Neurology_Adams

Neurology_Adams. This is an autosomal recessive disease without ethnic predominance, first described by Gaucher in 1882. The onset of the neuronopathic form is usually before 6 months and frequently before 3 months. The clinical course is more rapid than that of Tay-Sachs disease (most patients with infantile Gaucher disease do not survive beyond 1 year and 90 percent not beyond 2 years). Oculomotor apraxia and bilateral strabismus are early signs and are accompanied by rapid loss of head control, of ability to roll over and sit, and of purposeful movements of the limbs—along with apathy, irritability, frequent crying, and difficulty in sucking and swallowing. In some cases, progression is slower, with acquisition of single words by the first year, bilateral corticospinal signs (Babinski signs and hyperactive tendon reflexes), persistent retroflexion of the neck, and strabismus. Laryngeal stridor and trismus, diminished reaction to stimuli, smallness of the head, rare seizures, normal optic fundi,


Neurology_Adams

Neurology_Adams. tendon reflexes), persistent retroflexion of the neck, and strabismus. Laryngeal stridor and trismus, diminished reaction to stimuli, smallness of the head, rare seizures, normal optic fundi, enlarged spleen and slightly enlarged liver, poor nutrition, yellowish skin and scleral pigmentation, osteoporosis, vertebral collapse and kyphoscoliosis, and sometimes lymphadenopathy complete the clinical picture. The CSF is normal; the EEG is abnormal, but nonspecifically so.


Neurology_Adams

Neurology_Adams. The important laboratory findings are an increase in serum acid phosphatase and characteristic histiocytes (Gaucher cells) in marrow smears and liver and spleen biopsies. A deficiency of glucocerebrosidase in leukocytes and hepatocytes is diagnostic; glucocerebroside accumulates in the involved tissues. The characteristic pathologic feature is the Gaucher cell, 20 to 60 µm in diameter, with a wrinkled appearance of the cytoplasm and eccentricity of the nucleus. These cells are found in the marrow, lungs, and other viscera; neuronal storage is seldom evident. In the brain, the main abnormality is a loss of nerve cells—particularly in the bulbar nuclei, but also in the basal ganglia, cortex, and cerebellum—and a reactive gliosis that extends into the white matter. In contrast to the type II form described above, type I


Neurology_Adams

Neurology_Adams. In contrast to the type II form described above, type I Gaucher disease is a nonneuronopathic and relatively benign form. A less-frequent type III Gaucher disease is neuronopathic. It expresses itself in late childhood or adolescence by a slowly progressive mental decline, seizures, and ataxia, and, later, by spastic weakness and splenomegaly. Vision and retinae remain normal. Highly diagnostic is the defect in voluntary lateral gaze (oculomotor apraxia), with full movements on the oculocephalic (“doll’s-head”) maneuver. These signs help to differentiate Gaucher from Niemann-Pick disease, in which vertical eye movements are lost (see below). The nucleotide sequence of the cloned glucocerebrosidase gene of type I Gaucher disease was found by Tsuji and associates (1987) to be different from that of types II and III. There is no treatment for the latter types. Infantile Niemann-Pick Disease (Sphingomyelinase Deficiency, NPC Mutation)


Neurology_Adams

Neurology_Adams. This is also an autosomal recessive disease. Two-thirds of the affected infants have been of Ashkenazi Jewish parentage. The onset of symptoms in the usual type A disease is between 3 and 9 months of age, frequently beginning with marked enlargement of liver, spleen, and lymph nodes and infiltration of the lungs; rarely, there is jaundice and ascites. Cerebral abnormalities are definite by the end of the first year, often earlier. The usual manifestations are loss of spontaneous movements, lack of interest in the environment, axial hypotonia with bilateral corticospinal signs, blindness and amaurotic nystagmus, and a macular cherry-red spot (in about one-quarter of the patients). Seizures may occur, but are relatively late. There is no acoustic- induced startle or myoclonus, and head size is normal or slightly reduced. Loss of tendon reflexes and slowed conduction in peripheral nerves have been recorded but are rare. Protuberant eyes, mild hypertelorism, slight yellowish pigmentation


Neurology_Adams

Neurology_Adams. is normal or slightly reduced. Loss of tendon reflexes and slowed conduction in peripheral nerves have been recorded but are rare. Protuberant eyes, mild hypertelorism, slight yellowish pigmentation of oral mucosa, and dysplasia of dental enamel have also been reported but are rare. Most patients succumb to an intercurrent infection by the end of the second year.


Neurology_Adams

Neurology_Adams. Vacuolated histiocytes (“foam cells”) in the bone marrow and vacuolated blood lymphocytes are the important laboratory findings. A deficiency of sphingomyelinase in leukocytes, cultured fibroblasts, and hepatocytes is diagnostic. Pathologic examination reveals a decrease in the number of neurons; many of the remaining ones are pale and ballooned and have a granular cytoplasm. The most prominent neuronal changes are seen in the midbrain, spinal cord, and cerebellum. The white matter is little affected. The retinal nerve cell changes are similar to those in the brain. The foamy histiocytes (Niemann-Pick cells) that fill the viscera contain sphingomyelin and cholesterol; the distended nerve cells contain mainly sphingomyelin. There are also less-severe late infantile and juvenile-adult forms of Niemann-Pick disease types C and D. These are discussed in a later section of this chapter. Infantile Generalized GM1 Gangliosidosis (Type I,


Neurology_Adams

Neurology_Adams. Infantile Generalized GM1 Gangliosidosis (Type I, Beta-Galactosidase Deficiency, Pseudo-Hurler Disease, GLB1 Mutation)


Neurology_Adams

Neurology_Adams. This is probably an autosomal recessive disease without ethnic predominance. The infants appear abnormal at birth. They have dysmorphic facial features, like those of the mucopolysaccharidoses: depressed and wide nasal bridge, frontal bossing, hypertelorism, puffy eyelids, long upper lip, gingival and alveolar hypertrophy, macroglossia, and low-set ears. These features, with the bone changes mentioned below, account for the term pseudo-Hurler. Other indications of the disease are the onset of impaired awareness and reduced responsivity in the first days or weeks of life; lack of psychomotor development after 3 to 6 months; hypotonia, and later hypertonia with lively tendon reflexes and Babinski signs. Seizures are frequent. The head size is variable (microcephaly more often than macrocephaly). Loss of vision, coarse nystagmus and strabismus, macular cherry-red spots (in half the cases), flexion pseudocontractures of elbows and knees, kyphoscoliosis, and enlarged liver and sometimes


Neurology_Adams

Neurology_Adams. Loss of vision, coarse nystagmus and strabismus, macular cherry-red spots (in half the cases), flexion pseudocontractures of elbows and knees, kyphoscoliosis, and enlarged liver and sometimes enlarged spleen are the other important clinical findings. Radiographic abnormalities include subperiosteal bone formation, midshaft widening and demineralization of long bones, and hypoplasia and beaking of the thoracolumbar vertebrae. Vacuoles are seen in 10 to 80 percent of blood lymphocytes and foam cells in the urinary sediment.


Neurology_Adams

Neurology_Adams. A partial or complete deficiency of beta-galactosidase and accumulation of GM1 ganglioside in the viscera and in neurons and glia cells throughout the CNS are the specific biochemical abnormalities. In addition, the epithelial cells of renal glomeruli, histiocytes of the spleen, and liver cells contain a modified keratan sulfate and a galactose-containing oligosaccharide. The changes in the bone are also like those in the Hurler form of mucopolysaccharidosis. The disease should be suspected in an infant having the facial features of mucopolysaccharidosis and severe early-onset neurologic abnormalities. A remarkably benign variant, also inherited as an autosomal recessive trait, begins later in childhood but may advance so slowly as to allow attainment of adult life. Dystonia, myoclonus, seizures, visual impairment, and macular red spots were features of the two cases described by Goldman and coworkers.


Neurology_Adams

Neurology_Adams. Globoid Cell Leukodystrophy (Krabbe Disease, Galactocerebrosidase Deficiency, GALC Mutation)


Neurology_Adams

Neurology_Adams. This is an autosomal recessive disease without ethnic predilection, first described by Krabbe, a Danish neurologist, in 1916. The onset is usually before the sixth month and often before the third month (10 percent after 1 year). Early manifestations are generalized rigidity, loss of head control, diminished alertness, frequent vomiting, irritability and bouts of inexplicable crying, and spasms induced by stimulation. With increasing muscular tone, opisthotonic recurvation of the neck and trunk develops. Later signs are adduction and extension of the legs, flexion of the arms, clenching of the fists, hyperactive tendon reflexes, and Babinski signs. Later still, the tendon reflexes are depressed or lost but Babinski signs remain, an indication that neuropathy is added to corticospinal damage. This finding, shared with some of the other leukodystrophies, is of diagnostic value. Blindness and optic atrophy supervene. Convulsions occur but are rare and difficult to distinguish from tonic


Neurology_Adams

Neurology_Adams. This finding, shared with some of the other leukodystrophies, is of diagnostic value. Blindness and optic atrophy supervene. Convulsions occur but are rare and difficult to distinguish from tonic spasms. Myoclonus in response to auditory stimuli is present in some cases. The head size is normal or, rarely, slightly increased. In the last stage of the disease, which may occur from one to several months after the onset, the child is blind and usually deaf, opisthotonic, irritable, and cachectic. Most patients die by the end of the first year and survival beyond 2 years is unusual, although a considerable number of cases of later onset have been reported (see below).


Neurology_Adams

Neurology_Adams. The EEG shows nonspecific slowing without spikes, and the CSF protein is usually elevated (70 to 450 mg/dL). Imaging shows symmetrical nonenhancing areas of increased signal in the internal capsules and basal ganglia. As the disease advances, more of the cerebral white matter and brainstem become involved (Fig. 36-2). An additional feature in many cases is enlargement of the prechiasmatic optic nerves, also shown in the figure. Neuropathy is a feature in most cases, but clinical signs may be difficult to detect except for a decrease or loss of tendon reflexes; however, there is evidence of denervation and slowed motor and sensory nerve conduction velocities, reflecting a demyelinating polyneuropathy (see later comments on late-onset cases).


Neurology_Adams

Neurology_Adams. The deficient lysosomal enzyme in Krabbe disease is galactocerebrosidase (GALC; also called galactosylceramide beta-galactosidase); it normally degrades galactocerebroside to ceramide and galactose. The deficiency results in the accumulation of galactocerebroside; a toxic metabolite, psychosine, leads to the early destruction of oligodendrocytes and depletion of lipids in the cerebral white matter. The globoid cell reaction, however, indicates that impaired catabolism of galactosylceramide is also important. Gross examination of the brain discloses a marked reduction in the cerebral white matter, which feels firm and rubbery. Microscopically, there is widespread myelin degeneration, absence of oligodendrocytes, and astrocytic gliosis in the cerebrum, brainstem, spinal cord, and nerves. The characteristic globoid cells are large histiocytes containing the accumulated metabolite. Schwann cells have tubular or crystalloid inclusions under electron microscopy.


Neurology_Adams

Neurology_Adams. About a dozen variants of globoid cell leukodystrophy have been reported, many of them allowing survival for years. In these, neurologic regression begins in the 2to 6-year-old period. Visual failure with optic atrophy and a normal electroretinogram is an early finding. Later there is ataxia, as well as spastic weakness of the legs, mental regression, and finally decerebration. In three patients observed by R.D. Adams, a progressive quadriparesis with mild pseudobulbar signs, slowly progressive impairment of memory and other mental functions, dystonic posturing of the arms, and preserved sphincteric control constituted the clinical picture. The patients were alive at ages 9, 12, and 16 years. We have observed another rare variant, beginning in adult years, with spastic quadriparesis (asymmetrical) and optic atrophy. Mentation was essentially normal and, on imaging, the cerebral lesion was restricted. Unlike typical Krabbe disease, these CNS abnormalities are unaccompanied by any


Neurology_Adams

Neurology_Adams. (asymmetrical) and optic atrophy. Mentation was essentially normal and, on imaging, the cerebral lesion was restricted. Unlike typical Krabbe disease, these CNS abnormalities are unaccompanied by any change in the spinal fluid. The nerve conduction velocities in the late-onset form may be either normal or abnormal.


Neurology_Adams

Neurology_Adams. Kolodny and colleagues reported 15 cases of even later onset (ages 4 to 73 years); pes cavus, optic pallor, progressive spastic quadriparesis, a demyelinating sensorimotor neuropathy, and symmetrical parietooccipital white matter changes (on imaging studies) were the main features. Galactocerebrosidase levels were not as reduced as in the infantile form; possibly these late-onset variants represent a structural mutation of the enzyme (see Farrell and Swedberg). In this disease, as well as others described in this chapter, it has become clear that different mutations involving the same enzyme or metabolic pathway can produce strikingly different phenotypes and that there is a wide range in the age of onset in what had been considered, until relatively recently, a disease confined to infancy and early childhood.


Neurology_Adams

Neurology_Adams. In what may be considered a breakthrough in the treatment of childhood metabolic disease, Escolar and colleagues reported the successful use of transplanted umbilical cord hematopoietic cells in asymptomatic babies with Krabbe disease. Patients who were treated after becoming symptomatic did not benefit, but 14 patients who had been diagnosed prenatally or very soon after birth demonstrated progressive myelination of the nervous system, normalization of blood galactocerebroside activity, and attained visual, developmental, and cognitive function. The donors were partially human leukocyte antigen (HLA)-matched and substantial antirejection medication was required.


Neurology_Adams

Neurology_Adams. This more recently described and peculiarly named disease with variable age of onset is most typically manifest in this age group. After a period of normal development, and sometimes precipitated by infection or fever, there is a progressive encephalopathy punctuated by episodes of more rapid deterioration. The core syndrome is of irritability, loss of vision, seizures, ataxia, and coma, sometimes with recovery to a disabled state. The denominative feature is a symmetrical leukodystrophy with progressive disappearance of white matter and replacement by CSF or gliosis. The nature of this disease appears to be predominantly genetic with most cases caused by one of five mutations in eIF2B. We include it in this section because exacerbation with fever, similar to the case in some mitochondrial diseases, is suggestive of a metabolic disorder (see Leegwater et al). Lipogranulomatosis (Farber Disease, Ceramidase Deficiency, ASAH1 Mutation)


Neurology_Adams

Neurology_Adams. Lipogranulomatosis (Farber Disease, Ceramidase Deficiency, ASAH1 Mutation) This is a rare autosomal disorder that is based on a mutation in ASAH1. The onset is in the first weeks of life, with a hoarse cry because of fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading finally to ankylosis. Usually there is severe psychomotor delay, but a few patients have been neurologically normal. Inanition and recurrent infections lead to death in the first 2 years. The diagnostic abnormality is a deficiency of ceramidase, leading to accumulation of ceramide. There is widespread lipid storage in neurons, granulomas of the skin, and accumulation of periodic acid-Schiff (PAS)-positive macrophages in periarticular and visceral tissues.


Neurology_Adams

Neurology_Adams. These are a heterogeneous group of disorders that have in common a defective myelination of the cerebrum, brainstem, cerebellum, spinal cord, and peripheral nerves. Morphologic peculiarities and genetic features separate a certain group called Pelizaeus-Merzbacher disease; other types have been artificially delineated; as a result, a relatively meaningless terminology has been introduced. The term sudanophilic refers to the tinctorial properties of staining with sudan dye, an indication of breakdown of the fatty component of myelin.


Neurology_Adams

Neurology_Adams. This is predominantly an X-linked disease of infancy, childhood, and adolescence, and includes other closely related pathologic entities with different modes of inheritance. The affected gene encodes proteolipid protein (PLP), one of the two myelin basic proteins. Koeppen and associates have provided evidence of a defective synthesis of this protein. While one group of PLP mutations causes Pelizaeus-Merzbacher disease, another set causes an infantile spastic paraplegia.


Neurology_Adams

Neurology_Adams. The onset of symptoms is most often in the first months of life; other cases begin later in childhood. The first signs are abnormal movements of the eyes (rapid, irregular, often asymmetrical pendular nystagmus), jerk nystagmus on extremes of lateral movements, upbeat nystagmus on upward gaze, and hypometric saccades (Trobe et al). There is spastic weakness of the limbs, optic atrophy (often with unexplained retention of pupillary light reflex), ataxia of limb movement and intention tremor, choreiform or athetotic movements of the arms, and slow psychomotor development with delay in sitting, standing, and walking. Seizures occur occasionally. In later-developing cases, pendular nystagmus, choreoathetosis, corticospinal signs, dysarthria, cerebellar ataxia, and mental deterioration are the major manifestations. There are milder cases of later onset with behavioral peculiarities and loss of tendon reflexes and, rarely, pure spastic paraparesis.


Neurology_Adams

Neurology_Adams. Imaging confirms the extensive and symmetrical white matter involvement. In the most severe cases, Seitelberger has observed an absence of oligodendrocytes and myelinated fibers. It is hypothesized that proteolipids accumulate in the endoplasmic reticulum of the oligodendrocytes, resulting in apoptosis. Patients may survive to the second and third decades. One group of cases resembles the Cockayne syndrome, with photosensitivity of skin, dwarfism, cerebellar ataxia, corticospinal signs, cataracts, retinitis pigmentosa, and deafness. Pathologically, islands of preserved myelin impart a tigroid pattern of degenerated and intact myelin in the cerebrum. Seitelberger has obtained pathologic verification of this lesion in cases beginning as late as adult years. This disease and Cockayne syndrome are the only leukodystrophies in which nystagmus has been an invariable finding.


Neurology_Adams

Neurology_Adams. Koeppen and Robitaille, in a review of the subject of the pathogenesis of Pelizaeus-Merzbacher disease, summarized the evidence supporting the concept that misfolding of myelin proteins is the essential cause. There may be other types of such leukodystrophies with sudanophilic pathology that do not appear to be Pelizaeus-Merzbacher disease. They are also characterized by psychomotor regression; spastic paralysis; incoordination; blindness and optic atrophy; seizures (rare); severe microcephaly. Diffuse degeneration of myelinated fibers (visible by MRI) with phagocytosis of the sudanophilic products of myelin and gliosis are the major changes. Spongy Degeneration of Infancy (Canavan-van Bogaert-Bertrand or Canavan Disease, ASPA Mutation) This is an autosomal recessive leukodystrophy that was described in 1931 by Myrtelle Canavan as a form of


Neurology_Adams

Neurology_Adams. Schilder disease (see Chap. 35), but later categorized as a special spongy degeneration of the brain by van Bogaert and Bertrand. Of 48 affected families reported by Banker and Victor, 28 were of Jewish ancestry. Onset is early, usually recognizable in the first 3 months of life and sometimes in the first neonatal weeks. There is either a lack of development or rapid regression of psychomotor function, loss of sight and optic atrophy, lethargy, difficulty in sucking, irritability, reduced motor activity, hypotonia followed by spasticity of the limbs with corticospinal signs, and an enlarged head (macrocephaly). There are no visceral or skeletal abnormalities but a variable sensorineural hearing loss has been found (Ishiyama et al). Seizures occur in some cases. An interesting but unexplored aspect of the disease is the occurrence of blond hair and light complexion in affected members, in contrast to the darker hair and complexion of their normal siblings (Banker and Victor).


Neurology_Adams

Neurology_Adams. The CSF is usually normal but the protein concentration is slightly elevated in some cases. The disease is characterized by an increased urinary excretion of N-acetyl-l-aspartic acid (NAA), which may be used as a biochemical marker, a feature also evident on MR spectroscopy of the brain. It reflects the basic enzyme abnormality, a deficiency of aminoacylase II, which catalyzes the breakdown of NAA (Matalon et al). On CT there is attenuation of cerebral and cerebellar white matter in an enlarged brain with relatively normal-size ventricles. The MRI appearance (Fig. 36-3) is that of diffuse, somewhat uneven, high signal intensity on T2-weighted images. A leukodystrophy with behavioral regression, an enlarging head, a characteristic MRI abnormality, and a marked elevation of urinary NAA should leave little doubt about the diagnosis. The closest phenotype is Tay Sachs disease.


Neurology_Adams

Neurology_Adams. The characteristic pathologic changes are an increase in brain volume (and weight), spongy degeneration in the deep layers of the cerebral cortex and subcortical white matter, widespread depletion of myelin involving the convolutional more than the central white matter, loss of Purkinje cells, and hyperplasia of Alzheimer type II astrocytes throughout the cerebral cortex and basal ganglia. Adachi and coworkers have demonstrated an abnormal vacuolar accumulation of fluid in astrocytes and between split myelin lamellae; they have suggested that the loss of myelin is secondary to these changes. The enlargement of the brain in this disease must be distinguished clinically from GM2 gangliosidosis, Alexander disease, Krabbe disease, and nonprogressive megalocephaly and pathologically from a variety of disorders characterized by vacuolation of nervous tissue. There is no treatment.


Neurology_Adams

Neurology_Adams. This distinctive disease shares certain features with the leukodystrophies and also with gray matter diseases (poliodystrophies), both clinically and pathologically. The onset is in infancy with a failure to thrive, psychomotor retardation, spasticity of the craniospinal musculature, and seizures. An early and progressive macrocephaly has been a consistent feature. Alexander was the first to call attention to the enlargement of the brain, the extensive loss of cerebral white matter, and highly characteristic inclusions (the so-called Rosenthal fibers noted below) in astrocytes, and subpial and periventricular regions.


Neurology_Adams

Neurology_Adams. Pathologically, there are severe destructive changes in the cerebral white matter, most intense in the frontal lobes. Distinctive eosinophilic hyaline bodies, most prominent just below the pia and around blood vessels, are seen throughout the cerebral cortex, brainstem, and spinal cord. These have been identified as Rosenthal fibers and probably represent glial degradation products.


Neurology_Adams

Neurology_Adams. The astrocytic changes have been traced to a mutation in the glial fibrillary acidic protein (GFAP), as described by Gorospe and colleagues. It is usually inherited in an autosomal dominant pattern, and gives rise to the intermediate filament protein in astrocytes and, presumably, to the Rosenthal fiber inclusions. On the basis of this and related gene mutations, apparent milder forms of Alexander disease have been reported in juveniles and adults. They differed clinically in lacking the cerebral leukoencephalopathy. Instead, after a long period of constipation, sleep disorder, and orthostatic hypotension during adolescence, bulbar symptoms (dysarthria, dysphonia, and dysphagia), seizures, and in some cases ataxia gradually emerged during adult years. The myelin changes and atrophy of the medulla seen in MRI were confirmed by postmortem examination and the Rosenthal fibers; GFAP fibers were present in two autopsied cases.


Neurology_Adams

Neurology_Adams. This is a progressive disease of the cerebral gray matter, known also as progressive cerebral poliodystrophy or diffuse cerebral degeneration in infancy. A familial form (probably autosomal recessive) as well many sporadic cases has been reported. In both groups there is a certain uniformity of clinical features—loss of smile and disinterest in the surroundings, sweating attacks, seizures, and diffuse myoclonic jerks beginning in early infancy and followed by incoordination of movements; progressive spasticity of limb, trunk, and cranial muscles; blindness and optic atrophy; growth retardation and increasing microcephaly; and finally virtual decortication (see Alpers original description). In some instances, the late onset of jaundice and fatty degeneration or cirrhosis of the liver have been described (Alpers-


Neurology_Adams

Neurology_Adams. Huttenlocher syndrome). By the age of 4 years, these patients are hypotonic, anemic, and thrombocytopenic. They also show fragile hair follicles that break at thickened nodes (trichorrhexis nodosa).


Neurology_Adams

Neurology_Adams. The nature of this combined hepatic–cerebral degeneration leads to EEG abnormalities, progressive atrophy (particularly occipital) on the CT, loss of visual evoked potentials, and abnormal liver function tests. Despite the nuclear location of the POLG mutation, the main ultrastructural change is a depletion of mitochondria in brain, liver, and muscle. Neuropathologic examination shows marked atrophy of the cerebral convolutions and cerebellar cortex, with loss of nerve cells and fibrous gliosis (“walnut brain”). The cerebral white matter and basal ganglia are relatively preserved. In some cases, the spongiform vacuolization of the gray matter of the brain resembles that seen in Creutzfeldt-Jakob disease. Hypoglycemic, hypoxic, and hypotensive encephalopathies must always be considered in the diagnosis but can usually be eliminated by knowledge of the clinical circumstances at the onset of the illness.


Neurology_Adams

Neurology_Adams. A number of biochemical abnormalities have been identified in patients with Alpers disease, including pyruvate dehydrogenase deficiency, decreased pyruvate utilization, dysfunction of the citric acid cycle, and decreased cytochromes a and aa3, all similar to the mitochondrial defects of Leigh’s disease.


Neurology_Adams

Neurology_Adams. This uncommon disease of the neonatal period or early infancy has many biochemical etiologies. The symptoms have consisted of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions, with intervening periods of normalcy. Choreoathetosis has been observed in a few cases. Death often occurs before the third year. The important laboratory findings are acidosis with an anion gap and high serum lactate levels and hyperalaninemia. Defects can be found in the pyruvate dehydrogenase complex of enzymes and the electron transport chain complexes, which function in the oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA), relating the disease to defects in the mitochondrial respiratory chain enzymes. Indeed, lactic acidosis is a feature of several of the mitochondropathies discussed later in this chapter. Cases examined postmortem have shown necrosis and cavitation of the globus pallidus and cerebral white matter. Possibly this is a variant of Leigh disease.


Neurology_Adams

Neurology_Adams. discussed later in this chapter. Cases examined postmortem have shown necrosis and cavitation of the globus pallidus and cerebral white matter. Possibly this is a variant of Leigh disease. It must be distinguished from the several diseases of infancy that are complicated secondarily by lactic acidosis, especially the organic acidopathies. Cases of benign transient infantile lactic acidosis have been reported, but their etiology is unclear.


Neurology_Adams

Neurology_Adams. Cerebrohepatorenal (Zellweger) Disease and the Peroxisomal Disorders (PEX1 and Other Mutations)


Neurology_Adams

Neurology_Adams. This disease, estimated to occur once in every 100,000 births, is inherited as an autosomal recessive trait. It has its onset in the neonatal period or early infancy and as a rule leads to death within a few months. Motor inactivity and hypotonia, dysmorphic alterations of the skull and face (high forehead, shallow orbits, hypertelorism, high arched palate, abnormal helices of ears, retrognathia), poor visual fixation, multifocal seizures, swallowing difficulties, fixed flexion posture of the limbs, cataracts, abnormal retinal pigmentation, optic atrophy, cloudy corneas, hepatomegaly, and hepatic dysfunction are the usual manifestations. Stippled, irregular calcifications of the patellae and greater trochanters are highly characteristic. Pathologically, there is dysgenesis of the cerebral cortex and degeneration of white matter as well as a number of visceral abnormalities— cortical renal cysts, hepatic fibrosis, intrahepatic biliary dysgenesis, agenesis of the thymus, and iron


Neurology_Adams

Neurology_Adams. cortex and degeneration of white matter as well as a number of visceral abnormalities— cortical renal cysts, hepatic fibrosis, intrahepatic biliary dysgenesis, agenesis of the thymus, and iron storage in the reticuloendothelial system.


Neurology_Adams

Neurology_Adams. As to the biochemical abnormality, Moser and coworkers (1984) demonstrated a fivefold increase of very-long-chain fatty acids, particularly hexacosanoic acid, in the plasma and cultured skin fibroblasts from 35 patients with Zellweger disease. A similar abnormality was found in cultured amniocytes of women at risk of bearing a child with Zellweger disease, thus permitting prenatal diagnosis. The findings of Moser and colleagues (1984) are in keeping with current notions about the basic abnormality in Zellweger syndrome, namely, that it is caused by a lack of liver peroxisomes (oxidase-containing, membrane-bound cytoplasmic organelles), in which the very-long-chain fatty acids are normally oxidized (Goldfischer et al).


Neurology_Adams

Neurology_Adams. Currently, a spectrum of at least 12 disorders of peroxisomal function is recognized, all of them characterized by deficiencies in the peroxisomal enzyme of fatty-acid oxidation. The most common form of Zellweger syndrome is due to a mutation in PEX1. However, the most widely recognized peroxisomal disorders are adrenoleukodystrophy and Refsum disease, but the Zellweger cerebrohepatorenal syndrome can be considered a prototype. Each variant can be identified by its characteristic profile of elevated longand very-long-chain fatty acids, and the specific diagnosis can be confirmed by enzymology of cultured fibroblasts or amniocytes. Several of them become manifest at a later age and are discussed further on. For an authoritative discussion of peroxisomal biogenesis, the reader is referred to the article by Gould and Valle. The Oculocerebrorenal (Lowe) Syndrome


Neurology_Adams

Neurology_Adams. Here the mode of inheritance is probably X-linked recessive, although sporadic cases have been reported in girls. The abnormal gene is located on chromosome Xq25.26. The clinical abnormalities comprise bilateral cataracts (which may be present at birth), glaucoma, large eyes with megalocornea and buphthalmos, corneal opacities and blindness, pendular nystagmus, hypotonia and absent or depressed tendon reflexes, corticospinal signs without paralysis, slow movements of the hands, tantrums and aggressive behavior, high-pitched cry, occasional seizures, and psychomotor regression. Later the frontal bones become prominent and the eyes sunken. The characteristic biochemical abnormality is a renal tubular acidosis, and death is usually from renal failure. Additional laboratory findings include demineralization of bones and typical rachitic deformities, anemia, metabolic acidosis, and generalized aminoaciduria. The neuropathologic changes are nonspecific; inconstant atrophy and poor


Neurology_Adams

Neurology_Adams. include demineralization of bones and typical rachitic deformities, anemia, metabolic acidosis, and generalized aminoaciduria. The neuropathologic changes are nonspecific; inconstant atrophy and poor myelination have been described in the brain and tubular abnormalities in the kidneys. The primary genetic defects are in the gene encoding inositol polyphosphate phosphatase of the Golgi complex. The main diagnostic distinction is from Zellweger disease. Treatment programs include antiepileptic medication, correction of electrolyte disorders, and removal of cataracts.


Neurology_Adams

Neurology_Adams. Menkes Disease (Kinkyor Steely-Hair Disease; Trichopoliodystrophy, ATP7A Mutation)


Neurology_Adams

Neurology_Adams. This rare disorder is inherited as a sex-linked recessive trait. In most of the cases known to us, birth was premature. Poor feeding and failure to gain weight, instability of temperature (mainly hypothermia), and seizures become apparent in early infancy. The hair is normal at birth but the secondary growth is lusterless and depigmented and feels like steel wool; hairs break easily and under the microscope they appear twisted (pili torti). Radiologic examination shows metaphysial spurring, mainly of the femurs, and subperiosteal calcifications of the bone shafts. Arteriography discloses tortuosity and elongation of the cerebral and systemic arteries and occlusion of some. The combination of intracerebral hemorrhage and metaphysial bone spurs, which may be interpreted as “corner fractures,” has led in some cases to the erroneous diagnosis of child abuse. There is no discernible neurologic development, and rarely does the untreated child survive beyond the second year. Three of our


Neurology_Adams

Neurology_Adams. has led in some cases to the erroneous diagnosis of child abuse. There is no discernible neurologic development, and rarely does the untreated child survive beyond the second year. Three of our cases were examined postmortem (Williams et al). There was a diffuse loss of neurons in the relay nuclei of the thalamus, the cerebral cortex, and the cerebellum (granule and stellate cells) and of dendritic arborizations of residual neurons of the motor cortex and Purkinje cells.


Neurology_Adams

Neurology_Adams. The manifestations of this disease are attributable to one of numerous known mutations in a copper- transporting adenosine triphosphatase (ATPase), ATP7A, that is attributed to a failure of absorption of copper from the gastrointestinal tract and a profound deficiency of tissue copper (Danks et al). Furthermore, because copper fails to cross the placenta, a severe reduction of copper in the brain and liver is evident from birth. In this sense, the abnormality of copper metabolism is the opposite of that in Wilson disease. A relationship between Wilson and Menkes disease is nonetheless evident at a genetic level as they arise from genes encoding two different copper-transporting proteins that are both ATPases. The situation, however, may be more complex, as samples of intestinal tissue show a buildup of copper that indicates the problem is in mobilization of copper from the gut to the bloodstream. Other copper-dependent enzymes show impaired function, such as cytochrome oxidase. For


Neurology_Adams

Neurology_Adams. a buildup of copper that indicates the problem is in mobilization of copper from the gut to the bloodstream. Other copper-dependent enzymes show impaired function, such as cytochrome oxidase. For the purposes of early diagnosis, Kaler and colleagues have taken advantage of the reduced activity of another copper-dependent enzyme, dopamine–b-hydroxylase, to detect increased plasma levels of its substrates (dopamine and dihydroxyphenylacetic acid [DOPAC]), as well as reduced levels of the enzyme products (norepinephrine and dihydroxyphenylglycol [DHPG]). The ratio of dopamine to norepinephrine and dihydroxyphenylacetic acid to dihydroxyphenylglycol proved, in their study, to be the most sensitive and specific for early detection. This has allowed the neonatal identification of cases in families with affected children and resulted in normal neurodevelopment in a few children who were treated with copper beginning in the first weeks of life. This same group has suggested that only those


Neurology_Adams

Neurology_Adams. with affected children and resulted in normal neurodevelopment in a few children who were treated with copper beginning in the first weeks of life. This same group has suggested that only those mutations in ATP7A that allow for some residual copper transport activity are associated with better outcomes.


Neurology_Adams

Neurology_Adams. Parenteral administration of cupric salts, usually in the form of copper histidine administered subcutaneously twice daily by the parents, restores the serum and hepatic copper and may allow normal development in a few children as noted above but it does not materially influence the neurologic symptoms if treatment is started later. However, even early treated cases showing limited neurodevelopment survive and show some neurologic advance, unlike the past experience in which few survived beyond 5 or 6 years. Diagnosis of Inherited Metabolic Diseases of Infancy


Neurology_Adams

Neurology_Adams. Diagnosis of Inherited Metabolic Diseases of Infancy It will be recognized from the foregoing synopses that many of the neurologic manifestations of the inherited metabolic diseases of infancy are nonspecific and are common to most or all of the diseases in this group. In general, in the early stages of all these diseases, there is a loss of postural tone and a paucity of movement without paralysis or loss of reflexes; later there is spasticity with hyperreflexia and Babinski signs. Equally nonspecific are features such as irritability and prolonged crying; poor feeding, difficulty in swallowing, inanition, and retarded growth; failure of fixation of gaze and following movements of the eyes (often misinterpreted as blindness); and tonic spasms, clonic jerks, and focal and generalized seizures.


Neurology_Adams

Neurology_Adams. The differentiation of the inherited metabolic diseases of infancy rests essentially upon four types of data: (1) a few highly characteristic neurologic and ophthalmic signs; (2) the presence of an enlarged liver and/or spleen; (3) dysmorphic features of the face; and (4) the results of several relatively simple laboratory tests, such as images of the thoracolumbar spine, hips, and long bones; smears of the peripheral blood and bone marrow; CSF examination; and certain urinary tests and other biochemical estimations (serum lactate, glucose, ammonia, and urinary ketones, amino acids, and organic acids). For purposes of differential diagnosis, we have found the flowcharts constructed by our colleague, E.H. Kolodny, to be very useful. One such schematic, illustrated in Fig. 36-4, is based on the subdivision of patients into three groups: (1) dysmorphic, (2) visceromegalic, and (3) purely neurologic. Only rarely does an inherited metabolic disease fall into more than one of these


Neurology_Adams

Neurology_Adams. based on the subdivision of patients into three groups: (1) dysmorphic, (2) visceromegalic, and (3) purely neurologic. Only rarely does an inherited metabolic disease fall into more than one of these categories. There is also considerable value in beginning the diagnostic process by classifying the syndrome as a leukodystrophy or a poliodystrophy (disease predominantly affecting neurons, see further on), although this distinction is easier to make in the older child.


Neurology_Adams

Neurology_Adams. Once the major category of disease has been identified, correct diagnosis depends on particular clinical and laboratory features tabulated below (Tables 36-5 and 36-6). Of course, in the current era genetic testing discloses the diagnosis of most of these disorders but unless whole exome screening is planned to be undertaken, the clinician must have some idea of the likely diagnosis. Panels of over 100 genes pertaining to nuclear and mitochondrial causes of leukodystrophy are available.


Neurology_Adams

Neurology_Adams. Neurologic signs that are more or less specific for certain metabolic diseases are as follows: 1. Acousticomotor obligatory startle: Tay-Sachs disease 2. Abolished tendon reflexes with definite Babinski signs: globoid cell (Krabbe) leukodystrophy, occasionally Leigh disease, and (beyond infancy) metachromatic leukodystrophy 3. Peculiar eye movements, pendular nystagmus, and head rolling: Pelizaeus-Merzbacher disease, Leigh disease; later, hyperbilirubinemia and Lesch-Nyhan hyperuricemia (see below) 4. Marked rigidity, opisthotonos, and tonic spasms: Krabbe, Alpers disease, or infantile Gaucher disease (classic triad: trismus, strabismus, opisthotonos) 5. Intractable seizures and generalized or multifocal myoclonus: Alpers disease 6. Intermittent hyperventilation: Leigh disease and congenital lactic acidosis (also nonprogressive familial agenesis of vermis) 7. Strabismus, hypotonia, seizures, lipodystrophy:


Neurology_Adams

Neurology_Adams. Ocular abnormalities of specific diagnostic value in this age group are as follows: 1. Rapid pendular nystagmus: Pelizaeus-Merzbacher disease, rarely Krabbe leukodystrophy, Cockayne syndrome (later age) 2. Macular cherry-red spots: Tay-Sachs disease and Sandhoff variant, some cases of infantile Niemann-Pick disease, and rarely lipofuscinosis (see Table 36-4) 3. Corneal opacification: Lowe disease, infantile GM1 gangliosidosis; later, the mucopolysaccharidoses 4. Cataracts: galactosemia, Lowe disease, Zellweger disease (also congenital rubella)


Neurology_Adams

Neurology_Adams. Several other medical findings are of specific diagnostic value: 1. Dysmorphic facies: generalized GM1 gangliosidosis, Lowe and Zellweger syndromes, and some early cases of mucopolysaccharidosis and mucolipidosis 2. Enlarged liver and spleen: infantile Gaucher disease and Niemann-Pick disease; one type of hyperammonemia; Sandhoff disease; later, the mucopolysaccharidoses and mucolipidoses 3. Enlarging head without hydrocephalus (macrocephaly): Canavan spongy degeneration of infancy, some cases of Tay-Sachs disease, Alexander disease 4. Beaking of vertebral bodies in radiographs: GM1 gangliosidosis (and, at a more advanced age, the mucopolysaccharidoses, fucosidosis, mannosidosis, and the mucolipidoses) 5. Multiple arthropathies and raucous dysphonia: Farber disease 6. Storage granules and vacuolated lymphocytes: Niemann-Pick disease, generalized GM1 gangliosidosis 7. Abnormal histiocytes in marrow smears: Gaucher cells, foamy histiocytes in Niemann-Pick disease, generalized GM1


Neurology_Adams

Neurology_Adams. and vacuolated lymphocytes: Niemann-Pick disease, generalized GM1 gangliosidosis 7. Abnormal histiocytes in marrow smears: Gaucher cells, foamy histiocytes in Niemann-Pick disease, generalized GM1 gangliosidosis and closely related diseases, Farber disease 8. Colorless, friable hair: Menkes disease


Neurology_Adams

Neurology_Adams. Included here are the diseases that become manifest between the ages of 1 and about 4 years. Diagnosis is less difficult than in the neonate and young infant. A pathologic process in the nervous system is reliably ascertained by the obvious progression of a neurologic disorder, such as a loss of ability to walk and to speak, which usually parallels a regression in other high-level (quasi-intellectual) functions. Embryologic anomalies, prenatal diseases, and birth injuries can be excluded with relative certainty if psychomotor development was normal in the first year or two. Diseases characterized by seizures and myoclonus may prove more difficult to interpret, for the seizures may occur at any age from a variety of distant or immediate neurologic causes and, if frequent, may cause a significant impairment of psychomotor function. The effects of anticonvulsant medications may add to the impairment of cortical function. Unfortunately, most of the slowly advancing metabolic diseases of


Neurology_Adams

Neurology_Adams. impairment of psychomotor function. The effects of anticonvulsant medications may add to the impairment of cortical function. Unfortunately, most of the slowly advancing metabolic diseases of the second year may be so subtle in their effects that for a time the physician cannot be sure whether a regression of intellectual functions is taking place or mental retardation or autism is becoming apparent for the first time. An added difficulty arises when, for a number of years, the hereditary metabolic abnormality merely slows development. Repeated examinations and testing will usually settle the matter. Suspicion of a progressive encephalopathy is heightened by the presence of certain ocular, visceral, and skeletal abnormalities, as described below.


Neurology_Adams

Neurology_Adams. Once a neurologic syndrome is clearly established, there is a particular advantage in determining whether its main characteristics reflect a disorder of the cerebral white matter (oligodendrocytes and myelin) or of gray matter (neurons). Indicative of predominantly white matter affection (leukodystrophy or leukoencephalopathy) are early onset of spastic paralysis of the limbs, with or without ataxia, and visual impairment with optic atrophy but normal retinae. Seizures and intellectual deterioration are late events. MRI usually confirms the involvement of white matter. Indicative of gray matter disease (poliodystrophy or polioencephalopathy) are the early onset of seizures, myoclonus, blindness with retinal changes, and mental regression. Choreoathetosis and ataxia, spastic paralysis, and signs of sensorimotor tract involvement occur later. On MRI, only a generalized atrophy and ventricular enlargement may be seen.


Neurology_Adams

Neurology_Adams. Neuronal storage diseases, such as those described in the previous section, as well as neuroaxonal dystrophy and the lipofuscinoses, conform to the pattern of gray matter diseases (see Table 36-5). Metachromatic leukodystrophy, globoid-cell (Krabbe) disease, sudanophilic leukodystrophy, and spongy degeneration of infancy (Canavan disease) exemplify white matter diseases (see Table 36-6). Although this mode of categorization is helpful, there is some degree of overlap; for example, Tay-Sachs disease, a poliodystrophy, also causes white matter changes, and metachromatic leukodystrophy may be accompanied by some degree of neuronal storage.


Neurology_Adams

Neurology_Adams. The following are inherited metabolic diseases that become evident clinically in late infancy and early childhood: 1. Many of the milder disorders of amino acid metabolism 2. Metachromatic and other leukodystrophies 3. Late infantile GM1 gangliosidosis 4. Late infantile Gaucher disease and Niemann-Pick disease 5. Neuroaxonal dystrophy 6. The mucopolysaccharidoses 7. The mucolipidoses 8. Fucosidosis 9. The mannosidoses 10. Aspartylglycosaminuria 11. Ceroid lipofuscinosis (Jansky-Bielschowsky disease) 12. Cockayne syndrome The Aminoacidopathies (Aminoacidurias)


Neurology_Adams

Neurology_Adams. In a group of 48 inherited aminoacidopathies tabulated by Rosenberg and Scriver, at least one-half were associated with recognizable neurologic abnormalities. Twenty other aminoacidopathies result in a defect in the renal transport of amino acids, some of which secondarily damage the nervous system. Usually, when the nervous system is involved, the only clinical manifestation is simply a lag in psychomotor development, which, if mild, does not become apparent until the second and third years or later. Like other inherited metabolic disorders, the aminoacidurias do not impair growth, development, or maturation in utero or interfere with parturition. (This is the result of the maternal blood supply, which defines the amino acid balance in utero.) No physical sign betrays their presence in the early months of life. The only possible means of detection is by the screening of all newborns. Table 36-1 indicates the relative frequency of these diseases and Table 36-2 summarizes the practical


Neurology_Adams

Neurology_Adams. early months of life. The only possible means of detection is by the screening of all newborns. Table 36-1 indicates the relative frequency of these diseases and Table 36-2 summarizes the practical tests for their identification.


Neurology_Adams

Neurology_Adams. Three aminoacidopathies of the late infantile and early childhood period—PKU, tyrosinemia, and Hartnup disease—are described here because of their clinical importance and because they exemplify different types of biochemical defects. Reference is also made to certain other aminoacidurias, described in the first part of this chapter, which, like Hartnup disease, are associated with intermittent ataxia. Only passing comments are made about the other aminoacidurias, which are exceedingly rare or have only an uncertain effect on the nervous system. A detailed account of these disorders can be found in the monograph of Scriver and coworkers. The Phenylketonurias (Phenylalanine Hydroxylase Deficiency, PAH Mutation)


Neurology_Adams

Neurology_Adams. The Phenylketonurias (Phenylalanine Hydroxylase Deficiency, PAH Mutation) Apart from being the most frequent of the aminoacidurias, this entity has a special historical significance. Since its discovery by Følling in 1934, it has remained the classic example of an aminoaciduria and illustrates three principles of medical genetics: first, it is inherited as an autosomal recessive trait; second, it exemplifies Garrod’s cardinal principle of gene action, in which genetic factors specify chemical reactions as well as biochemical individuality; third, PKU is expressed only in an environment that contains an abundance of l-phenylalanine. Thus, as predicted by Galton, the ultimate phenotype is a product of “nature and nurture” (Scriver and Clow).


Neurology_Adams

Neurology_Adams. One must refer to the phenylketonurias in the plural, for there are (1) the usual type and several mild and severe variants thereof, in all of which mental retardation is invariable if the disease is not treated early in life; (2) other types, presumably allelic mutations, in which there is hyperphenylalaninemia without PKU and without effect on the nervous system; and (3) a rare adult type with a progressive spastic paraparesis or without neurologic manifestations. Also there are a small number of patients (3 percent in our series) in whom a lowering of the hyperphenylalaninemia does not prevent the progression of the neurologic lesion.


Neurology_Adams

Neurology_Adams. At birth, the typical PKU infant is believed to have a normal nervous system. The disease appears later, only after long exposure of the nervous system to phenylalanine (PA), because the homozygous infant lacks the means of protecting the nervous system. However, if the mother is homozygous with high PA levels in the blood during pregnancy, the CNS is damaged in utero and the heterozygous infant is mentally defective from birth.


Neurology_Adams

Neurology_Adams. In the classic form of PKU, the impairment of psychomotor development can usually be recognized in the latter part of the first year, when expected performance lags. By 5 to 6 years in an untreated child, when the IQ can be estimated, it is usually less than 20, occasionally 20 to 50, and exceptionally above 50. Hyperactivity, aggressivity, self-injurious behavior—including severe injury to the eyes, clumsy gait, fine tremor of the hands, poor coordination, odd posturings, repetitious digital mannerisms and other so-called rhythmias, and slight corticospinal tract signs stand out as the main clinical manifestations. Athetosis, dystonia, and frank cerebellar ataxia have been described but must be rare. Also, seizures occur in a small minority of severely affected patients, taking the form at first of flexor spasms and later of absence and grand mal attacks. Most PKU patients are blue-eyed and fair in skin and hair color, and their skin is rough and dry and subject to eczema. A musty


Neurology_Adams

Neurology_Adams. at first of flexor spasms and later of absence and grand mal attacks. Most PKU patients are blue-eyed and fair in skin and hair color, and their skin is rough and dry and subject to eczema. A musty body odor (because of phenylacetic acid excretion) can often be detected. Two-thirds are slightly microcephalic. The fundi are normal, and there is no visceral enlargement or skeletal abnormality.


Neurology_Adams

Neurology_Adams. There are some people living in the community with asymptomatic PKU and normal intelligence. Instances of PKU in which the symptoms are of adult onset are rare but of interest because of the entirely unexpected diagnosis. The few such cases reported and summarized by Kasim and colleagues, with a case of their own, developed a progressive spastic paraparesis, some with mild dementia. The phenylalanine levels were at values that reflect total or partial enzyme deficiency.


Neurology_Adams

Neurology_Adams. The finding of high levels of serum phenylalanine (above 15 mg/dL) and of phenylpyruvic acid in the blood, CSF, and urine is diagnostic of PKU. The level is normal at birth and rises only after the first few days. But screening by the Guthrie (ferric chloride) test will reliably identify the patient at risk. The addition of 3 to 5 drops of 10 percent ferric chloride to 1 mL of urine is a simple and informative test that was used at the neonates or child’s bedside in the past. It yields an emerald-green color that reaches peak intensity in 3 to 4 min and fades in 20 to 40 min. In contrast, the green-brown color in the urine of patients with histidinemia is permanent. In maple syrup urine disease, the ferric chloride test gives a navy-blue color; propionic and methylmalonic acidemia and either ketones or salicylates in the urine yield a purple color.


Neurology_Adams

Neurology_Adams. The fundamental biochemical abnormality is a deficiency of the hepatic enzyme PA hydroxylase; the failure of conversion of PA to tyrosine results in the excretion of phenylpyruvic acid by affected individuals. The precise step that is faulty in the complex phenylalanine hydroxylating reaction is still unknown. Pathologic examination shows poor staining of myelin in the cerebral hemispheres. This can be visualized by MRI in untreated children. Another instructive feature is that the pigmented nuclei (substantia nigra, locus ceruleus, dorsal vagal motor) fail to acquire dark coloration because of a block in the production of neuromelanin. Reduction in size of cortical neurons and their dendritic arborizations is said to be demonstrable in some cases.


Neurology_Adams

Neurology_Adams. Treatment If instituted in infancy, diets low but not totally lacking in PA can improve intellectual development (blood level should be maintained at 5 to 10 mg/dL). Careful dietary management may result in completely normal intellectual development. Once the neurologic picture unfolds, diet has little or no effect on the mental status but may improve behavior. Prolonged dietary treatment has many untoward effects and should be supervised by physicians and nutritionists experienced in its use; if too restricted, it may retard growth. This is particularly important, as it has been shown that intellectual impairment is greatest among children who were the earliest to abandon their diets, permitting the PA concentration to rise above 15 mg/dL, and least in children who maintained dietary control the longest (Holtzman et al). Continued dietary treatment is probably necessary, but the degree of restriction of PA may be relaxed once the nervous system is fully developed. The precise degree


Neurology_Adams

Neurology_Adams. the longest (Holtzman et al). Continued dietary treatment is probably necessary, but the degree of restriction of PA may be relaxed once the nervous system is fully developed. The precise degree of allowed restriction of dietary PA restriction is not known but many children, having been raised on a low PA diet, will have little or no difficulty in maintaining the restrictions into adulthood.


Neurology_Adams

Neurology_Adams. With the widespread screening for PKU and the initiation of dietary control during early postnatal life, this metabolic brain disease has virtually disappeared in the New England states. Treated women who reach childbearing age should be particularly careful about dietary restriction, because high levels of phenylalanine are harmful to the normal fetus. Mild cases of PKU have been successfully treated with the cofactor tetrahydrobiopterin (Muntau et al). The late forms of maple syrup urine disease, and hydroxyprolinemia evolve in much the same fashion as PKU and raise similar problems in diagnosis and therapy. Histidinemia can be detected by screening but is now considered a benign biochemical variant.


Neurology_Adams

Neurology_Adams. A small number of infants have a variant of PKU in which a restricted PA diet does not prevent neurologic involvement. In some such infants, a dystonic extrapyramidal rigidity (“stiff-baby syndrome”) has appeared as early as the neonatal period, and, according to Allen and coworkers, it responds to biopterin. Such infants have normal levels of PA hydroxylase in the liver. The defect is a failure to synthesize the active cofactor tetrahydrobiopterin, because of either an insufficiency of dihydropteridine reductase or an inability to synthesize biopterin (see “Biopterin Deficiency”). The urinary metabolites of catecholamines and serotonin are reduced and are not responsive to low-PA diets. There is some evidence that the underlying neurotransmitter fault can be corrected by l-dopa and by 5-hydroxytryptophan (Scriver and Clow).


Neurology_Adams

Neurology_Adams. This is a rare, predominantly dermatologic aminoacidopathy, that exists in three types, each with an underlying mutation (FAH, TAT, and HPD), and in more than one-half of the infants there is developmental delay. The protein product of these genes pertain to the breakdown of tyrosine. Also, as in some other aminoacidopathies, there may be self-mutilation and incoordination of limb movements. Language defects are prominent. Toward the end of the first or second year of life, lacrimation, photophobia, and redness of the eyes (because of corneal erosions) appear. Neovascularization of the corneas and opacification follow. Palmar and plantar keratosis with hyperhidrosis and pain are frequently present as a result of an inflammatory reaction to deposits of crystalline tyrosine (also the cause of the corneal changes). Elevated tyrosine in the blood (>0.18 mM) and urine is diagnostic. The most severe form (type 1) is caused by a mutation in the gene (FAH) that codes for fumarylacetoacetate


Neurology_Adams

Neurology_Adams. of the corneal changes). Elevated tyrosine in the blood (>0.18 mM) and urine is diagnostic. The most severe form (type 1) is caused by a mutation in the gene (FAH) that codes for fumarylacetoacetate hydrolase, the final enzymatic step in tyrosine metabolism, a deficiency of which results in the accumulation of tyrosine and its metabolites.


Neurology_Adams

Neurology_Adams. A low-tyrosine and low-PA diet, optimized to allow growth and development, has resulted in rapid amelioration of symptoms but must be started early. Retinoids given orally improve the skin lesions. Neonatal tyrosinemia can cause liver failure and early death. This disease can be distinguished from the Cross syndrome (albinism with mental retardation, growth impairment, spastic weakness, and alkalosis) and from the Waardenburg ocular albinism syndrome (white forelock, hypertelorism, deafness). For a detailed discussion of the albinism syndromes, see the article by Oetting and King.


Neurology_Adams

Neurology_Adams. This disease causes a progressive infantile encephalopathy; it is of special interest because tyrosine is the precursor of l-dopa and the other catecholamines. Levels of these chemical substances in the brain are greatly reduced. As a result, the encephalopathy takes the form mainly of fluctuating extrapyramidal signs in combination with ocular and vegetative symptoms. l-Dopa causes some improvement in the motor symptoms (see Hoffmann et al). This disease has similarities to juvenile dopa-responsive dystonia, which is exquisitely sensitive to l-dopa treatment (as discussed in Chap. 38) and to the deficiency of l-amino decarboxylase, described above, which also causes low levels of catecholamines and a movement disorder.


Neurology_Adams

Neurology_Adams. This amino acid disorder, named after the family in which it was first observed, is probably transmitted in an autosomal recessive pattern. The babies are normal at birth. The onset of symptoms is in late infancy or early childhood. The clinical features consist of an intermittent red, scaly rash over the face, neck, hands, and legs, resembling that of pellagra. It is often combined with an episodic personality disorder in the form of emotional lability, uncontrolled temper, and confusional-hallucinatory psychosis; episodic cerebellar ataxia (unsteady gait, intention tremor, and dysarthria); and, occasionally, spasticity, vertigo, nystagmus, ptosis, and diplopia. Attacks of disease are triggered by exposure to sunlight, emotional stress, and sulfonamide drugs and last for about 2 weeks, followed by variable periods of relative normalcy. The frequency of attacks diminishes with maturation, but some children suffer retarded growth and development with a mild persistent mental


Neurology_Adams

Neurology_Adams. 2 weeks, followed by variable periods of relative normalcy. The frequency of attacks diminishes with maturation, but some children suffer retarded growth and development with a mild persistent mental retardation.


Neurology_Adams

Neurology_Adams. The metabolic faults are the result of a transport error of neutral amino acids across renal tubules, with excretion of greatly increased amounts of these amino acids in the urine and feces. In particular, there is the excretion of large amounts of indicans, mainly indoxyl sulfate, particularly after oral l-tryptophan loading, and an abnormally high excretion of nonhydroxylated indole metabolites. Impaired intestinal transport of tryptophan and loss in the urine reduce its availability for the synthesis of niacin and accounts for the pellagrous skin changes. The pathologic basis of the disease is undetermined. It must be differentiated from the large number of intermittent and progressive cerebellar ataxias of childhood, described below.


Neurology_Adams

Neurology_Adams. Treatment consists of avoiding exposure to sunlight and to sulfonamide drugs. Because of the similarities between pellagra and Hartnup disease, the usual practice is to give nicotinamide in doses of 50 to 300 mg daily. The skin lesions disappear and there are reports of subsidence of ataxia and psychotic behavior. However, the results of treatment are inconsistent. Possibly a better response is obtained by the administration of l-tryptophan ethyl ester in doses of 20 mg/kg tid. Other Metabolic Diseases With Episodic or Persistent Ataxia, Seizures, and Developmental Delay


Neurology_Adams

Neurology_Adams. Other Metabolic Diseases With Episodic or Persistent Ataxia, Seizures, and Developmental Delay In addition to Hartnup disease, a number of other metabolic diseases give rise to intermittent episodes of ataxia during early childhood. These are (1) mild forms of maple syrup urine disease and the congenital hyperammonemias (type II hyperammonemia, citrullinemia, argininosuccinic aciduria, hyperornithinemia), described in an earlier part of the chapter; (2) subacute necrotizing encephalomyelopathy (Leigh disease), described further on; (3) hyperalaninemia and hyperpyruvic acidemia (Lonsdale et al; Blass et al); and (4) autosomal dominant, acetazolamide-responsive ataxia that may have its onset in childhood but usually appears later (see Griggs et al); and (5) familial hypobetalipoproteinemia—Bassen-Kornzweig disease.


Neurology_Adams

Neurology_Adams. In all of these conditions, the ataxia, which is of cerebellar type, is variable from time to time and may follow a burst of seizures (such as occur in argininosuccinic aciduria). The seizures are treated with antiepileptic drugs, which may at first be held responsible for the ataxia. In time, however, it becomes apparent that the ataxia lasts a week or two and bears no relation to the anticonvulsant therapy. Indeed, seizures and ataxia are both a result of the common biochemical abnormality. Between attacks, in all the intermittent ataxias, the patient’s movements are relatively normal, but most of the affected children have learning disabilities to a varying degree. Progressive Cerebellar Ataxia of Early Childhood


Neurology_Adams

Neurology_Adams. The differentiation among the childhood ataxias is difficult. The problem is twofold—first, to be certain that ataxia exists and, second, to differentiate cerebellar ataxia from the sensory ataxia of peripheral nerve disease and from generalized tremor and polymyoclonus. Because cerebellar ataxia is more a disorder of voluntary than of postural movements, its presence usually cannot be determined with certainty until intentional (projected) movements become part of the child’s repertoire of motor activity. As indicated in Chap. 27, the earliest signs become manifest in the arms when the infant reaches for an object and brings it to his mouth or transfers it from hand to hand. A jerky, wavering, tremulous movement then appears; in sitting, titubation of the head and a tremor of the trunk may be apparent. Once walking begins, apart from the usual clumsiness of the toddler, there is a similar incoordination of movement. Sensory ataxia is always difficult to distinguish but is rare at


Neurology_Adams

Neurology_Adams. may be apparent. Once walking begins, apart from the usual clumsiness of the toddler, there is a similar incoordination of movement. Sensory ataxia is always difficult to distinguish but is rare at this age and usually accompanied by weakness and absence of tendon reflexes. By the fourth or fifth year, when more detailed sensory testing becomes possible, the presence or absence of a proprioceptive disturbance and a Romberg sign can be demonstrated.


Neurology_Adams

Neurology_Adams. The group of persistent and progressive cerebellar ataxias is heterogeneous and of varied etiology; some of them merge with Friedreich ataxia, Levy-Roussy neuropathy, and other adolescent–adult degenerative hereditary ataxias. These disorders are discussed in Chap. 38. There are many other childhood ataxias that probably belong in the category of degenerative disease, some in which cerebellar ataxia is the most prominent disorder and in which other neurologic abnormalities are more prominent. To describe each in detail would be impractical in a book on the principles of neurology; consequently, the non- Friedreich ataxias are only tabulated here. 1. Cerebellar ataxia with diplegia, hypotonia, and mental retardation (also called atonic diplegia of Foerster); this is a form of cerebral palsy.


Neurology_Adams

Neurology_Adams. Friedreich ataxias are only tabulated here. 1. Cerebellar ataxia with diplegia, hypotonia, and mental retardation (also called atonic diplegia of Foerster); this is a form of cerebral palsy. 2. Agenesis of the cerebellum: early cerebellar ataxia (with or without mental retardation) and episodic hyperventilation; this group included the selective agenesis of the vermis—Joubert syndrome. 3. Cerebellar ataxia with cataracts and oligophrenia: onset from childhood (mainly) to as late as adult years (Marinesco-Sjögren disease). 4. Familial cerebellar ataxia and retinal degeneration (Behr disease). 5. Familial cerebellar ataxia with cataracts and ophthalmoplegia or with cataracts and mental as well as physical retardation. 6. Familial cerebellar ataxia with mydriasis. 7. Familial cerebellar ataxia with deafness and blindness and a similar combination, called retinocochleodentate degeneration, involving the loss of neurons in these three structures.


Neurology_Adams

Neurology_Adams. 7. Familial cerebellar ataxia with deafness and blindness and a similar combination, called retinocochleodentate degeneration, involving the loss of neurons in these three structures. 8. Familial cerebellar ataxia with choreoathetosis, corticospinal tract signs, and mental and motor retardation. In none of the syndromes mentioned above has a biochemical abnormality been established, so their metabolic nature is a matter of speculation. However, disorders of the electron transport chain can, on occasion, present as the Marinesco-Sjögren phenotype, mentioned above. The persistent cerebellar ataxias of childhood in which a metabolic fault or mutation has been demonstrated are as follows: 1. Refsum disease 2. Abetalipoproteinemia (Bassen-Kornzweig syndrome) 3. Ataxia-telangiectasia (see Chap. 37) 4. Galactosemia 5. Friedreich ataxia


Neurology_Adams

Neurology_Adams. Bassen-Kornzweig syndrome (onset more often in late than in early childhood) is described in the following section of this chapter. Ataxia-telangiectasia is described below. Generally, it is not difficult to differentiate these diseases from the acquired postinfectious variety that occurs predominantly in children (see Chap. 36). Metachromatic Leukodystrophy (MLD, Arylsulfatase Deficiency, ARSA Mutation)


Neurology_Adams

Neurology_Adams. Metachromatic Leukodystrophy (MLD, Arylsulfatase Deficiency, ARSA Mutation) This is another of the lysosomal (sphingolipid) storage diseases (see Tables 36-3 and 36-6). The abnormality is the mutation of the gene for enzyme arylsulfatase A (ARSA), which prevents the conversion of sulfatide to cerebroside (a major component of myelin) and results in an accumulation of the former. The disease is transmitted as an autosomal recessive trait and usually becomes manifest between the first and fourth years of life (variants have their onset in the congenital period, in late childhood, and even in adult life). Variability of gene mutation accounts for the different forms. A less frequent form is due to a mutation in PSAP, which also results in the inability to break down sulfatides.


Neurology_Adams

Neurology_Adams. The disease in this age group is characterized clinically by progressive impairment of motor function (gait disorder, spasticity) in combination with reduced output of speech and mental regression. At first the tendon reflexes are usually brisk, but later, as the peripheral nerves become more involved, the tendon reflexes are decreased and eventually lost. Or, there may be variable hypotonia and areflexia from the beginning, or spasticity may be present throughout the illness, but with hyporeflexia and slowed conduction velocities. Signs of mental regression may be apparent from the onset or appear after the motor disorder has become established. Later there is impairment of vision, sometimes with squint and nystagmus; intention tremor in the arms and dysarthria; dysphagia and drooling; and optic atrophy (one-third of patients), sometimes with grayish degeneration around the maculae. Seizures are rare, and there are no somatic abnormalities. The head size is usually normal, but rarely


Neurology_Adams

Neurology_Adams. optic atrophy (one-third of patients), sometimes with grayish degeneration around the maculae. Seizures are rare, and there are no somatic abnormalities. The head size is usually normal, but rarely there is macrocephaly. Progression to a bedridden quadriplegic state without speech or comprehension occurs over a 1to 3-year period, somewhat more slowly in late-onset types. The CSF protein is elevated.


Neurology_Adams

Neurology_Adams. There is widespread degeneration of myelinated fibers in the cerebrum (Fig. 36-5), cerebellum, spinal cord, and peripheral nerves. The presence of metachromatic granules in glia cells and engorged macrophages is characteristic and enables the diagnosis to be made from a biopsy of a peripheral nerve. The stored material, sulfatide, stains brown-orange rather than purple with aniline dyes. Sulfatides are also PAS-positive in frozen sections.


Neurology_Adams

Neurology_Adams. Genetic testing is now widely available but the diagnostic laboratory findings, in addition to the MRI and histologic changes, are the elevated CSF protein (75 to 250 mg/dL) and a marked increase in sulfatide in urine and an absence of arylsulfatase A in white blood cells, in serum, and in cultured fibroblasts. Assays of arylsulfatase A activity in cultured fibroblasts and amniocytes permit the identification of carriers and prenatal diagnosis of the disease but a pseudodeficiency of the enzyme is known (the Pd allelic variant). In this condition, measured enzyme activity is 10 percent of normal, but no clinical manifestations result. Treatment with enzyme replacement or bone marrow transplantation is being tried. Marrow transplant appears to be of less benefit once the patient becomes symptomatic, but it may be useful early in the disease and in the treatment of an asymptomatic sibling of an index case.


Neurology_Adams

Neurology_Adams. The differential diagnosis of this leukodystrophy includes neuroaxonal dystrophy (see below), cases of early-onset inherited polyneuropathy, late-onset Krabbe disease, and childhood forms of Gaucher disease and Niemann-Pick disease. A variant of metachromatic leukoencephalopathy, caused by a deficiency of the isoenzymes of arylsulfatase A, B, and C, was described by Austin in 1973 and called multiple sulfatase deficiency. The neurologic manifestations resemble those of metachromatic leukodystrophy but, in addition, there are facial and skeletal changes similar to those of a mucopolysaccharidosis. Deafness, hepatic enlargement, ichthyosis, and beaking of lumbar vertebrae are additional findings in some cases. Metachromatic material is found in the urinary sediment. Pathologically, in addition to metachromasia of degenerating white matter in cerebrum and peripheral nerve, there may be storage material (sulfated glycolipids), like that found in the gangliosidoses in neurons as well as in


Neurology_Adams

Neurology_Adams. to metachromasia of degenerating white matter in cerebrum and peripheral nerve, there may be storage material (sulfated glycolipids), like that found in the gangliosidoses in neurons as well as in liver, gallbladder, and kidney. Granules are demonstrable in neutrophilic leukocytes. There has also been described a state of “arylsulfatase pseudodeficiency,” which exists as a polymorphism in approximately 7 percent of Europeans and makes the point that low enzyme levels alone are insufficient to be expressed as a phenotype of metachromatic leukodystrophy.


Neurology_Adams

Neurology_Adams. Forms of metachromatic leukodystrophy developing in adult years are discussed further on. This is a rare disease, inherited as an autosomal recessive trait. In the largest group of cases (77 collected by Aicardi and Castelein), the onset was near the beginning of the second year in 50 patients and before the third year in all instances. The clinical constellation comprised psychomotor deterioration (loss of ability to sit, stand, and speak), marked hypotonia but brisk reflexes and Babinski signs, and progressive blindness with optic atrophy but normal retinae. Seizures, myoclonus, and extrapyramidal signs were rare. Loss of sensation was found later in some cases. Terminally, bulbar signs, spasticity, and decerebrate rigidity often supervened. The course was relentlessly progressive, with fatal issue in a decorticate state in 3 to 8 years. There were no abnormalities of the liver and spleen and no facial or skeletal changes.


Neurology_Adams

Neurology_Adams. Pathologic examination reveals eosinophilic spheroids of swollen axoplasm in the posterior columns and nuclei of Goll and Burdach and in the Clarke column, substantia nigra, subthalamic nuclei, central nuclei of brainstem, and cerebral cortex. There is cerebellar atrophy, affecting the granule cell layer predominantly, and increased iron-containing pigment in the basal ganglia (like that observed in the PANK2 mutation type of iron deposition discussed in a later section).


Neurology_Adams

Neurology_Adams. The CT and CSF are normal, and there are no biochemical or blood cell abnormalities. MRI may show decreased signal intensity of the pallidum bilaterally corresponding to iron deposition. Some reports are confusing in reporting an area of necrosis around a high signal that is characteristic of the aforementioned PANK2 mutation, with which it has overlapping clinical and pathologic features. After the age of 2 years, however, the EEG shows characteristic high-amplitude fast rhythms (16 to 22 Hz). Evoked responses may be abnormal. Nerve conduction velocities are normal despite EMG evidence of denervation. The diagnosis can be reliably established during life by electron microscopic examination of skin and conjunctival nerves, which show the characteristic spheroids within axons.


Neurology_Adams

Neurology_Adams. There is a later-onset form of the disease in which the course is more protracted and the neurologic manifestations (rigidity and spasticity, cerebellar ataxia, and myoclonus) are more pronounced. In these cases, the mental regression is slow. Vision may be retained but retinal degeneration has been documented. Some of the late-onset cases are indistinguishable from PKAN (formerly Hallervorden-Spatz) disease. In early infantile forms there is a mutation in a lysosomal hydrolase. The primary mutation in the infantile form is in the PLA2G6 gene.


Neurology_Adams

Neurology_Adams. In early infantile forms there is a mutation in a lysosomal hydrolase. The primary mutation in the infantile form is in the PLA2G6 gene. As stated earlier, Gaucher disease usually develops in early infancy, but some cases, so-called Gaucher disease type III, may begin in childhood, between 3 and 8 years of age. The clinical picture is variable and combines features of infantile Gaucher disease—such as abducens palsies, dysphagia, trismus, rigidity of the limbs, and dementia—with features of the late childhood–early adult form, such as palsies of horizontal gaze, diffuse myoclonus, generalized seizures, and a chronic course. The diagnosis is established by the finding of splenomegaly, Gaucher cells, glucocerebroside storage, and deficient activity of glucocerebrosidase in leukocytes or cultured fibroblasts.


Neurology_Adams

Neurology_Adams. Niemann-Pick disease is a subacute or chronic neurovisceral storage disease with early signs of hepatosplenomegaly and later signs (2 to 4 years) of neurologic involvement. These later-onset types have been termed C and D, and formerly, III and IV, to differentiate them from infantile forms discussed earlier. The neurologic disorder consists of progressive dementia, dysarthria, ataxia, rarely extrapyramidal signs (choreoathetosis), and paralysis of horizontal and vertical gaze, the latter being a distinguishing feature of the later-onset types. On attempting to look to the side, some of the patients make head-thrusting movements of the same type that one observes in ataxia- telangiectasia and the oculomotor apraxia of Cogan. Lateral eye movements are full on passive movement of the head (oculocephalic maneuver). Convergence is also deficient. A subtype called juvenile dystonic lipidosis is characterized by extrapyramidal symptoms and paralysis of vertical eye movements. The syndrome


Neurology_Adams

Neurology_Adams. (oculocephalic maneuver). Convergence is also deficient. A subtype called juvenile dystonic lipidosis is characterized by extrapyramidal symptoms and paralysis of vertical eye movements. The syndrome of the “sea-blue histiocyte” (liver, spleen, and bone marrow contain histiocytes with sea-blue granules)—in which there is retardation in mental and motor development, grayish macular degeneration, and, in rare cases, posterior column and pyramidal degeneration—may be another variant.


Neurology_Adams

Neurology_Adams. The diagnosis is made by measuring the defect in cholesterol esterification in cultured skin fibroblasts.


Neurology_Adams

Neurology_Adams. In type 2 or so-called juvenile GM1 gangliosidosis, the onset is between 12 and 24 months, with survival for 3 to 10 years. The first sign is usually difficulty in walking, with frequent falls, followed by awkwardness of arm movements, loss of speech, severe mental regression, gradual development of spastic quadriparesis and pseudobulbar palsy (dysarthria, dysphagia, drooling), and seizures. Retinal changes are variable—usually they are absent—but macular red spots may be seen at the age of 10 to 12 years; vision is usually retained, but strabiusmus is common. There is a facial dysmorphism resembling that of the Hurler syndrome, and the liver and spleen are enlarged. Important laboratory findings are hypoplasia of the thoracolumbar vertebral bodies, mild hypoplasia of the acetabula, and the presence in the bone marrow of histiocytes with clear vacuoles or wrinkled cytoplasm. As noted in the discussion of Tay-Sachs disease, leukocytes and cultured skin fibroblasts show a deficiency or


Neurology_Adams

Neurology_Adams. presence in the bone marrow of histiocytes with clear vacuoles or wrinkled cytoplasm. As noted in the discussion of Tay-Sachs disease, leukocytes and cultured skin fibroblasts show a deficiency or absence of beta-galactosidase activity. GM1 ganglioside accumulates in the cerebral neurons.


Neurology_Adams

Neurology_Adams. Although not strictly speaking, a metabolic disturbance, under this title, Kinsbourne described a form of widespread, continuous myoclonus (except during deep sleep) affecting male and female infants whose development had been normal until the onset of the disease at the age of 9 to 20 months. It is therefore referable to the other forms of childhood and infantile myoclonus as discussed in Chap. 30 with paraneoplastic disorders. The myoclonus evolves over a week or less, affects all the muscles of the body, and interferes seriously with all the natural muscular activities of the child. The eyes are notably affected by rapid (up to 8/s), irregular conjugate movements (“dancing eyes” of an opsoclonic type). The child is irritable and speech may cease. All laboratory tests are normal.


Neurology_Adams

Neurology_Adams. Treatment Dexamethasone in doses of 1.5 to 4.0 mg/d suppresses the myoclonus and permits developmental progress. Some patients have recovered from the myoclonus but have been left mentally slow and mildly ataxic. Others have required corticosteroid therapy for 5 to 10 years, with relapse whenever it was discontinued. Ordinary anticonvulsants seem to have no effect. The pathology has not been determined. A similar syndrome has been observed in conjunction with neuroblastoma in children and as a transient illness of unknown cause (probably viral or postinfectious) in young adults (Baringer et al). A similar condition is also known in adults as a paraneoplastic disease with ovarian, breast, gastric, and bronchogenic carcinomas and with other occult tumors.


Neurology_Adams

Neurology_Adams. In a broader survey of the pediatric opsoclonus-myoclonus syndrome, Pranzatelli and associates reported their experience with 27 cases, some with neural crest tumors, others with viral infections or hypoxic injury (intention myoclonus). In nearly all of their patients there was cerebellar ataxia and mental disorder, and 10 percent had seizures. The CSF was normal. The investigators have emphasized the pathogenetic heterogeneity and defined a rare serotoninergic type (low levels of 5-hydroxytryptophan and homovanillic acid in the CSF) that responds to 5-hydroxyindole acetic acid. The Neuronal Ceroid Lipofuscinoses (“Batten Disease,” CLN, TPP1, PTT1 Mutations)


Neurology_Adams

Neurology_Adams. The Neuronal Ceroid Lipofuscinoses (“Batten Disease,” CLN, TPP1, PTT1 Mutations) Four types of lipofuscinoses have been identified, formerly defined largely by the age of onset: Santavuori-Haltia Finnish infantile type, Jansky-Bielschowsky early childhood type, Vogt-Spielmeyer juvenile type, and Kufs adult type. They have been referred to collectively as Batten disease, although that term has been applied to the juvenile form. The storage material in neuronal cytoplasm consists of two pigmented lipids, presumably ceroid and lipofuscin, which are cross-linked polymers of polyunsaturated fatty acids and have the property of autofluorescence.


Neurology_Adams

Neurology_Adams. Newer classifications have confused the picture and use a numbered nomenclature, NCL 1 through NCL 10; the older classification would have approximated forms 1 through 4, most due to mutations in CLN or less often, TPP1 or PPT1. All except a few adult cases are autosomal recessive and the diagnosis can be made by genetic study. The type of mutation (nonsense, frame shift, missense) also has an influence on the clinical syndrome that results (Wisniewski et al). All the infantile forms and one of the juvenile forms of the disease are due to of mutations affecting the lysosomal enzyme palmitoyl–protein thioesterase. Other lysosomal enzymes are abnormal in the remaining juvenile and in the adult forms. Each of these disorders is discussed in more detail with the other metabolic disorders that appear at each age of life.


Neurology_Adams

Neurology_Adams. In the infantile Santavuori-Haltia form of the disease (NCL 1, PPT1 mutation), infants from 3 to 18 months of age, after a normal period of development, undergo psychomotor regression with ataxia, hypotonia, and widespread myoclonus. There are retinal changes with extinction of the electroretinogram, slowing of the EEG with spike and slow-wave discharges, and eventually an isoelectric record. Within a few years these patients become blind, develop spastic quadriplegia and microcephaly, and succumb.


Neurology_Adams

Neurology_Adams. In the late infantile-juvenile Jansky-Bielschowsky type (NCL 2, TPP1 mutation), the onset of symptoms is between 2 and 4 years, after normal or slightly slow earlier development, with survival to 4 to 8 years of age. Usually the first neurologic manifestations are seizures (petit mal or grand mal) and myoclonic jerks evoked by proprioceptive and other sensory stimuli, including voluntary movement and emotional excitement. Incoordination, tremor, ataxia, and spastic weakness with lively tendon reflexes and Babinski signs, deterioration of mental faculties, and dysarthria proceed to dementia and eventually to mutism. In patients with relatively late onset, a progressive dementia is the cardinal manifestation. Visual failure may occur early in some cases because of retinal degeneration (of rods and cones) with pigmentary deposits, but in others vision is normal. The electroretinogram becomes isoelectric if vision is affected. Abnormal inclusions (translucent vacuoles) are seen in 10 to


Neurology_Adams

Neurology_Adams. rods and cones) with pigmentary deposits, but in others vision is normal. The electroretinogram becomes isoelectric if vision is affected. Abnormal inclusions (translucent vacuoles) are seen in 10 to 30 percent of circulating lymphocytes, and azurophilic granules in neutrophils. High-voltage EEG spikes are induced by photic stimuli. Only in early-onset cases is there microcephaly. It is in this type of Batten disease that an intraventricularly administered enzyme replacement treatment (cerolipinase alpha) by Schulz and coworkers has met with provocative success in reducing the degree and rapidity of cognitive decline compared to historical controls, at the price of serious adverse events, many from the intraventricular catheter.


Neurology_Adams

Neurology_Adams. In the juvenile form (NCL 3, CLN3 mutation), visual loss, seizures and ataxia predominate. The adult Kuf type (NCL 4, CLN6 and other mutations) has manifestations that are varied, including dementia, as discussed further on. Pathologic examination shows neuronal loss in the cerebral and cerebellar cortices (granule and Purkinje cells), and curvilinear storage particles and osmophilic granules are visible in the remaining neurons. Inclusions are also observed in cutaneous nerve twigs and endothelial cells of blood vessels, findings that permit diagnosis during life by electron microscopy of skin, conjunctival, or rectal mucosal biopsies. In many patients with lipofuscinoses, diagnosis can be confirmed by demonstrating the presence of one of several recently identified gene mutations. There are no definite markers for the group in blood or urine, but in some patients a structural component of mitochondria is excreted in excess (the so-called C-fragment).


Neurology_Adams

Neurology_Adams. In the differential diagnosis, one must consider late infantile GM1 gangliosidosis, idiopathic epilepsy, Alpers disease, and other forms of neuronal ceroid-lipofuscinosis. This is a group of diseases in which the storage of lipid in neurons is combined with that of polysaccharides in connective tissues. As a consequence, there is a conjunction of neurologic and skeletal abnormalities that is virtually unique. The nervous system may also be involved secondarily as a result of skeletal deformities and thickening and hyperplasia of connective tissue at the base of the brain, leading to obliteration of the subarachnoid space and obstructive hydrocephalus or compression of the cervical cord. The prevalence of mucopolysaccharides as a whole is approximately 1 per 8,000 births, according to Meikle and colleagues. Depending on the degree of visceral-skeletal and neurologic changes, at least 7 distinct clinical subtypes are recognized (see Table 36-7).


Neurology_Adams

Neurology_Adams. The basic abnormality is an enzymatic defect that prevents the degradation of acid mucopolysaccharides (now called glycosaminoglycans). The latter can be measured and are increased in serum, leukocytes, or cultured fibroblasts. The storage is, again, within lysosomes in the brain, spinal cord, heart, viscera, bone, and connective tissue. All forms of the disease except the Hunter syndrome, which is sex-linked, are inherited in an autosomal recessive pattern. Studies over a 50-year period have established that each type of mucopolysaccharidosis is caused by a defect in a different enzyme and in keeping with progress in the field, the mutation of each disorder has been established. Hurler Disease (MPS I, IDUA Mutation)


Neurology_Adams

Neurology_Adams. This, the classic form, also known as MPS I, begins clinically toward the end of the first year. Mental retardation is severe, and skeletal abnormalities are prominent (dwarfism; gargoyle facies; large head with synostosis of longitudinal suture; kyphosis; broad hands with short, stubby fingers; flexion contractures at knees and elbows). Conductive deafness and corticospinal signs are usually present. Protuberant abdomen, hernias, enlarged liver and spleen, valvular heart disease, chronic rhinitis, recurrent respiratory infections, and corneal opacities complete the picture. The biochemical abnormalities consist of the accumulation of dermatan and heparan sulfate (glycosaminoglycans) in the tissues and their excretion in the urine, probably as a consequence of absence of activity of a-l-iduronidase. Also, there is an increase in the ganglioside content in nerve cells of the brains of these patients. In the milder Scheie (MPS V) variant of Hurler disease, intelligence and life span are


Neurology_Adams

Neurology_Adams. Also, there is an increase in the ganglioside content in nerve cells of the brains of these patients. In the milder Scheie (MPS V) variant of Hurler disease, intelligence and life span are normal. A few newborn screening programs in the United States test the infant’s blood for MPS I.


Neurology_Adams

Neurology_Adams. Treatment Enzyme replacement therapy (laronidase) is available. The enzyme is produced with recombinant technology and is successful where previous attempts with enzymes delivered by white cell or other infusions had been ineffective. Hematopoietic stem cell bone marrow transplantation (cord blood from unrelated donors) has also been used (see Staba et al). To be effective, treatment must commence before the accumulation of glycosaminoglycans and neurologic decline. The eye and bone deterioration associated with Hurler disease is not improved. In children with the milder Scheie form and those with CNS involvement, bone marrow transplantation is not helpful and enzyme replacement is recommended. Enzyme treatment is also being tried concurrently with bone marrow transplantation in early cases. These approaches have not been effective in the Hunter or the Sanfilippo diseases, discussed below. Hunter Disease (MPS II, IDS Mutation)


Neurology_Adams

Neurology_Adams. Hunter Disease (MPS II, IDS Mutation) Unlike the Hurler and other types, the Hunter form (MPS II) is transmitted as an X-linked trait. The Hurler and Hunter syndromes are clinically alike except that the Hunter form is milder: developmental delay is less severe than in the Hurler type, deafness is less common, and corneal clouding is usually absent. Probably there are two forms of the syndrome—a more severe one, in which the patients do not survive beyond their midteens, and a less severe form with relatively normal intelligence and survival to middle age. Excessive amounts of dermatan and heparan sulfate are excreted in the urine. The basic abnormality is a deficiency of iduronate sulfatase. The enzyme replacement therapy, idursulfase, administered weekly, intravenously may delay some of the features of the disorder. Sanfilippo Disease (MPS III, Several Genes Implicated)


Neurology_Adams

Neurology_Adams. Sanfilippo Disease (MPS III, Several Genes Implicated) This form, or MPS III, expresses itself clinically between 2 and 3 years of age, with progressive intellectual deterioration. The patients are of short stature, but in other respects the physical changes are fewer and less severe than in the Hunter and Hurler syndromes. Four types of Sanfilippo disease, designated A, B, C, and D, are distinguished on the basis of their enzymatic defects. All subtypes are phenotypically similar, and all of them may excrete excessive amounts of heparan sulfate in the urine. Morquio Disease (MPS IV, GALNS and GLB1 Mutations)


Neurology_Adams

Neurology_Adams. Morquio Disease (MPS IV, GALNS and GLB1 Mutations) This form of the disease, MPS IV, is characterized by marked dwarfism and osteoporosis. Skeletal deformity and compression of the spinal cord and medulla are constant threats because of hypoplasia of the odontoid process and atlantoaxial dislocation and thickening of the dura around the cervical cord and inferior surface of the cerebellum. Intelligence is affected only slightly or not at all. Corneal opacities may be present. Patients excrete large amounts of keratan sulfate in the urine; two types of enzymatic deficiencies have been identified. Replacement with elosulfase has been partially effective and stem cell transplantation and gene therapy are being investigated. Maroteaux-Lamy Disease (MPS VI, ARSB Mutation)


Neurology_Adams

Neurology_Adams. Maroteaux-Lamy Disease (MPS VI, ARSB Mutation) This syndrome, MPS VI, includes severe skeletal deformities (short stature, anteriorly beaked vertebrae) but normal intelligence. Several patients observed by our colleagues have had a cervical pachymeningitis with spinal cord compression and hydrocephalus during adult life. Spinal cord function improved with cervical decompression and the hydrocephalus with ventriculoatrial shunting (Young et al). Hepatosplenomegaly is often present. Large amounts of dermatan sulfate are excreted in the urine, as a result of an arylsulfatase B deficiency. Enzyme replacement with galsulfase has been implemented. β-Glucuronidase Deficiency (Sly Disease, MPS VII,


Neurology_Adams

Neurology_Adams. β-Glucuronidase Deficiency (Sly Disease, MPS VII, This (MPS VII) is a rare type of mucopolysaccharidosis, the clinical features of which have yet to be sharply delineated. Short stature, progressive thoracolumbar gibbus, hepatosplenomegaly, and the bony changes of dysostosis multiplex (as in the Hurler type) are the main clinical features. There is excessive excretion of dermatan and heparan sulfate, the result of a deficiency of b-glucuronidase. Attempts to treat the mucopolysaccharidoses by enzyme replacement therapy, bone marrow transplantation, and gene transfer are in progress. The enzyme replacement, vestronidase, is in use. Mucolipidoses and Other Diseases of Complex Carbohydrates (Sialidoses; Oligosaccharidoses) (See Table 36-3)


Neurology_Adams

Neurology_Adams. Mucolipidoses and Other Diseases of Complex Carbohydrates (Sialidoses; Oligosaccharidoses) (See Table 36-3) Several diseases have been described in which there is an abnormal accumulation of mucopolysaccharides, sphingolipids, and glycolipids in visceral, mesenchymal, and neural tissues, because of an a-N-acetylneuraminidase defect. In some types there is an additional deficiency of beta-galactosidase. All are autosomal recessive diseases that manifest many of the clinical features of Hurler disease, but—in contrast to the mucopolysaccharidoses—normal amounts of mucopolysaccharides are excreted in the urine. Frequently, GM1 gangliosidosis, described above, is also classified with the mucolipidoses. The other members of this category are synopsized below and in Table 36-3. There is yet no specific treatment for these disorders.