Neurology_Adams

Neurology_Adams. At least three and possibly four closely related forms have been described. In mucolipidosis I (lipomucopolysaccharidosis), the morphologic features are those of gargoylism, with slowly progressive developmental impairment. Cherry-red spots in the maculae, corneal opacities, and ataxia have been noted in some patients. Vacuolation of lymphocytes, marrow cells, hepatocytes, and Kupffer cells in the liver and metachromatic changes in the sural nerve have been described.


Neurology_Adams

Neurology_Adams. In mucolipidosis II (I-cell disease), the most common of the mucolipidoses, there is usually an early onset of psychomotor delay, but in some cases this does not appear until the second or third decade of life. Abnormal facies and periosteal thickening (dysostosis multiplex, like that of GM1 gangliosidosis and Hurler disease) are characteristic. Gingival hyperplasia is prominent, and the liver and spleen are enlarged; but deafness is not found and corneal opacities are slower to develop. Tonic-clonic seizures are frequent in older patients. In most cases, death from heart failure occurs by the third to eighth year. There is a typical vacuolation of lymphocytes, Kupffer cells, and cells of the renal glomeruli. Bone marrow cells are also vacuolated and contain refractile cytoplasmic granules (hence the designation inclusion-cell, or I-cell, disease). A deficiency of several lysosomal enzymes required for the catabolism of mucopolysaccharides, glycolipids, and glycoproteins have been


Neurology_Adams

Neurology_Adams. (hence the designation inclusion-cell, or I-cell, disease). A deficiency of several lysosomal enzymes required for the catabolism of mucopolysaccharides, glycolipids, and glycoproteins have been found.


Neurology_Adams

Neurology_Adams. In mucolipidosis III (pseudo-Hurler polydystrophy), the biochemical abnormalities are like those of I-cell disease, but there are clinical differences. In the pseudo-Hurler type, symptoms do not appear until 2 years of age or later and are relatively mild. Retardation of growth, fine corneal opacities, and valvular heart disease are the major manifestations. Yet another variant, mucolipidosis IV, has been described (see Tellez-Nagel et al). Here, clouding of the corneas is noticed soon after birth, and profound developmental retardation is evident by 1 year of age. Skeletal deformities, enlargement of liver and spleen, seizures, or other neurologic abnormalities are notably lacking. Ultrastructural examination of conjunctival and skin fibroblasts has demonstrated lysosomal inclusions of material similar to lipids and mucopolysaccharides that remain to be further characterized.


Neurology_Adams

Neurology_Adams. This is another rare hereditary disorder with poorly differentiated symptomatology but with dysmorphic features of broad nose, depressed bridge, thick lips, and protruding tongue. The mutated gene codes for lysosomal alpha mannosidase. The onset is in the first 2 years, with Hurler-like facial and skeletal deformities, mental retardation, and slight motor disability. Corticospinal signs, loss of hearing, variable degrees of gingival hyperplasia, and spoke-like opacities of the lens (but no diffuse corneal clouding) may be present. The liver and spleen are enlarged in some cases. Radiographs show beaking of the vertebral bodies and poor trabeculation of long bones. Vacuolated lymphocytes and granulated leukocytes are present and aid in diagnosis. The urinary mucopolysaccharides are normal. Mannosiduria is diagnostic, caused by a defect in a-mannosidase. Mannose-containing oligosaccharides accumulate in nerve cells, spleen, liver, and leukocytes (see Kistler et al).


Neurology_Adams

Neurology_Adams. This also is a rare autosomal recessive disorder, with neurologic deterioration beginning usually at 12 to 15 months and progressing to spastic quadriplegia, decerebrate rigidity, severe psychomotor regression, and death within 4 to 6 years. The affected gene codes for alpha-l-fucosidase. Hepatomegaly, splenomegaly, enlarged salivary glands, thickened skin, excessive sweating, normal or typical gargoyle facies, beaking of the vertebral bodies, and vacuolated lymphocytes are the main features. A variant of this disease has been described with slower progression and survival into late childhood and adolescence and even into adult life (Ikeda et al). The latter type is characterized by mental and motor retardation, along with the corneal opacities, coarse facial features, skeletal deformities of gargoylism, and dermatologic changes of Fabry disease (angiokeratoma corporis diffusum), but no hepatosplenomegaly. The basic abnormality in both types is a lack of lysosomal l-fucosidase,


Neurology_Adams

Neurology_Adams. of gargoylism, and dermatologic changes of Fabry disease (angiokeratoma corporis diffusum), but no hepatosplenomegaly. The basic abnormality in both types is a lack of lysosomal l-fucosidase, resulting in accumulation of fucose-rich sphingolipids, glycoproteins, and oligosaccharides in cells of the skin, conjunctivae, and rectal mucosa.


Neurology_Adams

Neurology_Adams. This disease is characterized by the early onset of psychomotor regression; delayed, inadequate speech; severe behavioral abnormalities (bouts of hyperactivity mixed with apathy and hypoactivity or psychotic manifestations); progressive dementia; clumsy movements; corticospinal signs; corneal clouding (rare); retinal abnormalities and cataracts; coarse facies including low bridge of the nose, epicanthi, thickening of the lips and skin; enlarged liver; and abdominal hernias in some. Radiographs show minimal beaking of the vertebral bodies, and the blood lymphocytes are vacuolated.


Neurology_Adams

Neurology_Adams. The pattern of inheritance in this entire group of diseases, as already stated, is probably autosomal recessive. Diagnostic methods applicable to amniotic fluid and cells are being developed so that prenatal diagnosis will be possible, prompted often by the occurrence of the disease in an earlier child. Neurons are vacuolated rather than stuffed with granules, much like the lymphocytes and liver cells. The specific biochemical abnormalities, as far as they are known, are listed in Table 36-3. There is no specific treatment although bone marrow transplantation has been investigated.


Neurology_Adams

Neurology_Adams. This disorder is probably inherited as an autosomal recessive trait. The onset is in late infancy, after apparently normal earlier development. The main clinical findings are stunting of growth, evident by the second and third years; photosensitivity of the skin; microcephaly; retinitis pigmentosa, cataracts, blindness, and pendular nystagmus; nerve deafness; delayed psychomotor and speech development; spastic weakness and ataxia of limbs and gait; occasionally athetosis; amyotrophy with abolished reflexes and reduced nerve conduction velocities; wizened face, sunken eyes, prominent nose, prognathism, anhidrosis, and poor lacrimation (resembling progeria and bird-headed dwarfism). Some cases show calcification of the basal ganglia. The CSF is normal, and there are no diagnostic biochemical findings.


Neurology_Adams

Neurology_Adams. Pathologic examination reveals a small brain, striatal and cerebellar calcifications, leukodystrophy like that of Pelizaeus-Merzbacher disease, and a severe cerebellar cortical atrophy. The peripheral nerve changes are those of a primary segmental demyelination. It is now apparent that Cockayne syndrome, like ataxia-telangiectasia, is a consequence of mutations in genes that mediate DNA repair. At least three different forms of Cockayne syndrome have been identified, each with a different underlying mutation. Other Metabolic Diseases of Late Infancy and Early Childhood


Neurology_Adams

Neurology_Adams. Other Metabolic Diseases of Late Infancy and Early Childhood Globoid cell leukodystrophy (Krabbe), subacute necrotizing encephalomyelopathy (Leigh), and Gaucher disease may also begin in late infancy or early childhood. They are described in the preceding section of this chapter. Familial striatocerebellar calcification (Fahr disease) and Lesch-Nyhan disease may also become manifest in this age period, but they usually have a later onset and are therefore described with the diseases of later childhood in the section that follows.


Neurology_Adams

Neurology_Adams. This group of metabolic disorders presents many of the same diagnostic problems as those of early infancy. The flow chart in Fig. 36-6, which divides these disorders into dysmorphic, visceromegalic, and purely neurologic groups, is equally useful in the differential diagnosis of both age groups. As with the early infantile diseases, certain clusters of neurologic, skeletal, dermal, ophthalmic, and laboratory findings are highly distinctive and often permit the identification of a particular disease. These signs are listed below: 1. Evidence of involvement of peripheral nerves (weakness, hypotonia, areflexia, sensory loss, reduced conduction velocities) in conjunction with lesions of the CNS—metachromatic leukodystrophy, Krabbe leukodystrophy, neuroaxonal dystrophy, and Leigh disease 2. Ophthalmic signs a. Corneal clouding—several of the mucopolysaccharidoses (Hurler, Scheie, Morquio, Maroteaux-Lamy), mucolipidoses, tyrosinemia, aspartylglycosaminuria (rare) b. Cherry-red macular


Neurology_Adams

Neurology_Adams. 2. Ophthalmic signs a. Corneal clouding—several of the mucopolysaccharidoses (Hurler, Scheie, Morquio, Maroteaux-Lamy), mucolipidoses, tyrosinemia, aspartylglycosaminuria (rare) b. Cherry-red macular spot—GM2 gangliosidosis, GM1 gangliosidosis (half the cases), lipomucopolysaccharidosis, occasionally Niemann-Pick disease c. Retinal degeneration with pigmentary deposits—Jansky-Bielschowsky lipid storage disease, GM1 gangliosidosis, syndrome of sea-blue histiocytes d. Optic atrophy and blindness—metachromatic leukodystrophy, neuroaxonal dystrophy e. Cataracts—Marinesco-Sjögren syndrome, Fabry disease, mannosidosis f. Ocular apraxia—ataxia-telangiectasia, Niemann-Pick disease g. Impairment of vertical eye movements—late infantile Niemann-Pick disease, juvenile dystonic lipidosis, sea-blue histiocyte syndrome, Wilson disease h. Jerky eye movements, limited abduction—late infantile Gaucher disease 3. Extrapyramidal signs—late-onset Niemann-Pick disease (rigidity, abnormal postures),


Neurology_Adams

Neurology_Adams. histiocyte syndrome, Wilson disease h. Jerky eye movements, limited abduction—late infantile Gaucher disease 3. Extrapyramidal signs—late-onset Niemann-Pick disease (rigidity, abnormal postures), juvenile dystonic lipidosis (dystonia, choreoathetosis), Rett, ataxia- telangiectasia (athetosis), Sanfilippo mucopolysaccharidosis, type I glutaric acidemia, Wilson disease, Segawa dopa-responsive dystonia 4. Facial dysmorphism—Hurler, Scheie, Morquio, and Maroteaux-Lamy forms of mucopolysaccharidosis, aspartylglycosaminuria, mucolipidoses, GM1 gangliosidosis, mannosidosis, fucosidosis (some cases), multisulfatase deficiencies (Austin), some mitochondrial disorders 5. Dwarfism, spine deformities, arthropathies—Hurler, Morquio, and other mucopolysaccharidoses, Cockayne 6. Enlarged liver and spleen—Niemann-Pick disease, Gaucher disease, all mucopolysaccharidoses, fucosidosis, mucolipidoses, GM1 gangliosidosis 7. Alterations of skin—photosensitivity (Cockayne syndrome and one form of


Neurology_Adams

Neurology_Adams. and spleen—Niemann-Pick disease, Gaucher disease, all mucopolysaccharidoses, fucosidosis, mucolipidoses, GM1 gangliosidosis 7. Alterations of skin—photosensitivity (Cockayne syndrome and one form of porphyria); papular nevi and angiokeratoma (Fabry disease, fucosidosis); telangiectasia of ears, conjunctiva, chest (ataxia- telangiectasia); ichthyosis (Sjögren-Larsen disease, caused by fatty alcohol dehydrogenase deficiency); plaque-like lesions in Hunter syndrome 8. Beaked thoracolumbar vertebrae—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis; aspartylglycosaminuria, multiple sulfatase deficiencies 9. Deafness—mucopolysaccharidoses, mannosidosis, Cockayne syndrome 10. Hypertrophied gums—mucolipidoses, mannosidosis 11. Vacuolated lymphocytes—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis 12. Granules in neutrophils—all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis, multiple sulfatase deficiencies


Neurology_Adams

Neurology_Adams. One of the most difficult diagnostic problems in this age period is distinguishing neuroaxonal dystrophy, metachromatic leukodystrophy, subacute necrotizing encephalomyelopathy (Leigh disease), some cases of lipofuscinosis, and the late form of GM1 gangliosidosis. In none of these diseases is the clinical picture entirely stereotyped. The clinician is aided in identifying neuroaxonal dystrophy by noting an onset, at 1 to 2 years of age, of severe hypotonia with retained reflexes and Babinski signs, early visual involvement without retinal changes, lack of seizures, normal CSF, physiologic evidence of denervation of muscles, fast-frequency EEG, normal CT, but the definitive diagnosis is established by the genetic signature of each. Metachromatic leukodystrophy can be excluded if the CSF protein is normal and if nerve conduction velocities are normal. Similar criteria enable one to rule out GM1 gangliosidosis. Mitochondrial disorders (Leigh disease) may begin at the same age; in many


Neurology_Adams

Neurology_Adams. protein is normal and if nerve conduction velocities are normal. Similar criteria enable one to rule out GM1 gangliosidosis. Mitochondrial disorders (Leigh disease) may begin at the same age; in many cases lactic acidosis and pyruvate decarboxylase defect will corroborate the diagnosis. Mitochondrial genetic testing allows definitive diagnosis in most cases, as described in a later section. Also in Leigh disease, imaging of the brain may disclose hypodense lesions in the basal ganglia and brainstem, in contrast to the normal CT in neuroaxonal dystrophy. In metachromatic leukodystrophy, the cerebral white matter shows a diffusely decreased attenuation and the MR images are striking. Lipofuscinosis cannot always be diagnosed accurately; curvilinear bodies in nerve twigs and in the endothelial cells in skin biopsies and the gene mutations are the most informative laboratory tests.


Neurology_Adams

Neurology_Adams. Unavoidably, one must refer here to certain inherited metabolic diseases already described that permit survival into late childhood and adolescence, as well as to diseases that begin in adolescence or adult life after a normal childhood. There is a tendency for them to be less severe and less rapidly progressive, an attribute shared by many diseases with a dominant mode of inheritance. Nonetheless, there are diseases, such as Wilson disease, in which the onset of neurologic symptoms occurs after the tenth year and in rare instances after the thirtieth year, and the mode of inheritance is autosomal recessive. However, in the latter instance, the basic abnormality has existed since early childhood in the form of a ceruloplasmin deficiency with early cirrhosis and splenomegaly; only the neurologic disorder is of late onset. This brings us to another principle: The pathogenesis of the cerebral lesion may involve a factor or factors once removed from the underlying biologic abnormality.


Neurology_Adams

Neurology_Adams. Genetic heterogeneity poses another problem with respect to both the clinical and biochemical findings. It is well established that a single clinical phenotype, such as the one seen in Hurler disease, can be the expression of a number of different alleles of a given gene mutation. Conversely, a number of different clinical phenotypes may be based on different degrees of the same enzyme deficiency. One must, therefore, not rely solely on clinical appearances for diagnosis but always combine them with genetic studies for confirmation.


Neurology_Adams

Neurology_Adams. The diseases in this category are probably of greater interest to neurologists than the preceding ones, for they more consistently cause familiar neurologic abnormalities such as epilepsy, polymyoclonus, dementia, cerebellar ataxia, choreoathetosis, dystonia, tremor, spastic-ataxic paraparesis, blindness, deafness, and stroke. These manifestations appear much the same in late childhood and adolescence as they do in adult life, and the neurologist whose experience has been mainly with adult patients feels quite comfortable with them.


Neurology_Adams

Neurology_Adams. Diseases in this age period have a diversity of manifestations, yet each disease tends to have a certain characteristic pattern of neurologic expression, as though the pathogenetic mechanism were acting more selectively on particular systems of neurons. Such affinities between the disease process and certain anatomic structures raise the question of pathoclisis, that is, specific vulnerability of particular neuronal systems to certain morbid agents. Stated another way, for each disease there is a common and relatively stereotyped clinical syndrome and a small number of variants; conversely, certain other symptoms and syndromes are rarely observed with a given disease. At the same time, however, it is clear that more than one disease may cause the same syndrome.


Neurology_Adams

Neurology_Adams. In deference to these principles, the diseases in this section are grouped according to their most common mode of clinical expression, as follows: 1. The progressive cerebellar ataxias of childhood and adolescence 2. The familial polymyoclonias and epilepsies 3. Extrapyramidal syndromes of parkinsonian type 4. The syndrome of dystonia and generalized choreoathetosis 5. The syndrome of bilateral hemiplegia, cerebral blindness and deafness, and other manifestations of focal cerebral disorder 6. Strokes in association with inherited metabolic diseases 7. Metabolic polyneuropathies 8. Personality changes and behavioral disturbances as manifestations of inherited metabolic diseases


Neurology_Adams

Neurology_Adams. It is advantageous to be familiar with these groupings. Like the age of onset and the distinctions between gray and white matter diseases of earlier onset, this scheme facilitates clinical diagnosis. One word of caution: It is a mistake to assume that the diseases in these categories affect one and only one particular part of the nervous system or to assume that they are exclusively neurologic. Once the biochemical and genetic abnormalities are discovered, they are usually found to implicate cells of certain nonneurologic tissues as well; whether or not the effects of such involvement become symptomatic is often a quantitative matter. Also, one encounters mixed neurologic syndromes in which tremor, myoclonus, cerebellar ataxia, seizures, and choreoathetosis are present in various combinations; it is then difficult to decide whether a movement disorder is of one type or another. The Progressive Cerebellar Ataxias of Late Childhood and Adolescence


Neurology_Adams

Neurology_Adams. In the preceding section, it was pointed out that there is a large group of diseases, some with a known metabolic basis, in which an acute, episodic, or chronic cerebellar ataxia becomes manifest in early childhood. Here the discussion of the cerebellar ataxias is continued, with reference to those forms that begin in late childhood and adolescence. In these later age periods, the number of ataxias of proven metabolic type diminishes markedly. Most of them, of chronic progressive type, are part of the late-onset lipid storage diseases. Of the other cerebellar ataxias of late childhood and adolescence, only the Bassen-Kornzweig acanthocytosis, late-onset GM2 gangliosidosis, Refsum disease, ataxia-telangiectasia, and a genetic fault in vitamin E metabolism fall into the category of truly metabolic disease. Refsum disease is so clearly a polyneuropathy (cerebellar features only in exceptional cases) that it is presented in Chap. 43. Ataxia-telangiectasia is usually encountered in late


Neurology_Adams

Neurology_Adams. metabolic disease. Refsum disease is so clearly a polyneuropathy (cerebellar features only in exceptional cases) that it is presented in Chap. 43. Ataxia-telangiectasia is usually encountered in late childhood, but the ataxia may begin as early as the second year of life; therefore it has been described in the preceding section with the ataxias of early childhood.


Neurology_Adams

Neurology_Adams. There are many other conditions of metabolic type in which cerebellar ataxia figures in the clinical picture. Some of these are associated with polymyoclonus and cherry-red macular spots (mainly sialidosis or a-neuraminidase deficiency; see below). Cerebellar ataxia is a prominent feature of Unverricht-Lundborg (Baltic) disease and Lafora-body disease (see Chap. 15). The Cockayne syndrome and Marinesco-Sjögren disease persist into later childhood and adolescence or may even have their onset in this later period. In cerebrotendinous xanthomatosis (see further on), spastic weakness and pseudobulbar palsy are combined with cerebellar ataxia. Prader-Willi children have a broad-based gait and are clumsy in addition to being obese, genitally deficient, and diabetic. Several diseases associated with hyperuricemia implicate defective purine and pyrimidine metabolism and fit into this category; the enzymatic defect of Lesch-Nyhan disease is not present, however. Marsden and coworkers (1982)


Neurology_Adams

Neurology_Adams. with hyperuricemia implicate defective purine and pyrimidine metabolism and fit into this category; the enzymatic defect of Lesch-Nyhan disease is not present, however. Marsden and coworkers (1982) have observed cerebellar ataxia beginning in late childhood as an expression of adrenoleukodystrophy (see below). The familial syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) caused by a mitochondrial genome mutation that impairs ATP synthase can cause ataxia and closely mimic the Marinesco-Sjögren syndrome.


Neurology_Adams

Neurology_Adams. Doubtless, many of the progressive forms of cerebellar ataxia now classified as degenerative and described in Chap. 38 will be proved to have an underlying biochemical or similar subcellular pathogenesis and will logically fall in place here, with the metabolic diseases. At present, when faced with a progressive ataxia of cerebellar type, even in a young adult, the reader should consult both this chapter and Chap. 38. The acute forms of cerebellar ataxia that occur in late childhood and adolescence are essentially nonmetabolic, being traceable to postinfectious encephalomyelitis (see Chap. 35) or to postanoxic, postmeningitic, or posthyperthermic states and certain drug intoxications. With relatively pure cerebellar ataxias of this age period, postinfectious cerebellitis, cerebellar tumors (medulloblastomas, astrocytomas, hemangioblastomas, and ganglioneuromas of Lhermitte-Duclos) should be considered in the differential diagnosis. MRI establishes the correct diagnosis.


Neurology_Adams

Neurology_Adams. Bassen and Kornzweig, in 1950, first described this rare metabolic disease of lipoproteins that causes ataxia, sensory neuropathy, and acanthocytic deformity of red cells. It excited great interest, for it gave promise of a breakthrough into a hitherto obscure group of “degenerative” disorders. The inheritance is autosomal recessive and the mutation affects an apolipoportien transfer protein that impairs the ability to produce very low density lipoprotein (VLDL). The initial symptoms, occurring between 6 and 12 years (range: 2 to 20 years), are weakness of the limbs with areflexia and ataxia of sensory (tabetic) type, to which a cerebellar component is added later (the first two aspects relating to a peripheral neuropathy are discussed in


Neurology_Adams

Neurology_Adams. Chap. 43). Steatorrhea, raising the suspicion of celiac disease (sprue), often precedes the appearance of a weak and unsteady gait. Later, in more than half the patients, vision may fail because of retinal degeneration (similar to retinitis pigmentosa). Kyphoscoliosis, pes cavus, and Babinski signs are other elements in the clinical picture. The neurologic disorder is relatively slowly progressive—by the second to third decade, the patient is usually bedridden. The diagnostic laboratory findings are spiky or thorny red blood cells (acanthocytes), low sedimentation rate, and a marked reduction in the serum of low-density lipoproteins (LDL cholesterol, phospholipid, and b- lipoprotein levels are all subnormal). The detection of the characteristic malformed red cells requires special handling of a wet preparation of blood diluted in isotonic saline and experienced microscopists. Despite the abnormal red cells, anemia is not found.


Neurology_Adams

Neurology_Adams. Pathologic study has revealed the presence of foamy, vacuolated epithelial cells in the intestinal mucosa (causing absorption block); diminished numbers of myelinated nerve fibers in sural nerve biopsies, depletion of Purkinje and granule cells in all parts of the cerebellum; loss of fibers in the posterior columns and spinocerebellar tracts; loss of anterior horn and retinal ganglion cells and of muscle fibers and fibrosis of the myocardium. It has been proposed that the basic defect is an inability of the body to synthesize the proteins of cell membranes because of the impaired absorption of fat through the mucosa of the small intestine. Vitamin E deficiency, which is malabsorbed, may be a pathogenic factor, because the administration of a low-fat diet and high doses of vitamins A and E may prevent progression of the neurologic disorder according to Illingworth and colleagues, but the pathophysiology appears to be far more complex.


Neurology_Adams

Neurology_Adams. Often mentioned in the context of acanthocytosis is a related rare condition, McLeod syndrome, in which progressive muscular atrophy, seizures, involuntary movements, and elevated serum creatine kinase (CK) are combined in various configurations. The acanthocytosis in this disease is the result of an abnormality of the red cell surface Kell antigen (Kx, coding for the protein XK).


Neurology_Adams

Neurology_Adams. This is another rare but well-defined disease resembling abetalipoproteinemia, in which there is hypocholesterolemia, acanthocytosis of red blood corpuscles, retinitis pigmentosa, and a pallidal atrophy (HARP syndrome). Inheritance is autosomal dominant, and heterozygotes may exhibit some part of the syndrome. Many cases are caused by mutations in the gene encoding b-lipoprotein B. Fat droplets may be seen in the jejunal mucosa, indicating malabsorption. Cases have been reported from Europe, Asia, and the United States. Treatment consists of restriction of dietary fat and supplements of vitamin E. Several genes have been implicated. An adult form of acanthocytosis unrelated to the above several diseases is associated with hereditary chorea and dystonia but evidence of lipid malabsorption is lacking. This disease is described in Chap. 38.


Neurology_Adams

Neurology_Adams. As stated in Chap. 4, the term myoclonus is applied to many conditions that are not at all alike but share a single clinical feature—a multitude of exceedingly brief, random, arrhythmic twitches of parts of muscles, entire muscles, or groups of muscles. Myoclonic jerks differ from chorea by virtue of their brevity (15 to 50 ms). Notably, both phenomena are considered to be symptomatic of “gray matter” diseases (“polioencephalopathies”). Myoclonus or polymyoclonus may, in certain conditions, stand alone as a relatively pure syndrome. In most other cases, it is mixed with epilepsy or athetosis and dystonia, discussed further on. Most often, myoclonus is associated with cerebellar ataxia; thus it is being considered here, with the progressive cerebellar ataxias. The many acquired forms of polymyoclonus, such as subacute sclerosing panencephalitis, were mentioned in Chap. 4. This chapter is concerned only with those of known or presumed metabolic origin.


Neurology_Adams

Neurology_Adams. Five major categories of familial polymyoclonus of late childhood and adolescence have been delineated: (1) Laforaor amyloid-body type, (2) juvenile cerebroretinal degeneration, (3) cherry-red spot myoclonus (sialidosis or a-neuraminidase deficiency), (4) mitochondrial encephalopathy, and (5) a more benign degenerative disease (dyssynergia cerebellaris myoclonica of Hunt). Familial myoclonus may also be a prominent feature of two other diseases—GM2 gangliosidosis and Gaucher disease—which occasionally have their onset in this age period.


Neurology_Adams

Neurology_Adams. This disease, which is inherited as an autosomal recessive trait, was first identified by Lafora in 1911 on the basis of the large basophilic cytoplasmic bodies that were found in the dentate, brainstem, and thalamic neurons. These inclusions have been shown by Yokoi and colleagues to be composed of a glucose polymer (polyglucosan; abnormally shaped glycogen molecules). Possibly some of the cases of familial myoclonus epilepsy reported by Unverricht and by Lundborg were of this type, but because these authors provided no pathologic data, one cannot be sure. The disease is the result of mutations in EPM2A or the NHLRC1, which code for laforin and malin, which regulate glycogen production.


Neurology_Adams

Neurology_Adams. Beginning in late childhood and adolescence (11 to 18 years) in a previously normal individual, the disease announces itself by a seizure, a burst of myoclonic jerks, or both. In about half the cases there are focal (often occipital) seizures. The illness may at first be mistaken for ordinary epilepsy, but within a few months it becomes evident that something far more serious is occurring. The myoclonus becomes widespread and can be evoked as a startle by noise, an unexpected tactile stimulus (even the tap of a reflex hammer), and also by excitement, or certain sustained motor activities. An evoked train of myoclonic jerks may progress to a generalized seizure with loss of consciousness. As the disease advances, the myoclonus interferes increasingly with the patient’s motor activities until voluntary function is seriously impaired. Speech may be marred, much as it is in chorea. Close examination may also reveal an alteration in muscle tone and a slight degree of cerebellar ataxia. At


Neurology_Adams

Neurology_Adams. voluntary function is seriously impaired. Speech may be marred, much as it is in chorea. Close examination may also reveal an alteration in muscle tone and a slight degree of cerebellar ataxia. At this time, or even before the onset of myoclonus and seizures, the patient may experience visual hallucinations or exhibit irritability, odd traits of character, uninhibited or impulsive behavior, and, ultimately, progressive failure in all cognitive functions. Deafness has been an early sign in a few cases. Rigidity or hypotonia, impaired tendon reflexes, acrocyanosis, and rarely corticospinal tract signs are late findings. Finally, the patient becomes cachectic and bedfast and succumbs to intercurrent infection. Most do not survive beyond their twenty-fifth birthday. Nonetheless there are isolated reports of Lafora-body disease in which symptoms began as late as age 40 years, with death as late as age 50 years. These late cases may constitute a separate genetic type.


Neurology_Adams

Neurology_Adams. No biochemical abnormalities of the blood, urine, or CSF have been detected. The genetics have been mentioned and testing can be used to affirm the diagnosis. Skin biopsy, showing Lafora bodies, may be helpful ion diagnosis, especially if none of the known mutations is detected. The EEG shows diffuse slow waves and spikes as well as bursts of focal or multifocal discharges. Altered hepatocytes with homogeneous PAS-positive bodies that displace the nuclei have been observed in both the presymptomatic and symptomatic stages of the disease. These inclusions have been seen in skin and liver biopsies, even though liver function tests were normal. Neuropathologic examinations have shown a slight loss of granule and Purkinje cells and loss of neurons in the dentate nuclei, inner segment of globus pallidus, and cerebral cortex in addition to the Lafora bodies. The latter may also be seen in the retina, cerebral cortex, myocardium, and striated muscles. Antiepileptic drugs, especially


Neurology_Adams

Neurology_Adams. of globus pallidus, and cerebral cortex in addition to the Lafora bodies. The latter may also be seen in the retina, cerebral cortex, myocardium, and striated muscles. Antiepileptic drugs, especially methsuximide and valproic acid, help in the control of the seizures but have no effect on the basic process.


Neurology_Adams

Neurology_Adams. Juvenile Ceroid Lipofuscinosis (Batten Disease,


Neurology_Adams

Neurology_Adams. As stated earlier, this is one of the most variable forms of the lipidoses. The salient clinical features of the later-onset types are severe myoclonus, seizures, and visual loss. In the juvenile type, the first lesions are seen in the maculae; they appear as yellow-gray areas of degeneration and stand in contrast to the cherry-red spot and the encircling white ring of Tay-Sachs disease. At first, the particles of retinal pigment are fine and dust-like; later they aggregate to resemble more the bone-corpuscular shapes of retinitis pigmentosa. The liver and spleen are not enlarged and there are no osseous changes. The usual development of these and other manifestations of the disease were outlined by Sjögren, who studied a large number of the late infantile and juvenile types of cases in Sweden. He divided the illness into stages, the first of which was visual impairment, followed approximately sequentially by generalized seizures and myoclonus, often with irritability, poor control of


Neurology_Adams

Neurology_Adams. He divided the illness into stages, the first of which was visual impairment, followed approximately sequentially by generalized seizures and myoclonus, often with irritability, poor control of emotions, and stuttering, jerky speech at 2 years, then gradual intellectual deterioration to which were added cerebellar ataxia and intention tremor, in this respect coming to resemble Wilson disease. Finally, the patient lies curled up in bed, blind and speechless, with strong extensor plantar reflexes, occasionally adopting dystonic postures. Life usually ends in 10 to 15 years.


Neurology_Adams

Neurology_Adams. As mentioned earlier, the genetic underpinnings of this group of lipidoses have been determined for most of the subtypes of neuronal ceroid lipofuscinosis (see Mole and Cotman). These genes have been designated CLN 1 through 9 and they embody over 100 different mutations. Batten disease is caused by CLN3, which codes battenin, a lysosomal transmembrane protein but its function is currently not known. In the early stages, the EEG pattern of random, high-voltage, triphasic waves is diagnostic; later, as the seizures and myoclonic jerks become less frequent and finally cease, only delta waves remain. The electroretinographic waveforms are lost once the retina is affected. The lateral ventricles are slightly dilated on CT and on MRI. The CSF is normal. Diagnosis can be confirmed by the appearance of inclusions of a curvilinear “fingerprint” pattern in electron microscopic study of biopsy material, particularly of the eccrine sweat glands of the skin.


Neurology_Adams

Neurology_Adams. The type of ceroid lipofuscinosis that develops later (15 to 25 years of age or older) is often unattended by visual or retinal changes and is even slower in its evolution. It is presented here for ease of exposition, but it becomes relevant mostly in relation to dementing illness in young adulthood. Personality change or dementia is one constellation, the other being myoclonic seizures with subsequent dementia and even later pyramidal and extrapyramidal signs. As the disease progresses, cerebellar ataxia, spasticity, rigidity or athetosis, or mixtures thereof, are combined with dementia. As a reflection of the variability of the clinical presentation, a recent patient of ours had vague visual difficulties at age 51 years and evolved a spastic quadriparesis with disinhibited behavior over 5 years. Additional comments regarding the unusual presentations of this disease can be found further on, under “Adult Forms of Inherited Metabolic Disease.” van Bogaert pointed out to our colleague


Neurology_Adams

Neurology_Adams. 5 years. Additional comments regarding the unusual presentations of this disease can be found further on, under “Adult Forms of Inherited Metabolic Disease.” van Bogaert pointed out to our colleague R.D. Adams that relatives of these patients may have retinal changes without neurologic accompaniments. The mutations that give rise to this and related disorders are mentioned above. The difficulties in making the diagnosis in adults with dementia is discussed by Berkovic and coworkers (2016).


Neurology_Adams

Neurology_Adams. Of all the lipidoses, these cerebroretinal degenerations had for decades defied unifying biochemical definition. Our understanding of these diseases is difficult because they embody both enzymatic defects and structural protein dysfunctions. In a few of the early childhood types, mutations of one of several lysosomal enzymes have been identified. Zeman and coworkers showed that the cytoplasmic inclusions are autofluorescent and give a positive histochemical reaction for both ceroid and lipofuscin, but this material is not different biochemically from the lipid substance that accumulates in aging cells. In addition to the presence of curvilinear bodies in the cytoplasm of neurons and other tissues, some in a fingerprint pattern, there is a reduction in type II synapses in the distal parts of the axon. All these changes precede nerve cell loss. The genetics (CLN mutations) have been discussed above.


Neurology_Adams

Neurology_Adams. Instances of the recessive type of GM2 gangliosidosis may have their onset in this age period. Twenty-four such cases (from 20 kindreds) were collected from the medical literature by Meek and coworkers. Ataxia and dysarthria were frequently the presenting symptoms, followed by dementia, dysphagia, spasticity, dystonia, seizures, and myoclonus. Degeneration of anterior horn cells with progressive muscular atrophy may be a feature, although this is more characteristic of the adult-onset variety (see further on). Atypical cherry-red spots are observed in some patients. The biochemical abnormality, that is, a deficiency of hexosaminidase A, is the same as in Tay-Sachs disease, but not as severe or as extensive. Progression of the disease is slow, over a period of many years.


Neurology_Adams

Neurology_Adams. A type of Gaucher disease is occasionally encountered in which seizures, severe diffuse myoclonus, supranuclear gaze disorders (slow saccades, saccadic and pursuit horizontal gaze palsies), and cerebellar ataxia begin in late childhood, adolescence, or adult life. The course is slowly progressive. The intellect is relatively spared. The spleen is enlarged. The pathologic and biochemical abnormalities are the same as those of Gaucher disease of earlier onset. Type 1, α-Neuraminidase Deficiency; NEU1 Mutation) This is a genetically distinct class of disease characterized by the storage in nervous tissue of sialylated glycopeptides. It is caused by a deficiency of neuraminidase, a lysosomal enzyme. In some of the patients, the onset was in late childhood or adolescence, and in others, even later. In addition to the patients initially reported by Rapin and coworkers, a few dozen similar cases have appeared in the medical literature.


Neurology_Adams

Neurology_Adams. In the cases described by Rapin and colleagues the first findings were visual impairment with cherry-red macular spots, similar to those seen in Tay-Sachs disease and less consistently in GM1 gangliosidosis, Niemann-Pick disease, and metachromatic leukodystrophy. In one case, there was severe episodic pain in the hands, legs, and feet during hot weather, reminiscent of Fabry disease. Polymyoclonus followed within a few years and, together with cerebellar ataxia, disabled the patients. Mental function remained relatively normal. Liver and spleen were not enlarged, but storage material was found in the Kupffer cells, neurons of the myenteric plexus, and cerebral neurons, and presumably in cerebellar and retinal neurons.


Neurology_Adams

Neurology_Adams. The cases reported by Thomas and colleagues were young adults, all members of one generation, who had developed dysarthria, intention myoclonus, cerebellar ataxia, and cherry-red macular lesions. Like the cases of Rapin and coworkers, the heredity was autosomal recessive. There was urinary excretion of sialylated oligosaccharides and a sialidase deficiency in cultured fibroblasts. The two patients described by Tsuji and associates (1982) are noteworthy in that they were of age 50 and 30 years. In addition to the macular lesions, polymyoclonia, and cerebellar ataxia, there were gargoyle-like facial features, corneal opacities, and vertebral dysplasia. These patients also had a neuraminidase (partial beta-galactosidase) deficiency.


Neurology_Adams

Neurology_Adams. This progressive degeneration of the cerebellar-dental efferent system was originally described by Ramsay Hunt under the title of dyssynergia cerebellaris myoclonica but no has an uncertain meaning. It was classified as Ramsay Hunt syndrome type 1 to distinguish from the more common herpes zoster oticus syndrome that also carries his name. It probably should be considered a rare form of spinocerebellar ataxia. The onset is in late childhood; both sexes are vulnerable, and it probably has more than one cause. In Hunt’s case, a progressive ataxia was accompanied by a striking degree of action myoclonus. Seizures are infrequent, and the intellect is relatively preserved. The neurons of the dentate nuclei and their ascending and descending brainstem axons gradually disappear. Berkovic and associates studied 84 cases of polymyoclonus, 13 of which conformed to the Hunt syndrome. Of these, 9 proved to have a mitochondrial encephalomyopathy. However, there are other reports (Tassinari et al)


Neurology_Adams

Neurology_Adams. studied 84 cases of polymyoclonus, 13 of which conformed to the Hunt syndrome. Of these, 9 proved to have a mitochondrial encephalomyopathy. However, there are other reports (Tassinari et al) in which muscle biopsies showed no mitochondrial abnormalities. In the series of 30 cases reported by Marsden and coworkers (1990) the onset was usually before the age of 21 years. Cortical electrographic discharges were found to precede each myoclonic twitch (cortical myoclonus). A biochemically supported diagnosis could not be made in nearly half of their cases.


Neurology_Adams

Neurology_Adams. Another mitochondrial disorder, the myoclonic epilepsy ragged red fiber (MERRF) disease, begins in the second decade or later with myoclonus and ataxia and enters into the differential diagnosis of this group of diseases. The mitochondrial diseases as a group are considered in the last part of this chapter. Epilepsies of Hereditary Metabolic Disease (See Chap. 15)


Neurology_Adams

Neurology_Adams. Epilepsies of Hereditary Metabolic Disease (See Chap. 15) Convulsive seizures may complicate nearly all hereditary metabolic diseases. The seizures may occur at all ages but more frequently in the neonate, infant, or young child than in the older child or adolescent. The seizures take many forms, as discussed in Chap. 15. Most often they are generalized grand mal or partial types; typical petit mal probably does not occur. Some diseases may cause focal seizures, simple or complex partial, before becoming generalized. The combination of series of polymyoclonic jerks progressing to a generalized motor seizure is always highly suggestive of one of the hereditary metabolic diseases. Another highly significant form of presentation is with sensory evoked seizures.


Neurology_Adams

Neurology_Adams. In the typical parkinsonian syndrome, with features of rigidity, tremor, and bradykinesia, strength remains relatively intact and corticospinal signs are absent, but effectiveness of movement is nonetheless impaired by the patient’s disinclination to use the affected parts (hypoor akinesia), by slowness (bradykinesia), and by rigidity and tremor (see Chap. 4). Other clinical syndromes in this category include choreoathetosis, dystonia, and spasms of gaze. When the parkinsonian syndrome or some component thereof has its onset in middle or late adult life, it usually indicates idiopathic Parkinson disease or related multisystem forms. The development of such an extrapyramidal motor disorder in late childhood and adolescence instead suggests Wilson disease, juvenile Huntington disease, Hallervorden-Spatz disease, and the Segawa type of l-dopa–responsive dystonia as well as other so-called parkin mutations (see Chap. 38).


Neurology_Adams

Neurology_Adams. Hepatolenticular Degeneration (Wilson Disease, Westphal-Strümpell Pseudosclerosis, ATP7B Mutation) Wilson’s description of “Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver” appeared in 1912. A similar neurologic disorder had been described previously by Gowers (1906) under the title of “tetanoid chorea” and by Westphal (1883) and Strümpell (1898), as “pseudosclerosis.” None of these authors, however, recognized the association with cirrhosis. The clinical studies of Hall (1921) and the histopathologic studies of Spielmeyer (1920), who reexamined sections from the liver and brain of Westphal’s and


Neurology_Adams

Neurology_Adams. Strümpell’s cases, clearly established that the pseudosclerosis described by these authors was the same disease as the one that had been described by Wilson. Interestingly, none of these authors, including Wilson, noticed the golden-brown (Kayser-Fleischer) corneal ring, the one pathognomonic sign of the disease. Rumpell had demonstrated the greatly increased copper content of the liver and brain as early as 1913, but this discovery was generally ignored until Mandelbrote (1948) found, quite by chance, that the urinary excretion of copper was greatly increased in patients with Wilson disease and that it was increased even more after the intramuscular administration of the chelating agent British anti-Lewisite (BAL). In 1952, Scheinberg and Gitlin discovered that ceruloplasmin, the serum protein that binds copper, is reduced in this disease (see reviews by Scheinberg and Sternlieb for a full historical account and references). Denny-Brown demonstrated a recession of symptoms after


Neurology_Adams

Neurology_Adams. protein that binds copper, is reduced in this disease (see reviews by Scheinberg and Sternlieb for a full historical account and references). Denny-Brown demonstrated a recession of symptoms after prolonged treatment with BAL.


Neurology_Adams

Neurology_Adams. The prevalence of the disease cannot be stated exactly, but is on the order of 1 per 50,000 to 1 per 100,000 of the general population. The disease is transmitted as an autosomal recessive trait. The gene, called ATP7B (homologous with the ATP7A gene, which is defective in Menkes disease), codes for a membrane-bound, copper-binding ATPase. One of the curious aspects of the genetics of the disease is the multitude of mutations within this gene that give rise to the disease and no one mutation accounts for more than 30 percent of cases. Inadequate functioning of the ATPase enzyme in some way reduces excretion of copper in the bile. As noted further on, liver transplantation halts progression of the disease, indicating that the primary biochemical effect of the mutation is in the liver rather than the nervous system.


Neurology_Adams

Neurology_Adams. The mutation gives rise to two fundamental disturbances of copper metabolism: (1) a reduced rate of incorporation of copper into ceruloplasmin and (2) a reduction in biliary excretion of copper. The deposition of copper in tissues is the cause of virtually all the manifestations of the disease—cirrhosis, hemolytic anemia, renal tubular changes, Kayser-Fleischer rings, and, in all likelihood, the cerebral damage—as discussed below.


Neurology_Adams

Neurology_Adams. The onset of neurologic symptoms is usually in the second, and less often in the third, decade, but rarely beyond that time. Half of patients are symptomatic by age 15 years, but exceptional cases, including two under our care, had their first clinical manifestations as late as their midfifties. In all instances the initial event is a deposition of copper in the liver, leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly (Scheinberg and Sternlieb). In childhood, the liver disorder often takes the form of attacks of jaundice, unexplained hepatosplenomegaly, or hypersplenism with thrombocytopenia and bleeding. Rarely is there clear evidence of cirrhosis alone. The hepatic abnormalities may be asymptomatic (except for elevated serum transaminases), in which case the initial clinical presentation is neurologic. In some instances, a hemolytic anemia or, less often, renal tubular acidosis may first draw attention to the disease.


Neurology_Adams

Neurology_Adams. The first neurologic manifestations are most often extrapyramidal with a proclivity to affect the oropharyngeal musculature. The typical presentations are tremor of a limb or of the head and generalized slowness of movement (i.e., a parkinsonian syndrome); or slowness of movement of the tongue, lips, pharynx, larynx, and jaws, resulting in dysarthria, dysphagia, and hoarseness; or there may be slowness of finger movement and occasionally choreic movements or dystonic postures of the limbs. Often the mouth is held slightly open in the early stage of the disease. Exceptionally, an abnormality of behavior (argumentativeness, impulsiveness, excessive emotionality, depression, delusions) or a gradual impairment of intellectual faculties precedes other neurologic signs by a year or more (see Starosta-Rubinstein et al).


Neurology_Adams

Neurology_Adams. As the disease progresses, the “classic syndrome” evolves: dysphagia and drooling, rigidity and slowness of movements of the limbs; flexed limb postures; fixity of facial muscles with mouth constantly agape, giving an appearance of grinning or a “vacuous smile”; dysarthria or virtual anarthria (bulbar extrapyramidal syndrome); and a tremor in repose that increases when the limbs are outstretched to a coarse, “wing-beating” movement. Slowed saccadic eye movements and limitation of upgaze are also characteristic. A notable feature is the tendency for the motor disorders to be concentrated in the bulbar musculature and to spread caudally. Thus, the syndrome differs from typical parkinsonism. Usually, elements of cerebellar ataxia and intention tremor of variable degree are added at some stage of the disease. Approximately 6 percent of patients develop seizures (Dening et al). Gradually the disability increases because of increasing rigidity and tremor. The patient becomes mute, immobile,


Neurology_Adams

Neurology_Adams. of the disease. Approximately 6 percent of patients develop seizures (Dening et al). Gradually the disability increases because of increasing rigidity and tremor. The patient becomes mute, immobile, extremely rigid, dystonic, and slowed mentally, the latter usually being a late and variable effect.


Neurology_Adams

Neurology_Adams. With progression of the neurologic disease, the Kayser- Fleischer rings become more evident (see Fig. 36-7). They take the form of a crescentic rusty-brown discoloration of the deepest layer of the cornea (Descemet membrane). In the purely hepatic stage of the disease, the rings may not be evident (in 25 percent of cases), but they are virtually always present (if properly sought) once the neurologic signs become manifest. A slit-lamp examination may be necessary for their early detection, particularly in brown-eyed patients, but in the majority of patients with neurologic signs the rings can be visualized with the naked eye or with the aid of an indirect ophthalmoscope focused on the limbus.


Neurology_Adams

Neurology_Adams. The diagnosis is virtually certain when there is a similar syndrome in a sibling or when an extrapyramidal motor disorder of this type is conjoined with liver disease and the corneal rings. Variants of the above syndrome that the authors have seen are an early choreoathetosis (like Sydenham chorea); prominent dystonic postures; a cerebellar ataxia with minimal rigidity; a syndrome of coarse action or action and intention tremor resembling that of dentatorubral degeneration; an immobile mute state with profound rigidity; and a dementia, character change, or psychosis with relatively few extrapyramidal signs. Action myoclonus as a prominent early manifestation has also been described. The parkinsonian features do not respond to l-dopa treatment.


Neurology_Adams

Neurology_Adams. Laboratory findings Although the diagnosis is currently established by sequencing the ATP7B gene for specific mutations, in both the typical and variant forms of the disease, the finding of a low serum ceruloplasmin level (less than 20 mg/dL in 80 to 90 percent of patients), low serum copper (3 to 10 mM/L; normal 11 to 24 mM/L), and increased urinary copper excretion (more than 100 mg Cu/24 h) serve to make the diagnosis likely. Because 90 percent of copper is carried by ceruloplasmin and the latter is generally reduced in Wilson disease, serum copper values alone may be misleadingly normal. In the past, the reliable findings early in the course of high copper content in a biopsy of liver tissue (more than 200 µg Cu/g dry weight) and a failure to incorporate labeled 64Cu into ceruloplasmin were used. The latter test, however, fails to dependably differentiate asymptomatic carriers from affected individuals. Measurement of increased cupruresis after the administration of penicillamine


Neurology_Adams

Neurology_Adams. were used. The latter test, however, fails to dependably differentiate asymptomatic carriers from affected individuals. Measurement of increased cupruresis after the administration of penicillamine was also not been shown to be more sensitive than an unenhanced 24-h urine collection for copper.


Neurology_Adams

Neurology_Adams. Persistent aminoaciduria, reflecting a renal tubular abnormality, is present in most but not all patients. Liver function tests are usually abnormal; some patients are jaundiced and other signs of liver failure may appear late in the illness. In these patients, the serum ammonia may be elevated and the symptomatology may worsen with increases in dietary protein. The cirrhosis is not always evident in a liver biopsy (some regenerative nodules are large, and the biopsy may be taken from one of them). On the other hand, the diagnosis in children may be revealed when a liver biopsy is taken for the evaluation of cirrhosis.


Neurology_Adams

Neurology_Adams. It has been established that copper deposition in the liver is the initial disturbance; over time it leads to cirrhosis, so that, as already mentioned, the hepatic stage of the disease precedes neurologic involvement. Cranial CT is abnormal even in the hepatic stage and are invariably so when the neurologic disorder supervenes. The lateral ventricles and often the third ventricle are slightly enlarged, the cerebral and cerebellar sulci are widened, the brainstem appears shrunken, and the posterior parts of the lenticular nuclei, red nuclei, and dentate nuclei become hypodense (Ropper et al). With treatment, these radiologic changes become less marked (Williams and Walshe). MRI is an even more sensitive means of visualizing the structural changes, particularly those in the subcortical white matter, midbrain, pons, and cerebellum (Starosta-Rubinstein et al). In the MRI survey by Saatci and colleagues, the putamen was involved most frequently (although not invariably), showing a


Neurology_Adams

Neurology_Adams. white matter, midbrain, pons, and cerebellum (Starosta-Rubinstein et al). In the MRI survey by Saatci and colleagues, the putamen was involved most frequently (although not invariably), showing a symmetrical T2 signal change in a laminar pattern; there was also an increase in T1 signal throughout the basal ganglia, particularly in the pallidum. Signal changes are almost universally found in the claustrum and also in the midbrain (pars compacta of the substantia nigra), dentate nucleus of the cerebellum, pons, and thalami. We have been impressed with a glassy diffuse and confluent signal abnormality on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the hemispheral white matter in some cases—findings that were mistaken for multiple sclerosis.


Neurology_Adams

Neurology_Adams. Neuropathologic changes These vary with the rate of progress of the disease. Exceptionally, in the rapidly advancing and fatal form, there is frank cavitation in the lenticular (putaminal and pallidal) nuclei, as observed in Wilson’s original cases. In the more chronic form, there is only shrinkage and a light-brown discoloration of these structures. Nerve cell loss and some degree of degeneration of myelinated fibers in lenticular nuclei, substantia nigra, and dentate nuclei are usually apparent. Subcortical myelin degeneration is found in some cases. More striking, however, is a marked hyperplasia of protoplasmic astrocytes (Alzheimer type II cells) in the cerebral cortex, basal ganglia, brainstem nuclei, and cerebellum, almost certainly a reaction to liver failure and hyperammonemia.


Neurology_Adams

Neurology_Adams. Treatment Ideally, treatment should be started before the appearance of neurologic signs; if this can be implemented, neurologic deterioration can be prevented to a large extent. Treatment consists of (1) reduction of dietary copper to less than 1 mg/d, which can usually be accomplished by avoidance of copper-rich foods (liver, mushrooms, cocoa, chocolate, nuts, and shellfish), and (2) administration of the copper chelating agent d-penicillamine (1 to 3 g/d) by mouth, in divided doses. Pyridoxine 25 mg/d should be added in order to prevent anemia. The use of d- penicillamine is associated with a number of problems. Sensitivity reactions to the drug (rash, arthralgia, fever, leukopenia) develop in 20 percent of patients and require a temporary reduction of dosage or a course of prednisone to bring them under control. Reinstitution of drug therapy should then be undertaken, using low dosages (250 mg daily) and, later, small, widely spaced increases. If the patient is still sensitive to


Neurology_Adams

Neurology_Adams. to bring them under control. Reinstitution of drug therapy should then be undertaken, using low dosages (250 mg daily) and, later, small, widely spaced increases. If the patient is still sensitive to d-penicillamine or if severe reactions (lupus-like or nephrotic syndromes or myasthenia gravis) occur, the drug should be discontinued and another chelating agent, triethylene tetramine (trientine) or ammonium tetrathiomolybdate may be substituted. Zinc, which blocks the intestinal absorption of copper, is also a suitable treatment, but ineffective alone. It is given as zinc acetate, 100 to 150 mg daily in 3 to 4 divided doses at least 1 h before meals (Hoogenraad et al). The appropriate drug must then be continued for the patient’s lifetime. Some women report improvement in neurologic symptoms during pregnancy, although there is no apparent change in copper metabolism during this time. In most patients, neurologic signs improve in response to decoppering agents. The Kayser-Fleischer


Neurology_Adams

Neurology_Adams. during pregnancy, although there is no apparent change in copper metabolism during this time. In most patients, neurologic signs improve in response to decoppering agents. The Kayser-Fleischer rings disappear and liver function tests may return to normal, although the abnormalities of copper metabolism remain unchanged. In moderately severe and advanced cases, clinical improvement may not begin for several months despite full doses of d-penicillamine, and it is important to resist discontinuing the drug during this latent period.


Neurology_Adams

Neurology_Adams. It is also well known that the institution of treatment with penicillamine may induce an abrupt worsening of neurologic signs, and we have witnessed several such instances, including one that culminated fatally from a cardiac arrhythmia. Furthermore, in many of these patients, the lost function is never retrieved. Presumably this deterioration is a result of the rapid mobilization of copper from the liver and its redistribution to the brain. The slow introduction of penicillamine may avoid this complication. The additional use of zinc or one of the newer agents mentioned above should be instituted as soon as neurologic deterioration becomes evident. In at least one reported case, new lesions of Wilson disease (shown by MRI) developed while the patient was receiving full doses of d-penicillamine and excellent decoppering of the liver had occurred (Brewer et al). In the few patients who develop seizures, they may become apparent soon after therapy is begun.


Neurology_Adams

Neurology_Adams. Many wilsonian patients with advanced liver disease have been subjected to liver transplantation, which is curative for the underlying metabolic defect. The degree of neurologic improvement varies; in some it has been remarkable and sustained, confirming that the hepatic defect is primary and that the brain is involved secondarily. According to Schilsky and coworkers, the main indication for transplantation is severe and progressive liver damage, but the operation has been used successfully in some patients with intractable neurologic deterioration and only mild signs of liver disease. An important aspect of treatment is the screening of potentially affected relatives for abnormalities of serum copper and ceruloplasmin; if any relative is found to have the disease, penicillamine should be given indefinitely to prevent the emergence of neurologic symptoms. A full explanation of the dangers of ceasing the medication must be given, and compliance may have to be monitored.


Neurology_Adams

Neurology_Adams. Hereditary Deficiency of Ceruloplasmin (Aceruloplasminemia, CP Mutation) This is a rare illness, biochemically similar to Wilson disease, occurring in patients with a recessively inherited deficiency of ceruloplasmin; it is not simply a heterozygous form of Wilson disease (the mutation involves a different gene). Cirrhosis and Kayser-Fleischer rings are not features of the disease but diabetes is common and extrapyramidal signs may or may not arise. Rather than copper, iron is deposited in the brain and liver (see discussion by Logan). Those few cases that have been well studied, mainly Japanese, show mainly an ataxic disorder (Miyajima et al).


Neurology_Adams

Neurology_Adams. Noted briefly here and discussed more extensively in Chap. 42, is an idiopathic progressive posterior and lateral column myelopathy that closely simulates subacute combined degeneration of B12 deficiency. It is associated with low serum copper levels, usually idiopathic but sometimes caused by malabsorption or the intake of zinc as an over-the-counter supplement to prevent colds or to improve the senses of smell and taste; zinc inhibits absorption of copper from the gut. Neurodegeneration With Brain Iron Accumulation (PKAN, Formerly, Hallervorden-Spatz Disease, PANK Mutation)


Neurology_Adams

Neurology_Adams. This disease, recently renamed because of ignoble associations of the eponymous Hallervorden and Spatz, is also known as pigmentary degeneration of the globus pallidus. It is inherited as an autosomal recessive trait and is caused by, in all classic cases, a defect in the gene encoding pantothenate kinase 2 (PANK2), usually in the form of a missense mutation. The onset of symptoms is in late childhood or early adolescence with slow progression over a period of 10 or more years. The early signs are highly variable but are predominantly motor, both corticospinal (spasticity, hyperreflexia, Babinski signs) and extrapyramidal (rigidity, dystonia, and choreoathetosis). General deterioration of intellect is conjoined. In individual cases, ataxia and myoclonus have appeared at some phase of the illness. The spasticity and rigidity are most prominent in the legs, but in some instances they begin in the bulbar muscles, interfering with speech and swallowing, as happens in Wilson disease. We


Neurology_Adams

Neurology_Adams. illness. The spasticity and rigidity are most prominent in the legs, but in some instances they begin in the bulbar muscles, interfering with speech and swallowing, as happens in Wilson disease. We have observed patients who, over a period of years, exhibited only dystonia of the tongue, blepharospasm, or arching of the back. The relationship of this restricted form to the complete syndrome remains unsettled. Eventually, the patient becomes almost completely inarticulate and unable to walk or use his or her arms. Hayflick and colleagues found that only one-third of patients with atypical forms of the disease have mutations of the PANK2 gene. Moreover, variant cases tended not to show the characteristic changes on MRI described below.


Neurology_Adams

Neurology_Adams. Reduced levels of PANK2 in the blood corroborate the diagnosis but this test is available only in research laboratories with an interest in the disease. The characteristic deposits of iron in the basal ganglia have not been associated with a demonstrable abnormality of serum iron or of iron metabolism. It has, however, been reported that there is increased uptake of radioactive iron in the region of the basal ganglia following intravenous injection of labeled ferrous citrate (Vakili et al; Szanto and Gallyas). CT reveals hypodense zones in the lenticular nuclei, resembling those of hepatolenticular degeneration (also of sulfite oxidase deficiency, glutaric acidemia and Leigh disease), although high-density lesions have been described in one autopsy-proven case of this disease (Tennison et al). The MRI findings are striking (Fig. 36-8). In T2-weighted images, the rim of the pallidum appears intensely black (iron deposition), with a small white area in its medial part that represents a


Neurology_Adams

Neurology_Adams. al). The MRI findings are striking (Fig. 36-8). In T2-weighted images, the rim of the pallidum appears intensely black (iron deposition), with a small white area in its medial part that represents a zone of necrosis (“eye-of-the-tiger” sign; see also Savoiardo et al).


Neurology_Adams

Neurology_Adams. The neuropathologic features prove to be the most distinctive attributes of the disease. There is an intense brown pigmentation of the globus pallidus, substantia nigra (especially the anteromedial parts), and red nucleus. Granules and larger amorphous deposits of iron mixed with calcium stud the walls of small blood vessels or lie free in the tissue. A loss of neurons and medullated fibers occurs in the most affected regions. Another unique feature is the presence of swollen axon fragments, which resemble those of neuroaxonal dystrophy. The significance of iron deposition is difficult to judge. To some extent, there is an increase of iron in the basal ganglia in other degenerative diseases. In Parkinson disease and striatonigral degeneration, for example, the deposition of iron is two to three times normal, presumably the result of degeneration of those tissues that are known to be rich in iron.


Neurology_Adams

Neurology_Adams. No treatment is known to be effective for the underlying disorder but treatment is available to ameliorate the dystonia and tremor. Some of our patients responded temporarily to l-dopa, but the effect was slight. The use of chelating agents to reduce iron storage has not helped.


Neurology_Adams

Neurology_Adams. This rare metabolic disease is inherited as an X-linked recessive trait. Although it carries the names of Lesch and Nyhan (see their 1964 description), the occurrence of uricemia in association with spasticity and choreoathetosis in early childhood had been described earlier by Cateland Schmidt. Essentially, it is a hereditary choreoathetosis with self-mutilation and hyperuricemia. The affected children appear normal at birth and usually develop on schedule up to 3 to 6 months of age. Maturational delay then sets in, initially with hypotonia that later gives way to hypertonia. Also, the patient’s behavior becomes abnormal, with aggressiveness and compulsive actions. The uncontrollable self-mutilation, mainly of the lips, occurs early (during the second and third year), and spasticity, choreoathetosis, and tremor come later. Most of the children learn to walk. Speech is delayed, and once attained, it is dysarthric and remains so throughout life. Mental retardation is moderately severe.


Neurology_Adams

Neurology_Adams. and tremor come later. Most of the children learn to walk. Speech is delayed, and once attained, it is dysarthric and remains so throughout life. Mental retardation is moderately severe. In patients more than 10 years of age, gouty tophi appear on the ears, and there is increasing risk from gouty nephropathy. The serum levels of uric acid are in the range of 7 to 10 mg/dL.


Neurology_Adams

Neurology_Adams. A deficiency of the enzyme hypoxanthine-guanine-phosphoribosyl transferase (HPRT) has been found in all typical cases of this disease. The HPRT gene lies on the X chromosome (Xq 26-q 27), and accurate diagnosis of affected males and carriers can be made by genetic analysis. As a result of this deficiency, hypoxanthine is either excreted or catabolized to xanthine and uric acid. The details of the biochemical abnormality responsible for CNS dysfunction are unclear.


Neurology_Adams

Neurology_Adams. In the differential diagnosis, one must consider nonspecific mental retardation or autism with hand biting and other self-mutilations, athetosis from birth trauma, and encephalopathies with chronic renal disease. Hyperuricemia has also been reported in a family with spinocerebellar ataxia and deafness and in another with autism and mental retardation, neither of them with the enzymatic defect of Lesch-Nyhan disease. As mentioned earlier, there are several other disorders of purine and pyrimidine metabolism, some of them with hyperuricemia, that present with a neurologic syndrome like that of Lesch-Nyhan.


Neurology_Adams

Neurology_Adams. Treatment This is with the xanthine oxidase inhibitor allopurinol, which blocks the last steps of uric acid synthesis, reduces the uric acid in Lesch-Nyhan disease, and prevents the uricosuric nephropathy, but it seems to have no effect on CNS symptoms. Guanosine 5-monophosphate and inosine 5-monophosphate, both of which are deficient in Lesch-Nyhan disease, have been replaced without benefit to the patient. Transitory success has also been achieved by the administration of 5-hydroxytryptophan in combination with l-dopa. Fluphenazine (Prolixin) is reported to have suppressed the self-mutilation after haloperidol (Haldol) had failed to do so. Behavior modification programs may be of some value. Symptomatic treatment is available for the dystonia. Calcification of Vessels in Basal Ganglia and Cerebellum


Neurology_Adams

Neurology_Adams. Calcification of Vessels in Basal Ganglia and Cerebellum Ferrugination and calcification of vessels in the basal ganglia occur to a slight degree in many elderly persons (and in other mammals) who are otherwise normal. The widespread use of CT and MRI has brought the condition to light with increasing frequency (Fig. 36-9). Usually the calcification may be dismissed as an aging phenomenon of no clinical significance. When it occurs early in life, or later in life with extrapyramidal symptoms, and is of such degree as to be visible in plain films of the skull, it must always be regarded as abnormal.


Neurology_Adams

Neurology_Adams. calcification) An adult case of this type was described by Fahr, so that his name is sometimes attached to this disorder. This is an idiopathic and sometimes familial form of calcification of the basal ganglia and cerebellum in which choreoathetosis and rigidity are prominent acquired features. The clinical state may also take the form of a parkinsonian syndrome or bilateral athetosis. In two of our patients there was unilateral choreoathetosis, which was replaced gradually by a parkinsonian syndrome, and in another of our sporadic cases, the initial abnormality was a unilateral dystonia responsive to l-dopa. Some patients have been developmentally delayed but most are intellectually normal. The serum calcium levels in the aforementioned diseases are usually normal and there is no explanation of the calcification. A mutation of SLC20A2, coding for a protein involved in phosphate transport, is responsible for half of instances and a smaller number are caused by mutations in the PDGFRB.


Neurology_Adams

Neurology_Adams. of the calcification. A mutation of SLC20A2, coding for a protein involved in phosphate transport, is responsible for half of instances and a smaller number are caused by mutations in the PDGFRB. Both are heritable in an autosomal dominant fashion. Other, less frequent mutations have been identified in small groups.


Neurology_Adams

Neurology_Adams. (a rare familial disease, caused by end-organ insensitivity to parathyroid hormone with distinctive skeletal and developmental abnormalities), the diminution in ionized serum calcium induces not only tetany and seizures but also choreoathetosis. This last symptom is presumably a result of calcification of the basal ganglia, which occurs in about one-half of the patients but of unknown mechanism. Also, in some instances there are signs of a cerebellar lesion. Pseudopseudohypoparathyroidism is a disorder that imitates the bony abnormalities seen in pseudohypoparathyroidism but in which calcium metabolism is normal and there are no neurologic features.


Neurology_Adams

Neurology_Adams. Sly and colleagues described the familial occurrence (21 cases in 12 families) of calcification in the caudate and lenticular nuclei, thalami, and frontal lobe white matter in association with osteopetrosis (“marble bones”) and renal tubular acidosis. Clinically, there were multiple cranial nerve palsies—including optic atrophy as well as psychomotor delay and learning disabilities—but no extrapyramidal signs. The cranial nerve palsies, which are a result of bony encroachment in neural foramina, were much less severe than in the lethal form of osteopetrosis. The pattern of inheritance of this disease is autosomal recessive (rarely X-linked), and the basic abnormality was found to be a deficiency in carbonic anhydrase II in red blood corpuscles and probably in kidney and brain. Several types of disease have been associated with corresponding mutations, mostly in CLCN7.


Neurology_Adams

Neurology_Adams. We emphasize that acquired extrapyramidal disorders are much more common than metabolic ones. For example, athetosis may follow hypoxic encephalopathy of birth or follow kernicterus caused by Rh and ABO blood incompatibilities and erythroblastosis fetalis. The same is true of the Crigler-Najjar form of hereditary hyperbilirubinemia, in which kernicterus (with ataxia or athetosis) may rarely appear as late as childhood or adolescence, the defect being one of glucuronide-bilirubin conjugation. Later in life, the more common causes are medications, illicit drug use, focal cerebral lesions, hyperosmolar nonketotic state, antiphospholipid antibody syndrome, among many others discussed in Chap. 4. Furthermore, a number of other rare diseases, which can only be classified as heredofamilial degenerations, also figure in the differential diagnosis of choreoathetotic or dystonic syndromes and are discussed in Chap. 39. Torsion dystonia is the best-known example.


Neurology_Adams

Neurology_Adams. With regard to rarer metabolic causes, ceroid- lipofuscinosis of the Kufs type, GM1 gangliosidosis, late-onset metachromatic leukodystrophy, Niemann-Pick disease (type C), PKAN disease, chorea-acanthocytosis, and Wilson disease may present with a syndrome of which dystonia or athetosis is an important component. Usually, there are other elements in the clinical picture as well, so that the correct diagnosis is seldom in doubt for long. dal Canto and colleagues have described a variant of neuronal ceroid-lipofuscinosis in which a boy and girl of unrelated non-Jewish parents developed severe choreoathetosis and dystonia at 6 to 7 years of age. Intellectual deterioration, gait abnormality, and seizures were added clinical features. Cerebral biopsy showed intraneuronal inclusions consisting of curvilinear bodies. These observations support the notion of nosologic heterogeneity among the nonglycolipid neuronal storage disorders.


Neurology_Adams

Neurology_Adams. Glutaric acidemia (type I) is another rare metabolic disorder, in which progressive choreoathetosis and dystonia are combined with intermittent acidemia. In some cases, ataxia of movement and a variable degree of mental retardation are also present. Glutaric acid is present in the urine, as are its metabolites 3-hydroxyglutarate and glutamate. The basic defect is in glutaryl CoA dehydrogenase, which has been found in leukocytes, hepatocytes, and fibroblasts. Neuropathologically, there is loss of neurons in the caudate, putamen, and pallidum, with gliosis. A spongy change is said to affect the white matter.


Neurology_Adams

Neurology_Adams. A spongy change is said to affect the white matter. Infants with glutaric acidemia are often subject to sudden episodes of acidosis, coma, and flaccidity. There are signal changes on MRI, corresponding to the acute necrosis of nerve cells in the basal ganglia. These crises can be prevented and the infants can develop normally if the diagnosis is made before the development of neurologic signs, for example, in the sibling of an older affected child, and treatment is undertaken with a diet low in protein, particularly in tryptophan and lysine (Cho et al). THE LEUKODYSTROPHIES: SYNDROMES OF BILATERAL HEMIPLEGIA, BLINDNESS,


Neurology_Adams

Neurology_Adams. Categorized here are late life manifestations of familial leukodystrophies. Of the several varieties of late-onset leukodystrophy, some are of unquestionable metabolic origin. The terms metachromatic, sudanophilic, orthochromic, etc., refer to the distinctive products of myelin degeneration and staining characteristics (or lack thereof) of the white matter in the individual leukodystrophies. As emphasized earlier, these are distinguished from the cerebral gray matter diseases (poliodystrophies), which have a different mode of presentation—seizures, myoclonus, chorea, choreoathetosis, and tremor being prominent. Instead, recognition of the entire group of leukodystrophies is based on symptoms and signs attributable to the interruption of tracts (corticospinal, corticobulbar, cerebellar peduncular, sensory) and visual pathways (optic nerve, optic tract, geniculocalcarine) and the infrequency or absence of seizures, myoclonus, and spike-and-wave abnormalities in the EEG. However, this


Neurology_Adams

Neurology_Adams. sensory) and visual pathways (optic nerve, optic tract, geniculocalcarine) and the infrequency or absence of seizures, myoclonus, and spike-and-wave abnormalities in the EEG. However, this distinction is not infallible, particularly in the later stages of the disease.


Neurology_Adams

Neurology_Adams. The syndrome of progressive spasticity and rigidity with spastic dysarthria and pseudobulbar palsy poses a difficult diagnostic problem. One’s first impulse is to assume the presence of a corticospinal disorder, especially if tendon reflexes are brisk, but frequently the plantar reflexes are flexor and the facial reflexes are not enhanced (“pseudo-pseudobulbar palsy,” a term we attribute to Marsden). In addition, unusual postures and a more plastic type of rigidity may occur, consistent with an extrapyramidal condition. Adrenomyeloneuropathy is another syndrome that combines reduced or absent tendon reflexes and Babinski signs, signifies a combination of corticospinal and peripheral nerve lesions, and is highly characteristic of metachromatic leukoencephalopathy.


Neurology_Adams

Neurology_Adams. The leukodystrophies that become apparent only in later life pose yet another problem: the clinical and radiologic differentiation from cerebral forms of multiple sclerosis. In identifying the metabolic diseases of myelin, one is helped by the relative symmetry and steady progression of the clinical signs; the early onset of cognitive impairment (which is uncharacteristic of multiple sclerosis); and the symmetrical and massive degeneration of the cerebral white matter (in distinction to the asymmetrical and often multiple lesions of demyelinative disease). At various times in life, particularly in young individuals, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) enters into the differential diagnosis (see Chap. 33); late in life, distinguishing a metabolic disorder of myelin from the subcortical multiple infarctions of Binswanger disease and from the ubiquitous rarefaction of the periventricular regions of the cerebrum may be a


Neurology_Adams

Neurology_Adams. a metabolic disorder of myelin from the subcortical multiple infarctions of Binswanger disease and from the ubiquitous rarefaction of the periventricular regions of the cerebrum may be a problem. Differentiation from cerebral gliomatosis, brain lymphoma, toxic forms of leukodystrophy, and progressive multifocal leukoencephalopathy, all affecting deep cerebral or white matter structures, offers less difficulty.


Neurology_Adams

Neurology_Adams. This disorder traditionally combines a cerebral leukodystrophy and Addison disease, originally included under the rubric of Schilder disease, but now set apart as an independent metabolic encephalopathy with specific genetic etiology. It is transmitted as an X-linked recessive trait with an incidence of 1 in 20,000 male births. The fundamental defect is impairment in peroxisomal oxidation of very-long-chain fatty acids (VLCFAs), leading to their accumulation in the brain and adrenal glands (see the publications of H.W. Moser and of Igarashi and associates). The deficient membrane protein, encoded by a gene that maps to chromosome X28, is a peroxisomal membrane transporter (ABCD1). The gene is located close to the gene for color vision. In the typical X-linked adrenoleukodystrophy (ALD), there is an inability to metabolize VLCFAs, but it came as a surprise that the disease was not caused by an enzyme deficiency. The modern classification of the disease categorizes it as a disorder of


Neurology_Adams

Neurology_Adams. there is an inability to metabolize VLCFAs, but it came as a surprise that the disease was not caused by an enzyme deficiency. The modern classification of the disease categorizes it as a disorder of peroxisomes, subcellular organelles containing numerous enzymes, each of which is unaffected. This peroxisomal assignation connects adrenoleukodystrophy with Zellweger and Refsum disease.


Neurology_Adams

Neurology_Adams. The onset is usually between 4 and 8 years, sometimes later; in the most common form of this disorder, only males are affected with the entire syndrome (women carriers may display a special myelopathy discussed further on). The signs of either the adrenal insufficiency or the cerebral lesion may be the first to appear. In the case described by Siemerling and Creutzfeldt, the first recorded example of this disorder, bronzing of the skin of the hands appeared at 4 years of age; quadriparesis, with dysarthria and dysphagia (i.e., pseudobulbar palsy), became evident at 7 years; a single seizure occurred at 8 years; and by 9 years, shortly before death, the patient was decerebrate and unresponsive. In personally observed cases, the first abnormalities appeared at 9 to 10 years and took the form of episodic vomiting, decline in scholastic performance and change in personality with inappropriate giggling and crying. After a time, severe vomiting and an episode of circulatory collapse


Neurology_Adams

Neurology_Adams. the form of episodic vomiting, decline in scholastic performance and change in personality with inappropriate giggling and crying. After a time, severe vomiting and an episode of circulatory collapse occurred, following which the gait became unsteady and arms ataxic with an intention tremor. Only then did the addisonian increase of pigmentation of the oral mucosa and the skin around nipples and over elbows, knees, and scrotum become evident. Cortical blindness follows in some instances. The late stages are marked by bilateral hemiplegia (at first asymmetrical), pseudobulbar paralysis, blindness, deafness, and impairment of all higher cerebral functions.


Neurology_Adams

Neurology_Adams. The severity of the disease varies. We have cared for adult men in whom the cerebral symptoms have been mild, allowing for high-level cognitive achievement, albeit with peculiarities of personality, and with mild spastic gait, urinary difficulty, testicular insufficiency, and baldness. In each family there was a male sibling who died in childhood, ostensibly of adrenal insufficiency.


Neurology_Adams

Neurology_Adams. neuropathic form of the disease (adrenomyeloneuropathy [AMN]). In their patients, evidence of adrenal insufficiency had been present since early childhood, but only in the third decade of life did a progressive spastic paraparesis and a relatively mild polyneuropathy develop. It should be noted that the spasticity is occasionally asymmetrical, and the gait may have an ataxic component. This neurologic picture, in mild form and without adrenal insufficiency, is also the manner in which the disease may present in female carriers of the gene abnormality (see below). Like adrenoleukodystrophy, adrenomyeloneuropathy is typically inherited as an X-linked, male-specific trait. However, we have encountered a large family with adrenomyeloneuropathy in which males and females are both affected in a pattern that suggests dominant inheritance. The VLCFAs are modestly elevated in affected individuals, and there is no evidence of cerebral involvement.


Neurology_Adams

Neurology_Adams. Moser and colleagues (1980), using clinical and biochemical criteria, identified the following clinical subtypes of ALD, all derived from similar mutations: 1. A progressive degeneration of cerebral white matter in young males, often with cortical blindness—the classic type, accounting for half of all cases (Fig. 36-10) 2. An intermediate form in juvenile or young adult males with cerebral and spinal involvement (5 percent of cases) 3. A progressive spinal cord tract degeneration in adult males (25 percent of cases) 4. A chronic mild, nonprogressive spastic paraparesis in heterozygous female carriers (10 percent of cases) 5. Familial instances of Addison disease without neurologic involvement in males (10 percent of cases) 6. Possibly, in male infants, a form originating at birth (e.g., Zellweger disease)


Neurology_Adams

Neurology_Adams. Illustrating the variability in presentation among kindreds, Marsden and colleagues (1982) and, subsequently, Kobayashi and coworkers described a familial spinocerebellar syndrome, and Ohno and associates reported a sporadic instance of adrenoleukodystrophy presenting as olivopontocerebellar atrophy. Moser found cerebral forms alone in 30 percent, adrenomyeloneuropathy alone in 20 percent, and combined childhood cerebral and myelopathic forms in the remaining half.


Neurology_Adams

Neurology_Adams. Female heterozygotes Neurologic manifestations develop in up to 50 percent of female carriers but in our experience with siblings of affected patients, the figure has been lower. The onset of a spastic paraparesis tends to occur later in life, usually in the third or fourth decade, often combined with gait ataxia and urinary incontinence and progression tends to be slow, but an explosive onset has been reported (see Chap. 42 and Engelen et al). As already mentioned, multiple sclerosis is the main consideration in differential diagnosis, particularly as 20 percent of heterozygotes have white matter changes on cerebral MRI. Overt adrenal insufficiency is rare in female carriers, but scalp hair may be scant as a subtle manifestation of adrenal hypofunction.


Neurology_Adams

Neurology_Adams. Pathologically in classic X-linked instances, massive degeneration of the myelin occurs, often asymmetrically in various parts of the cerebrum, brainstem, optic nerves, and sometimes spinal cord (see Fig. 36-10). Degradation products of myelin are visible in macrophages in recent lesions, namely, sudanophilic demyelination. There is extensive astrocytic gliosis. Axons are damaged, but to a lesser degree. The cortex of the adrenal glands is atrophic, and the cells and invading histiocytes contain an abnormal lipid material. The testes show marked interstitial fibrosis and atrophy of the seminiferous tubules. Electron microscopically, the macrophages of the brain and adrenals and the Leydig cells of the testes contain characteristic lamellar cytoplasmic inclusions.


Neurology_Adams

Neurology_Adams. Laboratory diagnosis The diagnosis can be made by gene sequencing but a specific laboratory marker of the disease is an excess of VLCFAs, in particular three measurements are of value: the absolute level of hexacosanoic acid (C26), the ratio of C26 to C22 (docosahexanoic acid; C26:C22), and of C24 (tetracosanoic acid) to docosahexanoic acid (C24:C22) in plasma, erythrocytes, leukocytes, or cultured fibroblasts as detailed by Moser and colleagues (1999). This reflects the basic biochemical fault in this disease, namely defective fatty acid oxidation within the peroxisomes. If skin fibroblasts and plasma testing are both performed, 93 percent of female carriers will show the abnormal VLCFA. MRI of the brain is abnormal in the majority of patients with cerebral symptoms and in a proportion of others.


Neurology_Adams

Neurology_Adams. Other laboratory findings are low serum sodium and chloride levels and elevated potassium levels reflecting the atrophy of the adrenal glands. The latter results in reduced excretion of corticosteroids, low serum cortisol levels, and lack of rise in 17-hydroxyketosteroids after adrenocorticotropic hormone (ACTH) stimulation. The CSF protein may be elevated. As a research tool, Öz and colleagues have shown that magnetic resonance spectroscopy that measures the concentrations of several metabolites can be used as a guide to the progression of the disease and to gauge the effects of new therapies as they are introduced.


Neurology_Adams

Neurology_Adams. Treatment Adrenal replacement therapy prolongs life and occasionally effects a partial neurologic remission. A diet enriched with monounsaturated fatty acids and devoid of long-chain fatty acids has been said to slow the progress of the disease when administered before the age of 6 years. Bone marrow transplantation, to date performed in more than 50 children, has been the only treatment shown to stabilize the disease and reverse some of the MRI changes. However, gene therapy with transduced autologous CD34+ cells (done ex vivo with a lentiviral vector) that contain ABCD1 complementary DNA has prevented the emergence of symptoms if instituted early in the disease, as in a preliminary report by Eichler and colleagues.


Neurology_Adams

Neurology_Adams. This form of leukodystrophy was described in relation to the inherited metabolic disorders of late infancy and early childhood in an earlier section. We mention it here to emphasize that the disease may have its onset at almost any age. Juvenile forms may begin between 4 and 12 years of age and adult forms between the midteens and the seventh decade of life. The mutations of the aryl sulfatase gene giving rise to these various forms are described in the earlier section on metachromatic leukodystrophy (MLD). Some of the sporadic cases reported in the adult probably were examples of cerebral multiple sclerosis, but we have seen, as have others, cases of MLD appearing as late as middle adult life. In almost all cases, the clinical picture, like those described by Turpin and Baumann, was one of slowly evolving intellectual decline or behavioral abnormality, followed by spastic weakness, hyperreflexia, Babinski signs, and stiff, short-stepped gait, with or without a polyneuropathy. Without


Neurology_Adams

Neurology_Adams. slowly evolving intellectual decline or behavioral abnormality, followed by spastic weakness, hyperreflexia, Babinski signs, and stiff, short-stepped gait, with or without a polyneuropathy. Without manifest neurologic signs, misdiagnosis of psychiatric disease is common. As the disease progresses over a period of 3 to 5 years there may be a loss of vision and speech, then of hearing, and finally a state of virtual decerebration.


Neurology_Adams

Neurology_Adams. In some of these cases it is impossible to distinguish the white matter disease from that of Pelizaeus-Merzbacher and of Cockayne, described in the preceding section.


Neurology_Adams

Neurology_Adams. This refers to a heterogeneous group of disorders, also called nonmetachromatic leukodystrophy, in which no enzyme defect or special staining characteristic of degenerated white matter has been identified. Furthermore, most of them have been sporadic, obscuring the nosology of the process. One type is associated with cerebellar ataxia and dementia; other adult cases have been described in which epilepsy was associated with a frontal lobe type of dementia. A surprising feature, such as in the cases of Letournel and colleagues, has been normal MRI, even with the more sensitive FLAIR sequences. With whole exome sequencing, it has been possible to identify mutations in over one-third of such cases as described, for example, by Vanderver and coworkers. Not unexpectedly, these comprise a heterogenous group of disorders, usually isolated to a single family and in which the mechanism of white matter destruction or dysmyelination is for the most part, obscure.


Neurology_Adams

Neurology_Adams. This rare disease is transmitted in an autosomal recessive pattern as a result of mutation in CYP27A, which codes for a hydroxylase involved in the metabolic pathway for cholesterol and resulting in an excess of cholestanol. It usually begins in late childhood, with cataracts and xanthomas of tendon sheaths and lungs. As it progresses, difficulty in learning, impairment of retentive memory, and deficits in attention and visuospatial perception (the earliest neurologic manifestations) give way to dementia, ataxic or ataxic-spastic gait, dysarthria and dysphagia, and polyneuropathy. In the late stages (after 5 to 15 years), the patient becomes bedfast and helpless; death occurs at 20 to 30 years of age. In other cases, the clinical course is much more benign. Neuropathologic examination shows masses of crystalline cholesterol in the brainstem and cerebellum and sometimes in the spinal cord, with symmetrical destruction of myelin in the involved areas. The white matter lesions are


Neurology_Adams

Neurology_Adams. shows masses of crystalline cholesterol in the brainstem and cerebellum and sometimes in the spinal cord, with symmetrical destruction of myelin in the involved areas. The white matter lesions are visible by CT and MRI.


Neurology_Adams

Neurology_Adams. The basic defect is in the synthesis of primary bile acids, leading to an increased hepatic production of cholesterol and cholestanol, which accumulate in brain and tendons. The serum cholesterol levels are normal in most cases but may be as high as 450 mg/dL in others. The tendon xanthomas contain cholesterol, of which 4 to 9 percent is cholestanol (dihydrocholesterol) according to the studies of Moser and colleagues (1984). Cholestanol levels in the serum and red cells are increased. The same elevated levels are found in heterozygotes. The causative mutation is in CYP27A.


Neurology_Adams

Neurology_Adams. Treatment In response to long-term treatment with chenodeoxycholic acid, 750 mg daily, the corticospinal and cerebellar signs and dementia receded in 10 of 17 patients treated and followed by Berginer and coworkers. This drug corrects the defective synthesis of bile acids and restores the low level of chenodeoxycholic acid. Ideally, treatment should begin before the neurologic symptoms appear (Meiner et al). Statin drugs are often added.


Neurology_Adams

Neurology_Adams. In Chap. 33 it was remarked that strokes occur from time to time in children and young adults, often as a result of inherited disorders of the clotting system typified by protein C deficiency, but also of a number of other metabolic derangements, including the mitochondrial disorder MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). Among the many causes, three metabolic diseases must always be considered in the diagnosis of such cases: homocystinuria, Fabry disease, and sulfite oxidase deficiency. Other less-common ones are Tangier disease and familial hypercholesterolemia. Stroke in young persons is also a central feature of the mitochondrial disorder MELAS, discussed further on in this chapter, and of the genetically determined microvasculopathy CADASIL (“Familial Subcortical Infarction” discussed in Chap. 33).


Neurology_Adams

Neurology_Adams. The typical form of this aminoaciduria is inherited as an autosomal recessive trait and simulates Marfan disease. Tall, slender habitus; great length of limbs, sometimes scoliosis and arachnodactyly (long, spidery fingers and toes); thin and rather weak muscles; knock-knees; highly arched feet; and kyphosis are the typical skeletal features. Sparse, blond, brittle hair; malar flush; and livedo reticularis are common dermal manifestations, and a dislocation of one or both lenses (usually downward, in contrast to Marfan syndrome) may occur, imparting a tremulous appearance to the irides (iridodonesis). The only neurologic abnormality is mental retardation, usually of mild degree, which sets this syndrome apart from Marfan disease, in which intellect is unimpaired. Several mutations in CBS, the gene that codes for cystathionine beta-synthase is most often implicated but other mutations that affect the conversion of methionine to cysteine to or, less often, homocystine to methionine.


Neurology_Adams

Neurology_Adams. Blood vessel changes of thickening and fibrosis of the coronary, cerebral, and renal arteries tend to appear later in the illness. An abnormality of platelets favoring clot formation and thrombosis of cerebral arteries has been observed. Some patients have died of coronary occlusions during adolescence, and a myocardial lesion may be the source of emboli to cerebral arteries.