than reddish. (Courtesy of Dr. Shirley Wray.) Figure 36-2. Krabbe disease. Axial T2-weighted MRI of a 6-month old with difficulty feeding, irritability, upper extremity hypertonia and lower extremity hypotonia, which began at 3 months. Laboratory testing confirmed low levels of leukocyte galactocerebrosidase activity. There is abnormal hyperintensity of the cerebral peduncles (corticospinal tract atrophy) as well as enlargement of the prechiasmatic optic nerves. Thalamic hypointensity, not shown here, is a common finding as well. (Image courtesy of Drs. Edward Yang and Sanjay Prabhu.)


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Neurology_Adams. Figure 36-3. Spongy degeneration of infancy (Canavan-van Bogaert-Bertrand disease). Axial T2-weighted MRI of a 5-week old with hypertonia, nystagmus, and macrocephaly. There is abnormal hyperintensity in the globus pallidus, ventrolateral thalamus, and internal capsule. Abnormal white matter hyperintensity extends to the cortex without sparing of the arcuate fibers. MR spectroscopy (not shown) revealed a markedly elevated N-acetyl aspartate peak. (Image courtesy of Drs. Edward Yang and Sanjay Prabhu.) Figure 36-4. A schematic for diagnosis of the inherited metabolic diseases of infancy. (Courtesy of Dr. Edwin Kolodny.) Figure 36-5. Metachromatic leukodystrophy. Axial T2-weighted MRI of a 2-year-old girl with developmental regression and EMG evidence of diffuse motor and sensory demyelination. There is abnormal symmetric central white matter hyperintensity with sparing of the subcortical arcuate fibers. (Image courtesy of Drs. Edward Yang and Sanjay Prabhu.)


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Neurology_Adams. Figure 36-6. Differential diagnosis of mucopolysaccharidoses from oligosaccharidoses. (Courtesy of Dr. Ed Kolodny.) Figure 36-7. Kayser-Fleischer corneal ring in Wilson disease. Brown coloration is seen near the limbus of the cornea and represents copper deposition in Descemet’s membrane. (Reproduced from Mackay D, Miyawaki E: Hyperkinetic Movement Disorders. ACP Medicine, Online S12C17, Topic ID 1271. © Decker Intellectual Properties. Courtesy of Drs. Edison Miyawaki and Donald Bienfang.) Figure 36-8. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease). T2-weighted MRI showing areas of decreased signal intensity of the pallidum bilaterally (corresponding to iron deposition) and a central high signal area because of necrosis (“eye-of-the-tiger” sign). (Reproduced with permission from Lyon et al. Courtesy of Dr. C. Gillain.)


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Neurology_Adams. Figure 36-9. Idiopathic basal ganglionic and cerebellar calcification discovered in a 54-year-old woman with a slowly progressive rigid Parkinson syndrome. Figure 36-10. Adrenoleukodystrophy. Axial T2-weighted MRI of an 8-year-old boy with headache. There is abnormal posterior periventricular white matter hyperintensity extending across the splenium of the corpus callosum. Laboratory testing confirmed adrenal insufficiency. (Image courtesy of Drs. Edward Yang and Sanjay Prabhu.) Chapter 36 Inherited Metabolic Diseases of the Nervous System VISCEROMEGALYNiemann-PickInfantile GaucherPompeFarberSandhoff (some cases)Later, mucolipidosis and polysaccharidosesPURELY NEUROLOGIC DISEASESPredominantly gray matterTay-SachsSandhoffGM1 gangliosidosisNeuronal ceroid lipofuscinosesLeighAlexanderNeuroaxonal dystrophySpongy degeneration (Canavan)Pelizaeus-MerzbacherAdrenoleukodystrophyGloboid-body (Krabbe)Metachromatic leukodystrophyPredominantly white matter


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Neurology_Adams. Developmental Diseases of the This broad heading subsumes a large number of both genetically driven developmental malformations and diseases acquired during intrauterine or early neonatal periods of life. They number in the hundreds according to the tabulation of Dyken and Krawiecki although many, if not most, are rare. Taxonomically, they make up two categories. The first includes specific gene defects, either mutations, deletions, or duplications of parts of genes (copy number variation), or single nucleotide polymorphisms that give rise to developmental aberrations or delays. The second category comprises a variety of environmental and infectious agents acting at different times on the immature nervous system during embryonal, fetal, and perinatal periods of life.


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Neurology_Adams. Several points should be noted regarding the frequency of malformations. Jones, in the Smith monograph, has pointed out that a single minor malformation, usually of no clinical significance, occurs in 14 percent of newborns. Two malformations appear in 0.8 percent of newborns, and in this group, a major defect is five times more frequent than in the normal population. Three or more malformations are found in 0.5 percent of newborns, and in this latter group, more than 90 percent have one or more major abnormalities that seriously interfere with viability or physical well-being. The figures for major congenital malformations compiled by Kalter and Warkany are comparable but somewhat higher. What is important for the neurologist is the fact that the nervous system is involved in most of infants with major malformations. Indeed, approximately 40 percent of deaths during the first postnatal year are in some manner related to prenatal malformations of the central nervous system.


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Neurology_Adams. Certain principles are applicable to the entire group of malformations. First, the abnormality of the nervous system is frequently accompanied by an abnormality of some other structure or organ (eye, nose, cranium, spine, ear, and heart), which relates them chronologically to a certain period of embryogenesis. Conversely, the presence of these malformations of nonnervous tissues suggests that an associated abnormality of the nervous system is developmental in nature. For example, the conjunction of cardiac, limb, gut, and bladder abnormalities with a neurologic disorder indicates the time at which the insult takes place: cardiac abnormalities occur between the fifth and sixth week; extroversion of the bladder at less than 30 days; duodenal atresia, before 30 days; syndactyly, before 6 weeks; meningomyelocele, before 28 days; anencephaly, before 28 days; cleft lip, before 36 days; syndactyly, cyclopia, and holoprosencephaly, before 23 days. Each is discussed in this chapter. This


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Neurology_Adams. 6 weeks; meningomyelocele, before 28 days; anencephaly, before 28 days; cleft lip, before 36 days; syndactyly, cyclopia, and holoprosencephaly, before 23 days. Each is discussed in this chapter. This principle is not inviolable; in certain maldevelopments of the brain that must have originated in the embryonal period, all other organs are normal. One can assume that the brain was more vulnerable than any other organ to prenatal as well as natal influences. Perhaps this occurs because the nervous system, of all organ systems, requires the longest time for its development and maturation, during which it is susceptible to disease. Low birth weight and gestational age, indicative of premature birth, increase the risk of cognitive or sensory developmental delay, seizures, and cerebral palsy.


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Neurology_Adams. A maldevelopment of whatever cause should be present at birth and remain stable thereafter, that is, be nonprogressive, in contrast to the majority of metabolic diseases of infancy discussed in the preceding chapter. However, this principle requires qualification: The abnormality may have affected parts of the brain that have not matured at birth, so that an interval of time must elapse postnatally before the defect can express itself. Many of the teratologic conditions that cause birth defects pass unrecognized because they end in spontaneous abortions. For example, defects caused by chromosomal abnormalities occur in approximately 0.6 percent of live births, but such defects are found in more than 5 percent of spontaneous abortuses at 5 to 12 weeks’ gestational age.


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Neurology_Adams. Regarding the genetic causes of malformations and developmental delay, much has been learned but a full picture of the genetic influences on these conditions remains incomplete. Whole chromosome karyotyping allowed the recognition of conditions such as Down syndrome and its association with triplication of the entire chromosome 21. As more refined techniques became available, such as high-resolution banding, subtle changes such as small deletions in chromosomal architecture became apparent, as occur in Angleman and Prader-Willi syndrome and fragile-X syndrome. What followed, by the use of linkage analysis and other genetic techniques, was the elucidation of single gene mutations that were obligatorily associated with malformations or developmental delays; most of the inherited metabolic disorders of infancy and childhood discussed in Chap. 36 are of this type but also certain gross malformations of the brain such as lissencephaly, discussed further on.


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Neurology_Adams. These were the forerunners of a completely different category of technical innovations, anchored by the original method of sequencing short lengths of part of a gene by the Sanger method and its derivatives. With the development of the polymerase chain reaction and automated methods, longer and longer sequences of genes could be studied. This has allowed large population studies, merged with statistical techniques that expose genes in affected individuals that may be responsible for disease and are not present in high frequency in the general populations. From there, the rapid evolution of technology able to analyze thousands of portions of DNA in parallel and compare numerous sequences to a reference library of DNA has revealed variants at the resolution of single base pairs, single nucleotide polymorphisms (SNPs). Most exploration of human disease has been, until recently, based on the “common disease–common variant” model, in which a disease is attributable to limited number


Neurology_Adams

Neurology_Adams. nucleotide polymorphisms (SNPs). Most exploration of human disease has been, until recently, based on the “common disease–common variant” model, in which a disease is attributable to limited number variants that exist in more than 1 to 5 percent of a population. For example, five polymorphisms are each responsible for doubling or tripling the risk of macular degeneration. However, most of these variants are probably not themselves responsible for the disease.


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Neurology_Adams. These types of genetic changes do not appear to explain the majority of the various developmental diseases. The relatively novel concept of duplication or deletion of portions of genes, copy number variation, emerged as explanatory of some proportion of diseases such as autism as discussed further on. What is interesting about copy number variation is that they may give rise to several phenotypes of similar disorder, quite unlike conventional mendelian mutations. This indicates that copy number variants, like SNPs, probably are not usually directly causative of a condition but instead modulate other functions that express proteins. This is the situation for many of the forms of developmental abnormalities such as generic cognitive developmental delay, autism, and certain psychiatric diseases.


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Neurology_Adams. Continued advances in molecular diagnostic techniques have allowed for sequencing of the whole exome as a means of assessing the genetic code for mutations or other irregularities associated with neurodevelopmental diseases. These techniques and their utility in clinical practice are reviewed by Sherr and colleagues, Srivastava and colleagues, and by Fogel. In parallel, investigations into epigenetic phenomena, that is, heritable alterations to DNA or RNA that do not affect the genetic code itself (i.e., DNA methylation, histone modifications, non-protein-coding RNA) are shedding new light on the mechanisms of a variety of neurodevelopmental and neurodegenerative diseases (see Klein and Benarroch).


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Neurology_Adams. A textbook on the principles of neurology cannot catalog all the hereditary and congenital developmental abnormalities that affect the nervous system. For such details, the interested reader should refer to several excellent monographs. Three that the authors consult are Brett’s Pediatric Neurology, Berg’s Principles of Child Neurology, and Lyon and Evrard’s Neuropediatrie. These are supplemented by special atlases of congenital malformations mentioned further on. In this chapter, we sketch only the major groups and discuss in detail a few of the more common entities. The classification in Table 37-1 adheres to a grouping in accordance with the main presenting abnormality. Represented here are the common problems that lead families to seek consultation with the pediatric neurologist: (1) structural defects of the cranium, spine, and limbs, and of eyes, nose, ears, jaws, and skin; (2) disturbed motor function, taking the form of retarded development or abnormal movements; (3) epilepsy;


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Neurology_Adams. defects of the cranium, spine, and limbs, and of eyes, nose, ears, jaws, and skin; (2) disturbed motor function, taking the form of retarded development or abnormal movements; (3) epilepsy; and (4) developmental delay—mental retardation. The following discussion focuses on each of these clinical states.


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Neurology_Adams. A majority of the disorders in this group is the result of a genetic error, including those with a specific chromosomal abnormality. One has only to walk through an institution for the developmentally delayed to appreciate the remarkable number and diversity of dysmorphisms that attend abnormalities of the nervous system. Smith, in the third edition of his monograph on the patterns of human malformations, listed 345 distinctive syndromes; in the fourth edition (edited by KL Jones [1988]), many new ones were added. Indeed, a normal-appearing and severely cognitvely impaired individual stands out in such a crowd and will frequently be found to have an inherited metabolic defect or birth injury.


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Neurology_Adams. The intimate relationship between the growth and development of the cranium and that of the brain is likely responsible for many of the associations in maldevelopment. In embryonic life the most rapidly growing parts of the neural tube induce unique changes in, and at the same time are influenced by, the overlying mesoderm (a process termed induction); hence abnormalities in the formation of skull, orbits, nose, and spine are regularly associated with anomalies of the brain and spinal cord. During early fetal life the cranial bones and vertebral arches enclose and protect the developing brain and spinal cord. Throughout the period of rapid brain growth, as pressure is exerted on the inner table of the skull, the latter accommodates to the increasing size of the brain. This adaptation is facilitated by the membranous fontanels, which remain open until maximal brain growth has been attained; only then do they ossify (close). In addition, stature is apparently controlled by the nervous


Neurology_Adams

Neurology_Adams. facilitated by the membranous fontanels, which remain open until maximal brain growth has been attained; only then do they ossify (close). In addition, stature is apparently controlled by the nervous system, as shown by the fact that a majority of mentally retarded individuals are also stunted physically to a varying degree. Thus disorders of craniovertebral development assume importance not merely because of the physical disfigurement but also because they often reflect an abnormality of the underlying brain and spinal cord, whereby they become the main diagnostic signs of the maldevelopment.


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Neurology_Adams. Certain alterations in size and shape of the head in the infant, child, or even the adult, always signify a pathologic process that affected the brain before birth or in early infancy. Because the size of the cranium reflects the size of the brain, the tape measure is one of the most useful tools in pediatric neurology—no examination in a neurologically affected child is complete without a measurement of the circumference of the head. Graphs of head circumference in males and females from birth to 18 years of age were compiled by Nellhaus and are, of course, of great use to pediatricians. A newborn whose head circumference is below the third percentile for age and sex and whose fontanels are closed may be judged to have a developmental abnormality of the brain. A head that is normal in size at term but fails to keep pace with body length (microcephaly) reflects a later failure of growth and maturation of the cerebral hemispheres (microencephaly).


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Neurology_Adams. Enlargement of the Head (Macrocephaly) This can be caused by factors extrinsic to the brain tissue, such as hydrocephalus and hydrancephaly (as defined below), or excessive brain growth (megaloor macroencephaly; Table 37-2). The hydrocephalic head is distinguished by several features: frontal protuberance, or bossing; a tendency for the eyes to turn down so that the sclerae are visible between the upper eyelids and iris (sunset sign); thinning of the scalp and prominence of scalp veins; separation of the cranial sutures; and a “cracked pot” sound on percussion of the skull. Infantile hydrocephalus usually comes to medical attention because of an expanding cranium that exceeds normal dimensions for age. The usual causes are type II Chiari malformation, hereditary aqueductal stenosis, and prenatal infections, for example, toxoplasmosis. These disorders are discussed further on.


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Neurology_Adams. Hydranencephaly, defined as hydrocephalus and destruction or failure of development of parts of the cerebrum, is often associated with enlargement of the skull. When the cranium is transilluminated with a strong flashlight in a darkened room, the fluid-filled region of the cranium glows like a jack-o’-lantern. It can be caused by cerebral infarction from intrauterine vascular occlusion or by diseases such as toxoplasmosis and cytomegalovirus (CMV), which destroy parts of each cerebral hemisphere. The lack of brain tissue reduces resistance to intraventricular pressure, permitting great enlargement of both lateral ventricles; it is especially marked if there is an added hydrocephalic state because of interference with cerebrospinal fluid circulation. This type of destruction of the cerebral mantle in the embryonal period may lead to the formation of large brain defects with apposition of ventricular and pial surfaces (porencephaly) and subsequent failure of development of that part of


Neurology_Adams

Neurology_Adams. mantle in the embryonal period may lead to the formation of large brain defects with apposition of ventricular and pial surfaces (porencephaly) and subsequent failure of development of that part of the brain. Yakovlev and Wadsworth referred to the localized failure of evagination as schizencephaly and postulated that it was the result of a focal developmental defect in the wall of the cerebral mantle. They based their interpretation on the finding of malformed cortex in the margins of the defect (in distinction to porencephaly) but this might indicate only that the lesion preceded neuronal migration. Levine and coworkers attributed it to a destructive, possibly ischemic, lesion occurring in the first few weeks of gestation, at a time when neuronal migration was incomplete. However, at least some forms have been traced to genetic defects as detailed further on.


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Neurology_Adams. The macrocephalic head (a large head with normal or only slightly enlarged ventricles) may be indicative of an advancing metabolic disease that enlarges the brain, as in Alexander disease, Canavan spongy degeneration of infancy, and later phases of Tay-Sachs disease, all of which are described in Chap. 36. Agenesis of the corpus callosum, a common congenital defect, may be associated with macrocephaly and varying degrees of mental impairment, optic defects, and seizures. In a series of 56 patients with agenesis of the corpus callosum, Taylor and David reported the presence of epilepsy in 32 and varying degrees of developmental delay in 28; only 9 had no recognizable neurologic defects. Also noted was a high incidence of psychiatric disturbances in these patients. In such cases, CT and MRI reveal the characteristic “bat-wing” deformity of the ventricles. There is also asynchrony of electrical activity of the two cerebral hemispheres on the electroencephalogram (EEG). In a few of these


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Neurology_Adams. reveal the characteristic “bat-wing” deformity of the ventricles. There is also asynchrony of electrical activity of the two cerebral hemispheres on the electroencephalogram (EEG). In a few of these patients, an autosomal dominant inheritance was found (Lynn et al). Agenesis of the corpus callosum is also part of the Aicardi syndrome (see further on) and the Andermann syndrome, and it has been noted, without explanation, in some cases of nonketotic hyperglycinemia.


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Neurology_Adams. Subdural hematomas also enlarge the child’s head and cause bulging of the fontanels and separation of the sutures. The infant is usually irritable and listless, taking nourishment poorly. Infants and children with neurofibromatosis, osteogenesis imperfecta, and achondroplasia also have enlarged heads; in the last of these, some degree of hydrocephalus appears to be responsible. Ultrasonography, which can be performed in the prenatal and neonatal periods, is usually diagnostic in all these cranial enlargements. Also MRI and CT will disclose the size of the ventricles and the presence of subdural blood or fluid (hygroma).


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Neurology_Adams. Apart from patients with these pathologic states, there are individuals whose heads and brains are enlarged but who are normal in all other respects. Many of them come from families with large heads. Schreier and colleagues, who traced this condition through three generations of several families, declared it to be an autosomal dominant trait. This group represented 20 percent of 557 children referred to a clinic because of cranial enlargement, according to Lorber and Priestley.


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Neurology_Adams. Hemimegalencephaly This term refers to a marked enlargement of one cerebral hemisphere as a result of a developmental abnormality. The cortical gray matter and sometimes the basal ganglia are greatly increased in volume and weight. The cerebellum, brainstem, and spinal cord retain their normal dimensions. The cranium may be misshapen or enlarged but is normal in size in some cases. Rarely, the face and body are enlarged on the side of the enlarged hemisphere. The cortex of the giant hemisphere is thick and disorganized. Neurons are in disarray and some are enlarged; in some places the natural lamination of the cortex is effaced. Nothing is known about causation, but clearly embryogenesis has been deranged at the stage of neuroblast formation.


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Neurology_Adams. Clinically, these individuals are cognitively delayed and some have epilepsy. A degree of hemiparesis may be present but severe hemispheral neurologic deficits are generally not reported. However, hemimegalencephaly has been discovered at autopsy in a few individuals who had no mental or neurologic deficits.