Chapter 24. Inherited Neurodegenerative Disorders

Understanding the inherited neurodegenerative diseases of childhood has evolved dramatically in the past 40 years. Fundamental discoveries in biochemistry uncovered the metabolic basis for many of these diseases. The subsequent identification of variant forms created additional challenges for the clinician. These variant forms share similar, if not identical, biochemical defects, but exhibit widely differing clinical expressions. Recent progress followed the rapid development and application of molecular-genetic strategies and the close linkage between clinical observations and basic science advances. The successes of molecular genetics have provided significant clarifications, but have also generated further examples of the marked heterogeneity within these disorders. These advances explain how disorders with clearly different phenotypic expression can result from different mutations within the same gene and, conversely, how disorders with similar clinical features result from mutations in different genes. Examples of the former include GM2-gangliosidosis variants and examples of the latter include the neuronal ceroid lipofuscinoses. Thus, at the clinical, biochemical, and molecular level, the clinician is faced with an increasingly complex knowledge base, the unraveling of which may present major diagnostic hurdles.

Inherited neurodegenerative diseases represent a significant proportion of referrals to tertiary care centers, especially those specializing in the care of children. For all inherited neurometabolic diseases as a group, the overall incidence is about 1 in 3700 births, and for those neurodegenerative disorders considered here, incidence may approach 1 in 5000 births. Technological advancements have in no way diminished the need for careful characterization of the clinical phenotype. Rather, enhanced diagnostic capabilities raise important public health policy issues including development of the necessary infrastructure to monitor outcome of diagnosis and treatment and to analyze the overall impact on society.

Regardless of the biochemical and molecular mechanisms, common patterns of disease expression emerge according to age at onset. Disorders presenting in infancy and early childhood are characterized by delayed development or loss of acquired developmental milestones that follows a period of delay or plateau in development. Onset in school-aged children or adolescents is characterized by declining school performance and behavioral or personality changes. In adulthood, faltering personal or work habits suggest declining cognitive abilities, movement disorder, or gait difficulties. As such, clinical assessment should include historical information regarding changes in development or behavior, evidence of cognitive difficulties, and altered motor control and a careful family history including consanguinity, previous deaths in childhood or adolescence, early-onset dementia, or a diagnosis of progressive cerebral palsy. Progressive neurological manifestations fall outside the established pathogenesis for cerebral palsy. A thorough clinical examination should incorporate assessment for dysmorphic features, hepatosplenomegaly, or skeletal deformities, and careful neurological and ophthalmologic evaluations, the latter for abnormalities of voluntary eye movement, corneal clouding, lens opacities, and retinal abnormalities such as retinitis pigmentosa, macular degeneration, cherry-red spot maculae, and optic atrophy.

Neurodegenerative disease may be explained by a number of processes that should be excluded including other metabolic conditions such as diabetes mellitus or porphyria, toxic encephalopathies (heavy metal poisoning, antiepileptic or neuroleptic preparations, or drugs of abuse), chronic viral infections (subacute sclerosing panencephalitis and the AIDS complex group), immunopathic disorders (systemic lupus erythematosis and related conditions), intracranial neoplasms, and psychiatric or behavioral disorders including autistic spectrum disorder and environmental deprivation.

Laboratory diagnosis involves a variety of biochemical, enzymatic, and molecular methodologies as well as clinical neurophysiology, neuroimaging, and histopathology. Careful clinical assessment should allow a quite precise tailored approach. However, for this to occur, a high index of suspicion for an inherited neurodegenerative process is essential.

In sum, the inherited neurodegenerative diseases represent important opportunities for advancement of knowledge, but at the same time present significant challenges to the neurologist in providing timely diagnosis, appropriate family counseling, and the consideration of new therapeutic strategies.

This chapter explores four groups of inherited neurodegenerative diseases presenting in childhood: the sphingolipidoses, the adrenoleukodystrophy complex, the neuronal ceroid lipofuscinoses, and the sialidosis/sialuria complex.1,2 Clinical heterogeneity is summarized and current approaches to diagnosis and treatment examined. In the past, these disorders have been classified in discrete forms according to age at onset and clinical severity. We now recognize that age at onset and clinical severity fall along a clinical continuum. Detailed descriptions of these diseases can be found elsewhere.

The sphingolipidoses, adrenoleukodystrophy complex, neuronal ceroid lipofuscinoses, and sialidosis/sialuria complex include disorders affecting both neuronal and glial function.1,2 Within each group, the principal clinical variants will be discussed in terms of age at onset, clinical features, prognosis, mode of inheritance, stored material when relevant, and enzyme defects when known. Variant forms that may begin in adolescence or adulthood are included for comparison.

Sphingolipidoses

The sphingolipidoses (Table 24-1) represent a model for understanding the inherited neurodegenerative diseases of children, encompassing within the respective disorders both neuronal storage and white matter involvement.3-11 The sphingolipids are normal lipid constituents of biological membranes. The sphingolipidoses reflect accumulation of the disease-related sphingolipid within the affected organ(s) as the result of defective catabolism. Catabolism of sphingolipids occurs within lysosomes by specific acid hydrolases (lysosomal hydrolases). With the exception of galactosylceramide lipidosis (Krabbe disease), the disease-related sphingolipid accumulates up to 100-fold that seen in normal tissue. Accumulation of the sphingolipid, galactosylceramide, does not occur in Krabbe disease, except within globoid bodies, the neuropathologic hallmark of this disease. In contrast, galactosylsphingosine (psychosine), the deacylated form of galactosylceramide and the principal cytotoxic component of Krabbe disease does accumulate.

The GM2 gangliosidoses (Box 24-1) are generally classified as acute (infantile), subacute (juvenile), and chronic (adult) types according to age at onset (Table 24-1). The majority manifest the acute-onset form, that is, classic Tay-Sachs disease. At least 10 clinical phenotypes are recognized,12 each caused by deficiency of hexosaminidase A, except in the case of Sandhoff disease and its variant forms that feature deficiencies of both hexosaminidase A and B (Hex A and Hex B), or the very rare form caused by deficiency of the GM2 activator protein. Tay-Sachs disease has been recognized in several population isolates, including Ashkenazi Jews, French-Canadians, Pennsylvania Dutch, and Cajuns (from Acadia). The incidence of Tay-Sachs disease is approximately 1 in 4000 among Ashkenazi Jews and about 1 in 200,000 in the general population. Only Hex A metabolizes GM2 ganglioside. Hex B metabolizes the neutral sphingolipid, globoside, in addition to the other compounds noted above. Children with GM2 activator deficiency resemble Tay-Sachs disease clinically. They have normal Hex A and Hex B activity, but lack the activator protein required for metabolism of GM2 ganglioside.

Clinical Characteristics

Acute GM2 Gangliosidosis

Acute GM2 gangliosidosis type I (Tay-Sachs disease) has its onset in infancy, following uneventful early development, marked by increasing irritability, seizures, exaggerated startle response, and rapidly progressive psychomotor deterioration. Weakness, hypotonia, and hyporeflexia appear initially and are gradually replaced by spasticity and extensor posturing. Seizures include repetitive generalized myoclonic jerks of the trunk and extremities. EEG may reveal hypsarrhythmia or multifocal cortical spike discharges and may be associated with laughter (gelastic seizures). Neuroimaging techniques demonstrate hyperdense cerebral cortical zones, decreased white matter, ventricular dilatation, and small cerebellum and brainstem. Electroretinography (ERG) is normal, but VERs are delayed. Death occurs by age 5. Cherry-red maculae, reflecting storage material within retinal ganglion cells and obscuring the choroidal vessels, were once considered a hallmark of the disease. They may also appear in other storage diseases, including GM1 gangliosidosis, metachromatic leukodystrophy, sphingomyelin lipidosis, and sialidase deficiency. Cherry-red maculae are easily detected at the onset, but may be obscured during later stages, so their absence does not rule out the diagnosis. Macrocephaly, if present, is due to gliosis and not GM2-ganglioside storage.

GM2 gangliosidosis type II (Sandhoff disease) differs clinically from type I by the presence of hepato-splenomegaly and biochemically by deficiency of both hexosaminidase A and B. GM2 ganglioside accumulates within the central nervous system and globoside, the principal glycosphingolipid of red cells, accumulates in visceral organs. The clinical onset, pattern, and progression of type II GM2 gangliosidosis are similar to Tay-Sachs disease. Death occurs by age 5.

Subacute Gm2 Gangliosidosis

Subacute (Juvenile) forms of Tay-Sachs and Sandhoff diseases present between 2 and 5 years as gait disturbance with ataxia and psychomotor deterioration.13 Neither cherry-red maculae nor hepatosplenomegaly are noted. Progression is relentless, with death occurring by adolescence.

Chronic Gm2 Gangliosidosis

Chronic forms of GM2 gangliosidosis present a variety of neurological manifestations, typically appearing in adolescents and adults, reflecting dysfunction of specific neuronal populations including anterior horn cells, brainstem, basal ganglia, thalamus, and cerebellum.14,15 These include spinal muscular atrophy, motor neuron disease, spinocerebellar degeneration, and progressive dystonia. Neurological involvement of one system often dominates, but significant overlap may occur. Mentation is generally preserved although progressive dementia or significant psychiatric manifestations ranging from depression to schizophrenia may occur.16,17 Most chronic forms of GM2 gangliosidosis appear to be due to deficiency of Hex A.

Pathology

Brain weight and volume increase markedly secondary to gliosis during the second year of life, often exceeding 2000 g (normal = 1000 g). Cystic degeneration of the cerebral white matter, along with atrophy of the cerebellar hemispheres, is frequently present. Neurons, including anterior horn cells, and glia store GM2 ganglioside. Myenteric plexus ganglion cells are also ballooned and distorted. Historically, rectal biopsy was performed as a diagnostic procedure for the storage diseases, but is obsolete due to the availability of biochemical and molecular diagnostic methodologies. Electron microscopy reveals lipid profiles within neuronal cytoplasm (most likely within lysosomes) referred to as membranous cytoplasmic bodies. In late-onset GM2 gangliosidosis, storage is preferentially localized to thalamus, substantia nigra, brainstem nuclei, and cerebellum.

Biochemistry

GM2 ganglioside accumulates in this group of disorders in neurons in the central, peripheral, and autonomic nervous systems (Table 24-2). Asialo-GM2-ganglioside (GM2 ganglioside minus sialic acid) and lyso-GM2 (GM2 ganglioside minus the fatty acid) also accumulate. The lyso-compound may be cytotoxic. Hex A activity is deficient in tissues of patients with Tay-Sachs disease and its variant forms, although total hexosaminidase activity may be increased. Hex A and B activities are deficient in Sandhoff disease and its variants. Diagnosis of each form of GM2 gangliosidosis can be made in leukocytes or cultured skin fibroblasts. In GM2 activator deficiency, Hex A and B activities are normal versus synthetic substrate, but GM2 metabolism is deficient in the absence of the activator. Multiple mutations in the respective genes have been identified.18

Management

Definitive therapy is not available. Carrier detection and prenatal diagnosis are feasible. Ashkenazi Jewish individuals are at high risk for transmitting the type I disorder. A population-based screening program has substantially reduced its incidence in this group.19,20

Clinical Characteristics

Acute Gm1 Gangliosidosis

Type I GM1 gangliosidosis, the most common form, is a rapidly progressive disorder of early infancy manifesting as profound psychomotor deterioration and hepatosplenomegaly as well as the dysmorphic and radiologic features of Hurler disease (Table 24-1, Box 24-2). The last consist of multiple bone deformities (skull, vertebral bodies, ribs, and extremities) called dysostosis multiplex, hence the former name of Hurler variant or Tay-Sachs disease with Hurler features.

Onset occurs within the first weeks of life with evident psychomotor delay marked by apathy, exaggerated startle, generalized seizures, and hypotonia that progresses to spasticity. Cherry-red maculae are found in about 50% of cases. Systemic features include corneal clouding, gingival hyperplasia, macroglossia, kyphoscoliosis, broad hands, and flexion contractures, particularly of fingers, elbows, and knees. Death occurs by age 2.

Neuroimaging reveals prominent atrophy, increased density of thalami and reduced density of basal ganglia by CT, and hyperintensity of thalami and basal ganglia on T1 and hypointensity on T2, along with evidence of delayed myelination by MRI.21 Electroretinography is normal whereas VERs are delayed. EEG findings generally consist of nonspecific slowing.

Subacute Gm1 Gangliosidosis

Type II GM1 gangliosidosis presents at 6 to 12 months with psychomotor regression after normal early development. Neurological features are dominated by spasticity, ataxia, dystonia, and prominent myoclonic and generalized seizures. Corneal clouding, cherry-red maculae, dysmorphic facies, and hepatosplenomegaly are not seen. Bony changes are typically limited to moderate beaking of vertebral bodies and hypoplasia of the hips. EEG and neuroimaging findings are similar to type I. Progression is relentless leading to death by age 3 to 10 years.

Chronic Gm1 Gangliosidosis

Type III begins in early childhood with slowly progressive ataxia and mild cognitive impairment followed by slurred speech and progressive extrapyramidal signs (dystonia and rigidity) in adulthood.22 Dysmorphic features, cherry-red maculae, corneal clouding, and hepatosplenomegaly are absent. Bony abnormalities of the vertebral bodies and hips are mild. MRI may show increased intensity of the putamen on T2. Longevity appears normal.

Pathology

Pathologic findings are described best for type I. Neurons, including those in Meissner plexus, and glia are involved diffusely, their cytoplasm stuffed with PAS-positive storage material. Bone pathology is similar to that for Hurler disease. Diffuse neuronal involvement is less evident in later onset forms. Neuronal involvement in type III is most prominent in caudate and putamen.

Biochemistry

GM1 ganglioside comprises 80% to 90% (normal = 20%) of total gray matter gangliosides (Table 24-2). Asialo-GM1 (GM1 minus sialic acid) also accumulates, exceeding normal values by up to 20 times. In the acute form, GM1 also accumulates in liver and spleen. In the chronic form, GM1 accumulation is generally limited to caudate and putamen. Deficient β-galactosidase activity in leukocytes or cultured skin fibroblasts establishes the diagnosis. Multiple mutations have been identified in GBL1, although five common mutations account for the majority.

A separate transcript of GBL1 encodes a β-galactosidase-like protein without enzyme activity and identical to the elastin-binding protein (EBP). Six infants with GM1 gangliosidosis and prominent cardiac involvement had GBL1 mutations in the region common to both enzyme and EBP proteins.

A unique feature of the acute-onset form is increased keratan sulfate levels in various tissues and excessive urinary excretion accounting for the Hurler-like appearance. Both GM1 ganglioside and keratan sulfate have a terminal β-galactose. Morquio disease, a mucopolysaccharidosis, is characterized by keratan sulfate accumulation and deficient β-galactosidase activity. As such, Morquio B disease is allelic with GM1 gangliosidosis, that is, both diseases are due to mutations in the same gene.

A number of children with mild to moderate reduction of β-galactosidase activity were once considered as variants of GM1 gangliosidosis. This disorder, galactosialidosis, is due to deficiency of a protective protein for sialidase deficiency and β-galactosidase.

Management

Effective treatment for GM1 gangliosidosis is lacking.

Box 24-3 gives an overview of Fabry disease.

Clinical Characteristics

Globotriaosylceramide lipidosis (angiokeratoma corporis diffusum universale, Fabry disease) is the lone X-linked sphingolipid storage disease (Table 24-1). The principal clinical manifestations involve skin, heart, and kidney. The cutaneous features (angiokeratoma) consist of violaceous angiectatic lesions over the genitalia, thighs, buttock, back, and lower abdomen. These are not unique to Fabry disease, occurring in fucosidosis, β-mannosidosis, galactosialidosis, and Schindler disease. Difficulties with sweating (hypohidrosis) result in temperature intolerance. Lymphedema and episodic diarrhea are also common. Fabry disease has its onset in adolescence or early adulthood,23-25 but despite major clinical issues, survival is often quite prolonged with death from renal or cardiac involvement in the fourth or fifth decades. Later-onset variants are now recognized.26 Cardiac involvement includes left ventricular hypertrophy, valvular dysfunction (especially mitral insufficiency), and conduction abnormalities.27 Obstructive pulmonary disease occurs in about one-third, usually after age 25. Interestingly, subclinical hypothyroidism appears to be more frequent as well.28

The principal neurological problem is painful peripheral neuropathy, generally involving the distal extremities (acroparesthesias). Both severe crises of lancinating pain precipitated by exercise, fatigue, stress, or exposure to sunshine or hot weather, and chronic, unremitting pain, may occur. Corneal and lenticular opacifications and retinal vasculopathies are common. CNS vaso-occlusive events, especially in the posterior circulation and periventricular white matter supply, should place Fabry disease in the differential diagnosis of cerebrovascular accidents in the young male.29 Cranial imaging may suggest prior vaso-occlusive events even without clinical accompaniment.30

Female carriers may develop signs similar to affected males, but usually in middle life. Corneal opacifications occur in approximately 75% of carriers. Other manifestations, while less common, may be as severe as in males, especially the painful peripheral neuropathy.

Natural history studies demonstrate cerebral lesions in some males in their mid-twenties but involvement is found in all males by age 55, whereas chronic renal insufficiency and end-stage renal disease are noted by age 40 to 50. Overall survival in males is age 50 and in carrier females age 70.

Cardiac Variant

A variant form is limited to cardiac involvement. The specific gene defect in this form results in more residual enzyme activity. Onset of cardiac disease is typically at age 40 or older but without the other features of Fabry disease except for mild proteinuria.

Pathology

Lipid accumulation occurs in vascular smooth muscle and endothelium, kidney, cornea, peripheral nerves, and in neurons of the autonomic nervous system, both central and peripheral. Electron microscopy of peripheral nerves reveals lamellar inclusions in perineurial cells. Peripheral nerve involvement can be easily assessed by analysis of skin biopsy.

Biochemistry

Globotriaosylceramide is a quantitatively significant sphingolipid in kidney and is also the first intermediate in the degradation of globoside, the prominent sphingolipid of red cell membranes (Table 24-2). Accumulation occurs in kidney, liver, and lung ranging from 30 to 300 times normal. Alpha-glactosidase (globotriaosylceramide α-galactosidase) activity is deficient. Diagnosis can be made in leukocytes and cultured skin fibroblasts. Numerous mutations have been described.31 A more benign mutation is associated with the cardiac variant.

Management

Renal transplantation may be required for renal failure, but may not result in overall improvement. Enzyme replacement therapy can reduce lipid storage and neuropathic pain and improve renal function and cerebral perfusion.32-38 Replacement therapy has also been safe and effective in symptomatic females.39 Individuals with the cardiac variant may benefit from infusion of galactose, which acts as a molecular chaperone to stabilize mutant enzyme activity. Carbamazepine, phenytoin, or gabapentin may be effective therapy for neuropathic pain or dysesthesias.

Box 24-4 gives an overview of Niemann-Pick disease.

Clinical Characteristics

Sphingomyelin lipidosis is characterized by storage of sphingomyelin (Table 24-1). Acute (type A) and chronic (type B) forms are clinically distinct. Two variants (types C and D), previously thought to have similar etiologies, are not disorders of sphingomyelin catabolism.

Acute Sphingomyelin Lipidosis

Type A is the predominant form, occurring prominently in Ashkenazi Jews and accounting for 85% of the total. Onset occurs in infancy, characterized by severe failure to thrive, hepatosplenomegaly, psychomotor retardation, and frequent respiratory infections. Persistent neonatal jaundice and ascites in later stages may be noted. Neurological abnormalities include hypotonia and weakness initially with progression to spasticity and rigidity. Seizures are rare. Cherry-red maculae are seen in approximately 50% and the ERG response may be diminished. EEG findings consist of nonspecific slowing and voltage attenuation. ABRs may be abnormal and nerve conduction velocities reduced. Death occurs by age 4.

Chronic Sphingomyelin Lipidosis

Type B sphingomyelin lipidosis typically spares the central nervous system. Onset occurs in childhood marked by hepatosplenomegaly and respiratory infections. Progression is remarkably indolent, the principal problems arising from the hepatosplenomegaly, cirrhosis, and chronic pulmonary disease. Survival into middle adulthood is usual.

Pathology

Neuropathologic findings are derived from type A. Brain weight is approximately 75% of normal. Light microscopy reveals large, distended neurons lacking their pyramidal shape. Neuronal storage is prominent, but lipid accumulation also occurs in liver, spleen, lymph nodes, bone marrow, and lung. Peripheral nerves are abnormal with segmental demyelination and cytoplasmic inclusions within axoplasm and Schwann cells.

Biochemistry

Sphingomyelin accumulation in brain and other tissues is characteristic of type A (Table 24-2). Sphingomyelin in brain is increased up to 50 times and may represent two-thirds of total phospholipid (normal = 20%). Tissue cholesterol levels are also increased up to 10-fold. Another phospholipid, bis(monoacylglycero)phosphate, is increased nearly 100-fold, and lyso-sphingomyelin or sphingosylphosphorylcholine is also increased in brain, liver, and spleen in type A, but only in liver and spleen in type B. Their role in the pathogenesis of neurological abnormalities is unknown. Brain content of sphingomyelin is normal in type B. Deficient sphingomyelinase activity in leucocytes and cultured skin fibroblasts is profound in both types. Sparing of the central nervous system and prolonged survival in type B patients reflects greater residual enzyme activity and possibly other factors. Multiple mutations have been defined in ASM, but three account for most of type A in the Ashkenazi population. A separate and less severe mutation is found in the majority of type B.

Niemann-Pick C (formerly types C and D) has its onset in early childhood (ages 1-6) with hepato-splenomegaly and hepatic dysfunction, gait difficulties, ataxia, vertical gaze deficit, and cognitive decline. Progression is relentless with death usually in adolescence. Lipid storage consists mainly of cholesterol but also both sphingomyelin and glucosylceramide. Sphingomyelin catabolism is normal in cultured skin fibroblasts. Deficient cholesterol esterification is the hallmark of Nieman-Pick C.

Management

Effective treatment is lacking for type A. Enzyme replacement should be effective in type B, but systematic trials have not been initiated.40

Glucosylceramide lipidosis (Gaucher disease; Box 24-5) has three principal forms (Table 24-1). Type I is prominent in Ashkenazi Jews with an incidence of 1:1600, the general incidence being 1:80,000-160,000. The variant forms are explained by different mutations in the gene for glucosylceramide β-glucosidase.41

Clinical Characteristics

Chronic Glucosylceramide Lipidosis

Type I, the chronic non-neuronopathic form, is the most common, representing approximately 85% of the total.42 The CNS is generally spared, although oculomotor apraxia, seen in acute and subacute forms, has been described. Onset occurs in childhood or adolescence with progressive hepatosplenomegaly.43 It may begin in early adulthood or later. Significant intrafamilial variability has been noted.44 Survival is typically prolonged, although early death from severe pancytopenia or other complications is possible. The principal clinical problems are hypersplenism, bony abnormalities including infarction, osteomyelitis, pathologic fractures, arthritis, chronic pulmonary hypertension, and growth retardation. Secondary neurological problems have been described.45 An association exists between Gaucher disease and Parkinson disease in the Ashkenazi population, but has not been noted in Norway.46-49 With the exception of multiple myeloma, cancer rates are not elevated.50

Acute Glucosylceramide Lipidosis

Type II (neuronopathic) or infantile glucosylceramide lipidosis is a fulminant disorder. Prominent features are failure to thrive, extensor posturing, laryngospasm, profound psychomotor retardation, and hepato-splenomegaly. Weakness and hypotonia quickly progress to rigidity. Oculomotor apraxia or strabismus is typical. Seizures may occur in later stages. Onset occurs in early infancy with survival rare beyond age 2. Fetal hydrops, also seen in other lysosomal disorders (ceramide lipidosis, sialidosis type II, galactosialidosis, β-glucuronidase deficiency, and infantile sialic acid storage disease) may be the presenting sign.51

Subacute Glucosylceramide Lipidosis

Type III (Norrbottnian form; subacute neuronopathic) is an intermediate form. Particularly prevalent in Sweden, this form occurs in childhood (4-8 years) with hepatosplenomegaly, horizontal gaze apraxia, motor dysfunction, seizures, and progressive cognitive impairment. In particular, progressive myoclonic epilepsy may be noted.52 Significant intrafamilial variability occurs, some presenting in early childhood, others with a more indolent course. Death often occurs during adolescence, whereas survival into middle age is possible.

Pathology

Lipid-laden cells are seen in liver, spleen, and bone marrow. The Gaucher cell, a derivative of the reticuloendothelial system, is characterized by wrinkled blue cytoplasm and easily distinguished from cells with foamy cytoplasm in Niemann-Pick disease. Neuronal loss and perivascular accumulation of glucosylceramide are noted in CNS.47 Neuronal loss (type III in particular) is most pronounced in the bulbar nuclei. Typical Gaucher cells are found in pyramidal cell layers of cerebral cortex.

Biochemistry

Glucosylceramide levels in liver and spleen may reach 100 times normal (Table 24-2). In types II and III, glucosylceramide content is increased by 80-fold in cerebral cortex and 40-fold in cerebellar cortex. Levels of glucosylsphingosine (lyso-glucosylceramide) are increased up to 1000-fold. Glycosphingosine accumulation, a potential cytotoxin, is prominent already in early fetal life.

Glucosylceramide β-glucosidase activity in leukocytes and cultured skin fibroblasts is markedly deficient. Variable levels of residual enzyme activity within the broad range of GBA mutations are responsible for the clinical variants. However, other biological or epigenetic factors could explain intrafamilial variability in type III (Norrbottnian).

Multiple mutations in GBA have been identified although five mutations account for more than 95% of those in the Ashkenazi population, but only about 50% of those in non-Jewish individuals.53 Different mutations are most common in neuronopathic forms.54 In the African-American population, the most common type I mutations are not seen, and seven other mutations are noted.

Deficiency of an activator protein that is essential for normal glucosylceramide β-glucosidase activity underlies a variant form of Gaucher disease similar to the subacute form. In this variant, glucosylceramide content is elevated in liver, spleen, and brain as in types II and III, while glucosylceramide β-glucosidase activity is normal.

Management

Replacement therapy using recombinant enzyme (glucosylceramide β-glucosidase) results in decreased accumulation of lipid in juvenile and adult forms of Gaucher disease.55-61 In chronic Gaucher disease, complete reversal of systemic involvement is possible. In type III, high-dose enzyme replacement ameliorates systemic involvement and stabilizes neurological involvement in the majority although pulmonary involvement is not improved.

Bone marrow transplantation has led to significant improvement, particularly in type III. Inhibitors of glycosphingolipid synthesis have provided modest benefit and may be adjunctive, especially in individuals who may not tolerate enzyme replacement therapy.62,63

In some individuals, splenectomy may be required. In type I Gaucher disease, it may be followed by increased bone pathology, and in type III may accelerate decline in cognitive function and increase glucosylceramide accumulation in other organs. Partial splenectomy may be a more prudent approach, allowing accumulation of glucosylceramide in the remaining splenic tissue.

Globoid cell leukodystrophy (Box 24-6) occurs in three principal forms: infantile (the more common) and two with later onset (Table 24-1). The incidence is 1 per 50,000 in Sweden but less than 1:100,000 outside Scandinavia. Both central and peripheral nervous systems are affected.

Clinical Characteristics

Acute Galactosylceramide Lipidosis

Infantile globoid cell leukodystrophy usually appears by 6 months of age characterized by developmental stagnation, marked irritability, hypertonia, increased muscle stretch reflexes, psychomotor regression, and unexplained fever. Subsequently, extensor posturing, rigidity, exaggerated startle response, optic atrophy, and cortical blindness are noted. Hypotonia then replaces hypertonia and muscle stretch reflexes are lost, reflecting peripheral nerve involvement. Microcephaly may be seen. Death usually occurs by age 12 months. Nerve conduction velocities are reduced and CSF protein is increased significantly, occasionally exceeding 300 mg/dL. Cranial CT reveals diminished white matter and increased density of internal capsule, thalamus, and basal ganglia as noted for GM1-gangliosidosis. Cranial MRI confirms the failure of myelination.

Subacute Galactosylceramide Lipidosis

Late-onset globoid cell leukodystrophy occurs from 1 to 10 years of age after a period of normal development.64 Gait abnormalities and ataxia progressing to spasticity, visual loss with optic atrophy and cortical blindness, and mild to profound psychomotor retardation may be seen. CSF protein and nerve conduction velocities may be normal. Cranial MRI demonstrates diffuse central white matter and pyramidal tract loss. Death may occur within 3 years or not until 20 years after onset.

Chronic Galactosylceramide Lipidosis

Adult onset features slowly progressive gait difficulties leading to spastic paraparesis.65 Dysmetria, brisk muscle stretch reflexes with clonus and extensor plantar responses, and optic disc pallor may be seen. Mentation is generally preserved. Nerve conduction velocities and CSF protein are typically normal. Cranial MRI and MRS reveal symmetrical subcortical white matter and pyramidal tract lesions.66 Periventricular and cerebellar white matter appears uninvolved.

Pathology

In the acute form, cerebral atrophy is prominent with marked gliosis and diminished white matter. Oligodendroglia are markedly reduced or absent. Globoid cells (multinucleate giant cells), apparently elicited by galactosylceramide, are numerous. Segmental demyelination is seen in peripheral nerves.

Biochemistry

Brain galactosylceramide levels are reduced, but globoid cells accumulate this lipid (Table 24-2). Galactosylsphingosine, or psychosine (lyso-galactosylceramide), accumulates up to 100 times normal. The loss of oligodendroglia is due to psychosine cytotoxicity. Psychosine promotes cytokine and inducible nitric oxide synthase production.

Galactosylceramide β-galactosidase activity in peripheral leucocytes or cultured skin fibroblasts is markedly deficient. Multiple mutations have been described, some associated with the late-onset forms.

Management

Effective therapy for globoid cell leukodystrophy is lacking, although recent hematopoietic stem-cell transplantation results are somewhat encouraging.67,68

Metachromatic leukodystrophy (MLD; Box 24-7), due to deficient arylsulfatase activity,69 occurs in three principal forms: late infantile (the most common), juvenile, and adult (Table 24-1). The juvenile form includes varying phenotypes. Children with sulfatide activator deficiency and normal arylsulfatase A activity display the juvenile pattern. MLD has an incidence of 1 in 40,000 except in the Navajo (1 in 2520 births). A separate entity due to deficiency of multiple sulfatase enzymes has the clinical appearance of a mucopolysaccharidosis, but follows the late infantile MLD course.

Clinical Characteristics

Acute Sulfatide Lipidosis

Late infantile MLD presents at 6 months to 2 years of age after normal early development. Regression includes gait difficulties, ataxia, optic atrophy, hypotonia, and extensor plantar responses. Muscle stretch reflexes are diminished or absent due to peripheral nerve involvement. Progression to a vegetative state is rapid. Nerve conduction velocities are markedly reduced and CSF protein is increased up to 300 mg/dL. Cranial CT and MRI reveal symmetric white matter abnormalities. Death occurs by age 6 years.

Subacute Sulfatide Lipidosis

Juvenile metachromatic leukodystrophy may exhibit different patterns. An early form, noted between 4 and 8 years of age, features gait disturbance, intellectual decline, ataxia, and upper motor neuron signs. Extrapyramidal signs and seizures may appear subsequently. Muscle stretch reflexes are increased initially but lost eventually. Progression is slower than in late infantile MLD, but death within 6 years of onset is typical.

A second juvenile form appears between 6 and 16 years of age. Personality and behavior changes and declining school performance are prominent, as well as seizures. Motor dysfunction occurs later. Progression is even slower, with survival into late adolescence or early adulthood. In both forms, nerve conduction velocities are reduced and CSF protein is elevated, but less than in the late infantile form. Cranial MRI demonstrates diminution of white matter and cortical atrophy.

Chronic Sulfatide Lipidosis

Adult-onset metachromatic leukodystrophy presents as decline in cognitive function or psychosis with onset ranging from 16 to 60 years. Declining school or work performance often is the first sign. Motor dysfunction progresses very slowly to spastic quadriparesis and signs of basal ganglia involvement, especially dystonia. Nerve conduction velocities and CSF protein may be normal. Cranial MRI demonstrates significant cortical atrophy and moderate white matter involvement as compared to other forms.

Multiple Sulfatase Deficiency Disease

Multiple sulfatase deficiency disease combines features of the late infantile form of metachromatic leukodystrophy, steroid sulfatase deficiency, and mucopolysaccharidoses. The clinical features of multiple sulfatase deficiencies deviate from MLD in that development is abnormal from birth with regression by age 1 year. Ichthyosis is apparent at birth. By 1 year of age, coarse facial features, hepatosplenomegaly, skeletal abnormalities, peripheral lens opacities, and retinal degeneration appear.

Pathology

MLD affects not only the central and peripheral nervous systems, but kidney, pancreas, adrenal, liver, and gallbladder. Neuropathology consists of widespread loss of central myelin, loss of oligodendroglia, and segmental demyelination of peripheral nerves. Light microscopy reveals PAS-positive metachromatic, birefringent material throughout cerebral white matter and peripheral nerve. Metachromatic material accumulates within glia and neurons.

Pathologic findings in multiple sulfatase deficiency reflect storage of both sulfatides and mucopoly-saccharides.

Biochemistry

In the acute form, white matter sulfatide levels are 4 to 8 times normal (Table 24-2). White matter sulfatide levels in adult MLD are increased only 1.2- to 2.5-fold. Unlike the acute form, significant sulfatide storage is noted in gray matter. Lyso-sulfatide is also markedly increased (up to 100 times normal). Sulfatide, along with the lactosylsulfate analogue, is increased in kidney and liver. Excretion of sulfatide in urine served as the diagnostic marker prior to enzyme diagnosis. Markedly decreased arylsulfatase A activity in leukocytes or cultured skin fibroblasts occurs in each type of MLD except those with activator protein deficiency.69 Peripheral nerve biopsy for the detection of metachromatic material is no longer required.

Several mutations have been identified in the arylsulfatase gene, but two major alleles are known, one detected exclusively in the late infantile form and the other in the juvenile and adult forms, providing a molecular basis for the phenotypic heterogeneity.70-72

Some individuals with the juvenile-onset phenotype have normal levels of arylsulfatase A, but lack the activator protein necessary for sulfatide degradation. Demonstrating abnormal sulfatide catabolism in cultured skin fibroblasts and absence of activator in leukocytes or cultured fibroblasts using specific antibodies will establish the diagnosis.

Multiple sulfatase deficiency disease is characterized by abnormal activity of several different enzymes comprising the known sulfatases. Mutations have not been found in the respective sulfatase genes. Rather, abnormal posttranslational processing of these sulfatases is responsible for abnormal enzyme catalytic activity.

Management

No effective treatment is available. Enzyme replacement by bone marrow transplantation may provide possible benefit in terms of improved arylsulfatase A activity and slowed disease progression, but beneficial response has not been seen uniformly.

Ceramide lipidosis (Farber disease; Box 24-8), initially called lipogranulomatosis, is a very rare disorder of early infancy leading to death by age 2 (Table 24-1).73 The principal clinical features are subcutaneous granulomas, most prominent over the interphalangeal and metacarpophalangeal joints and wrists and over the trunk and scalp, skeletal deformities including painful, swollen, and fixed joints, pulmonary infiltrates and frequent respiratory difficulties, hoarseness, cutaneous lesions, and psychomotor deterioration. Fetal hydrops may be the presenting feature. Feeding difficulties are significant leading to failure to thrive. Neurological involvement is not prominent, although hypotonia is common and cherry red maculae have been described. CSF protein is often increased. Cranial imaging reveals diffuse cortical atrophy.

Milder variants have been described with delayed onset and slower progression.

An additional variant with a phenotype more closely resembling acute glucosylceramide lipidosis (type II) is the result of a combined activator deficiency producing marked reduction in activity of three sphingolipid hydrolases: ceramidase, glucosylceramide β-glucosidase, and galactosylceramide β-galactosidase.

Pathology

Farber disease is a systemic disorder with firm, yellowish, periarticular and subcutaneous nodules, enlarged lymph nodes, and foam cells in lung, liver, spleen, and bone marrow. Neurons including anterior horn cells are involved throughout the CNS.

Biochemistry

Ceramide is increased up to 60-fold and may comprise one-fifth of total lipid within the granulomas and in lung, liver, kidney, lymph nodes, and neurons (Table 24-2). Ceramidase activity in leucocytes and cultured skin fibroblasts is significantly reduced. Several mutations have been identified in the ceramidase gene.74

Management

Effective treatment is lacking.

Clinical Characteristics

X-linked adrenoleukodystrophy (X-ALD) has a variable onset age, although typically appearing at age 6-10 years (Table 24-1, Box 24-9). The phenotypic expression of X-linked ALD can be quite variable also. Of more than 1000 individuals noted to have elevated VLCFA (very-long-chain fatty acids), 45% have the X-ALD phenotype with 38% beginning in childhood, 27% have X-AMN (adrenomyeloneuropathy), 10% have Addison disease, and 9% are asymptomatic.75 The most common presentation is in the early school age (Table 24-1), featuring behavioral disturbance and cognitive impairment, resulting in declining school performance. Impaired hearing and vision, motor difficulties, and seizures develop later. Visual and auditory evoked responses are reduced. Seizures are noted in 20% of children, often as the presenting feature. CSF protein is elevated. Cerebral progression occurs in 50% of those who are asymptomatic in childhood. Death usually occurs within 6 to 10 years of onset.

X-AMN, a variant of X-ALD, presents in young adulthood as slowly progressive spastic paraparesis. Sexual and urinary dysfunction and posterior column sensory difficulties usually present later. Reduced motor and sensory nerve conduction velocities and auditory and visual evoked responses are seen.76 Survival is typically prolonged. Both X-ALD and X-AMN may occur in the same kindred. More than 25% of individuals with X-AMN will develop cerebral demyelination.

Cranial imaging in X-ALD reveals progressive, symmetrical (occasionally unilateral) cerebral demyelination beginning occipitally and progressing rostrally with enhancing margins suggesting an inflammatory process. In AMN, cranial imaging is typically normal, although central abnormalities may occur. Prediction of disease progression is often difficult on clinical grounds. Contrast-enhanced cranial MRI may distinguish individuals likely to progress.77 Proton magnetic resonance spectroscopy (MRS) may predict disease progression more effectively.78

More than 90% with X-ALD and two-thirds with X-AMN have adrenal insufficiency.79 Occasionally, Addison disease is the only manifestation. Measurement of VLCFA is indicated in all males, including children, with Addison disease.

Female carriers may be symptomatic, almost all with signs of spastic paraparesis.80,81 About 10% to 15% of female heterozygotes have significant neurological problems and 50% have mild abnormalities.82 Adrenal function is normal. Typical X-ALD has been noted in some females.

Pathology

Neuropathology reveals cerebral demyelination with caudal-rostral progression and relative sparing of cortex. Perivascular inflammation is prominent. In X-AMN, the major abnormality is in spinal cord. Axonal changes are noted in corticospinal tracts and posterior columns. Peripheral neuropathic findings that may occur in both forms include loss of myelinated fibers. Adrenocortical cells and Schwann cells contain characteristic lamellar inclusions representing VLCFA cholesterol esters.

Biochemistry

Both X-ALD and X-AMN display elevated levels of saturated VLCFA (Table 24-2). These can be readily measured in plasma, cultured skin fibroblasts, and amniocytes. No correlation exists between VLCFA levels and type or severity of disease. The gene responsible for X-ALD encodes the X-ALD protein (ALDP), a peroxisomal membrane protein.83 ALDP is required for localization of VLCFA CoA synthetase within the peroxisome. It is unclear how mutations in the ALDP produce the glial responses and inflammatory changes.84,85 Numerous mutations in ALDP have been identified.

Plasma VLCFA levels are elevated in approximately 90% of obligate female carriers. Prenatal diagnosis of X-ALD is highly accurate, but cannot predict age of onset or severity of disease.

Management

Treatment is generally supportive. Dietary modification with restricted VLCFA intake and added erucic acid may normalize plasma VLCFA levels, but neurological improvement does not occur. Bone marrow transplantation retards disease progression when initiated before onset or with mild involvement.86 Presymptomatic treatment is confounded by the fact that some individuals with elevated plasma VLCFA will remain asymptomatic.

Clinical Characteristics

Neonatal adrenoleukodystrophy (NALD) is quite different from X-ALD (Table 24-1). Profound hypotonia is apparent at birth and developmental delay and seizures are noted in early infancy. Later neurological signs include tremor, ataxia, hyperreflexia, sensory deficits, and progressive visual and auditory dysfunction. Mid-facial hypoplasia is also noted. Developmental progress occurs in the first year of life such as walking, but cognitive function is severely impaired and speech is limited. Thereafter regression ensues. Mild cranial MRI reveals severe white matter deficiency. Adrenal insufficiency is rarely apparent, although response to ACTH is reduced. Most die within the first 5 years with occasional survival into adolescence.

Pathology

Neuropathologic findings include heterotopias, polymicrogyria, and demyelination similar to, but milder than in the related peroxisomal disorder, Zellweger syndrome. Adrenal cortical atrophy and lipid inclusions are prominent.

Conclusion

Each adrenoleukodystrophy disorder features elevated plasma and tissue very-long-chain fatty acids levels due to defective oxidation in peroxisomes (Table 24-2). The neonatal form is distinctly different, reflecting a pervasive defect in peroxisomal function due to the absence of recognizable peroxisomes.

The neuronal ceroid lipofuscinoses are autosomal recessive lysosomal storage disorders characterized by accumulation of autofluorescent material in neurons throughout the nervous system (Table 24-1), and as a group represent the most common inherited neurodegenerative storage disease of children with an overall incidence of 1 in 10,000.87-90 They have been referred to collectively as Batten disease, although this term should be reserved for the juvenile form. They result from abnormalities in lysosomal proteolysis or membrane function. The stored material in INCL, LINCL, and JNCL has a characteristic ultrastructural appearance, that is, granular osmiophilic deposits (GRODs) in INCL, curvilinear bodies in LINCL, and fingerprint bodies in JNCL. However, some children do not follow this pattern, such that definitive diagnosis cannot be based on biopsy findings alone. With the establishment of the molecular basis for these diseases, this discrepancy has been clarified.

Eight general categories have been described based on age at onset and clinical pattern: infantile, late infantile (LINCL), a Finnish LINCL (vLINCL), juvenile (JNCL), early JNCL (EJNCL), progressive epilepsy with mental retardation (EPMR), and adult (ANCL). A ninth category involving congenital onset has also been described in a small number of neonates and has now been associated with deficiency of cathepsin D activity and a specific mutation in this gene.91 In the United States, JNCL represents about one-half, LINCL one-third, and INCL one-tenth. ANCL or Kufs disease accounts for about 1%. In Newfoundland, LINCL predominates. The childhood forms are relentlessly progressive whereas ANCL (Kufs disease) is much more indolent.92

Clinical Characteristics

INCL is the most rapidly progressive form, presenting from 6 to 24 months, characterized by severe psychomotor deterioration, blindness with macular degeneration, microcephaly, hypotonia, ataxia, and myoclonic epilepsy (Table 24-1, Box 24-10). Hand stereotypies, which progress to choreoathetosis, may be noted early. Hand stereotypies, microcephaly, and visual inattentiveness may suggest the diagnosis of Rett syndrome, but the rapid progression of INCL leads to the correct diagnosis as spasticity and extensor posturing replace hypotonia. The EEG reveals generalized spike and wave activity and prominent amplitude reduction becoming isoelectric by age 2 to 3 years. Both ERG and VER are absent. This differs from Tay-Sachs disease in which the ERG is normal. Cranial CT and MRI reveal profound cerebral and cerebellar atrophy. Death occurs by age 10.

Pathology

Granular osmiophilic deposits (GRODs) are noted in epithelial cells of multiple organs and in neurons throughout the central and peripheral nervous systems. The brain is extremely firm, neuronal loss is profound, and white matter is minimal.

Biochemistry

The stored material includes specific lysosomal activator proteins required for sphingolipid catabolism, saposins A for glucosylceramide and galactosylceramide and D for ceramide (Table 24-2). The defective enzyme, lysosomal palmitoyl protein thioesterase, can be measured in leucocytes, cultured skin fibroblasts, plasma, CSF, amniotic fluid cells, and chorionic villi. Saposins A and D appear to be substrates for this enzyme. GRODs can be identified in skin or conjunctival biopsy, although the yield is often low, requiring multiple samples. A variant form with the clinical pattern of LINCL or JNCL and GRODs on biopsy was found to be allelic with INCL, representing different mutations within the same gene. More recently, adult onset has been described in association with mutations in the CLN1 gene.93

Clinical Characteristics

LINCL has its onset from age 2 to 4 years. The initial features are seizures and psychomotor deterioration followed by loss of vision (Table 24-1, Box 24-11). Myoclonus and ataxia are prominent. Death by age 15 is usual. EEG reveals exaggerated occipital response to photic stimulation. ERG is reduced and ultimately extinguished. VERs and SSEPs are exaggerated initially and then lost. Cranial imaging reveals cerebral and cerebellar atrophy and hyperintense periventricular white matter.

Pathology

Brain atrophy is evident, particularly involving the cerebellum, with loss of neurons and white matter. Autofluorescent material is present within neurons, and curvilinear bodies are seen by electron microscopy within neurons, glia, endothelial cells, and Schwann cells.

Biochemistry

ATP synthase subunit c is the principal storage material along with saposins A and D (Table 24-2). LINCL results from deficient lysosomal pepstatin-insensitive tripeptidyl-peptidase that can be measured in leucocytes, cultured skin fibroblasts, amniotic cells, and chorionic villi. This enzyme appears to be required for degradation of ATP synthase subunit c. Curvilinear bodies are present in skin or conjunctival biopsies, but again the yield may be low. Significant molecular heterogeneity has been described in individuals with the clinical picture of LINCL with some having mutations in the genes for INCL or JNCL whereas others with clinical features of JNCL had mutations in the LINCL gene. Mutations in this gene (CLN2) appear to impede transport of the enzyme into lysosomes.94

Clinical Characteristics

JNCL, the most common form of NCL appears at age 5 to 10 years, characterized by visual loss, declining school performance, and seizures (Table 24-1, Box 24-12). Dysarthria, ataxia, and extrapyramidal signs (rigidity and athetosis) follow the onset of seizures. Blindness is inevitable. Macular degeneration is noted with diminished ERGs and VERs. Agitation, restlessness, and psychotic or delusional behavior may occur. Efforts to codify behavior and adaptive function have led to development of a standardized rating scale.95,96 Cranial MRI reveals mild to moderate cerebral and cerebellar atrophy and increased intensity of periventricular white matter. EEG shows prominent slow spike-and-wave activity and background slowing. Death typically occurs by age 20.

Pathology

Brain atrophy is moderate. Neuronal storage of autofluorescent material is prominent but neuronal loss is minimal. Fingerprint bodies are noted both in neurons and axons as well as in skin and conjunctival biopsies.

Biochemistry

The stored materials are ATP synthase subunit c and, to a lesser extent, saposins A and D (Table 24-2). The JNCL gene encodes a lysosomal transmembrane protein called battenin, which appears to function as a palmitoyl-protein Δ-9 desaturase critical for proteolipid protein processing.97 Diagnosis is suggested by detection of fingerprint bodies in skin or conjunctival biopsy, but detection of specific mutations in the CLN3 gene is definitive.

Clinical Characteristics

Kufs disease is the least common NCL. Both dominant and recessive forms have been described, the latter being more common. Onset occurs by age 30 leading to death in 10 to 15 years (Table 24-1, Box 24-13). Variable clinical manifestations presenting in two principal forms are noted. The more common form begins as progressive myoclonic epilepsy. Dementia and ataxia soon follow. The second features dementia, dysarthria, ataxia, and a prominent movement disorders (especially facial dyskinesia). Vision is spared in each form. EEG shows background slowing and generalized spike-and-wave activity. ERG and VER are normal.

Pathology

Mild cerebral and prominent cerebellar atrophy is noted. Granular autofluorescent material is noted within neurons. Electron microscopy reveals curvilinear, fingerprint, and granular inclusion bodies within neurons.

Biochemistry

The biochemical and molecular bases of Kufs disease are unknown.

Neuronal Ceroid Lipofuscinosis Variants

Vlincl

vLINCL, also called CLN5, has been mapped to chromosome 13q22. This form has a phenotype with features of both LINCL and JNCL, that is, later onset and slower progression of LINCL pattern. Onset occurs from age 4 to 7 with psychomotor regression followed by seizures, myoclonus, ataxia, and visual decline. Macular degeneration and loss of ERG are noted. Death occurs within 10 to 20 years. Cerebral atrophy and neuronal loss are prominent. Electron microscopy reveals fingerprint and curvilinear (more rectilinear) profiles. ATP synthase subunit c and small amounts of saposins A and D are stored. CLN5 encodes lysosomal transmembrane protein CLN5, whose function remains to be determined. Mutations are uniformly severe.98

Ejncl

EJNCL or CLN6 has been linked to chromosome 15q21-23. This form follows the clinical pattern of JNCL with early visual loss followed by seizures, myoclonus, and psychomotor deterioration. Onset is noted at 4 to 5 years, earlier than JNCL, and death occurs from age 10 to 30. ERG is absent. Both curvilinear and fingerprint bodies are noted. The stored material has not been identified, but mutations in a novel transmembrane protein gene have been identified.

Epmr

EPMR or CLN8 is localized to the Finnish population. Onset occurs between age 5 and 10 years, characterized by progressive generalized or complex partial epilepsy and progressive cognitive and motor impairments. Storage material, comprised of ATP synthase subunit c, has curvilinear profiles. The gene encodes a transmembrane protein of unknown function with localization to the endoplasmic reticulum. Its role in the pathogenesis of CLN8 remains to be established. A single mutation has been identified with a carrier frequency of 1 in 135 in this population. It also appears that a variant LINCL form (CLN7) occurring in the Turkish population shares mutations with CLN8.99

The sialidoses are characterized by deficientα-neuraminidase (sialidase) activity or by abnormal lysosomal transport of sialic acid. Two forms of sialidase deficiency are allelic representing different mutations in the same gene: type I, the cherry-red spot-myoclonus syndrome; and type II, the infantile form (also called mucolipidosis I). A third disorder, galactosialidosis, results from deficient activity of both sialidase and GM1 β-galactosidase due to an abnormal protective protein required for stabilizing each enzyme. Two disorders of lysosomal sialic acid storage, infantile sialic acid storage disease (ISSD) and Salla disease, are allelic. A third type of sialic acid storage in cytoplasm, sialuria, unlike the other sialidoses is an autosomal dominant disorder involving the cyptoplasmic enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (Box 24-14).

Clinical Characteristics

Type I presents in adolescence with visual impairment, generalized myoclonus, or gait difficulty (Table 24-1). Visual loss is progressive involving disproportionate night blindness or loss of color vision. The cherry-red spot is uniformly present, and punctate lenticular opacities may occur. Myoclonus may be stimulus-sensitive or increased by stress, excitement, smoking, or menses and responds poorly to treatment. Intelligence is normal initially, but cognitive decline follows with abilities falling into the educable range. Generalized tonic-clonic seizures and worsening ataxia are noted. EEG reveals progressive background slowing and bilateral, photosensitive fast spike-and-wave activity. Cranial CT and MRI reveal progressive cerebral and cerebellar atrophy. Survival into the thirties is typical.

Type II sialidosis is much more devastating, closely resembling GM1 gangliosidosis. Onset is in infancy characterized by major joint contractures, mild dysostosis multiplex, coarse, puffy facies, hypertrophic gums, inguinal herniae, and hepatosplenomegaly. Severe nephropathy may develop. Type II may also present at birth as hydrops fetalis as in other lysosomal storage diseases. Neurological findings include progressive cognitive decline, cherry-red maculae, ataxia, hypotonia, reduced muscle mass, and peripheral neuropathy. Death in the infantile form occurs in the first or second decade. Survival is brief with neonatal onset. A juvenile form may have a more protracted course.

Pathology

Type I features diffuse cortical atrophy with neuronal storage as well as vacuolar inclusions in liver. Type II neuropathology is much more extensive with diffuse neuronal storage including brainstem nuclei, sympathetic neurons, and peripheral nerves.

Biochemistry

Glycoprotein sialidase and ganglioside sialidase are distinct enzymes (Table 24-2). Sialidosis I and II represent deficiency of glycoprotein sialidase activity. Ganglioside sialidase activity is normal. Tissue and urine sialic acid-containing oligosaccharide levels are elevated. Deficient sialidase (α-neuraminidase) activity should be measured in cultured skin fibroblasts. Several mutations have been identified in NEU with clinical severity correlating with mutation type.100-103

Clinical Characteristics

Galactosialidosis results from deficiencies of glycoprotein-specific α-neuraminidase and GM1 β-galactosidase activities secondary to mutations in a protective protein gene (Box 24-15). This protective protein is necessary for post-translational stabilization of the two enzymes and is identical with the serine protease, cathepsin A. The protective and protease functions appear distinct.

Three different phenotypic expressions have been described. Cherry-red maculae are noted uniformly along with coarse facies, skeletal abnormalities, inguinal herniae, and visceromegaly. The early infantile form resembles early infantile type II sialidosis. Onset is at birth with coarse facies and fetal hydrops. Death occurs in infancy. The infantile form occurs in the first months of life featuring coarse facies, severe skeletal dysplasia, hepatosplenomegaly, inguinal herniae, hearing loss, and valvular heart disease. Neurological involvement is mild, if any, and survival is prolonged. The juvenile/adult onset form, described almost exclusively in the Japanese, occurs in adolescence or later, with coarse facies, mild skeletal changes (mainly vertebrae), angiokeratoma as in Fabry disease, fucosidosis, and β-mannosidosis. Corneal clouding and punctate lens opacities but not hepatosplenomegaly have been described. Neurological involvement resembles type I sialidosis with progressive myoclonus and cognitive decline, ataxia, and generalized seizures leading to death within 20 to 30 years.

Pathology

Cerebral atrophy and neuronal storage are prominent. Involvement is most severe in the early infantile form.

Biochemistry

Urinary excretion of sialic acid–containing oligosaccharides is markedly increased. GM1-ganglioside is mildly elevated, GM3-ganglioside is increased 10-fold, and sialylglycoproteins are increased significantly in cerebral cortex. GM1 β-galactosidase and glycoprotein-specific α-neuraminidase activities are deficient in leukocytes and cultured skin fibroblasts. Several mutations in the protective protein gene have been identified.

Clinical Characteristics

Salla disease, prevalent in Finland, and infantile sialic acid storage disease are due to abnormal sialic acid transport (Table 24-1, Box 24-16). Free sialic acid is markedly increased in tissues, serum, urine, and cultured skin fibroblasts. In Salla disease, clinical features include cognitive decline, hypotonia, nystagmus, ataxia, and extrapyramidal (mainly athetosis) movements. Onset occurs in infancy with coarse facies and somatic growth retardation.104 One-fourth to one-third do not walk. By adulthood, intelligence is moderately to severely impaired. Absence-type seizures appear in later years. Cranial MRI reveals an arrest of myelination at the infantile level with hypoplasia of the corpus callosum and increased T2-weighted signal in white matter. Peripheral nerve myelin is abnormal with reduced nerve conduction velocities and prolonged distal latencies. Survival is prolonged, if not normal.

Infantile sialic acid storage disease has its onset prior to or at birth. Fetal hydrops may be seen. Severe failure to thrive, coarse facies, dysostosis multiplex, hepatosplenomegaly, and severe psychomotor deterioration are uniform. Death occurs by age 2. Cranial MRI reveals severely reduced white matter.

Pathology

In ISSD, brain atrophy is severe, mainly from reduced white matter. Neuronal storage is diffuse. In Salla disease, storage is less extensive. Cytoplasmic inclusions are present in lymphocytes and cultured skin fibroblasts.

Biochemistry

The basic defect is blockade of sialic acid transport105 from lysosomes resulting in tissue sialic acid storage and increased excretion in urine (Table 24-2). In ISSD, the increase is 100-fold over normal whereas in Salla disease it is approximately10-fold. Glucuronic acid, which utilizes the same transport system, is also stored. Increased sialic acid excretion in urine establishes the diagnosis, disease severity correlating with the level of sialic acid excretion. ISSD and Salla disease are allelic, due to different mutations in the sialic acid transporter gene.106,107

Sialuria is an autosomal dominant disorder described in only a handful of individuals characterized by developmental delay, coarse features, hepatosplenomegaly, and mild to moderate impairment of cognitive and fine-motor functions.108 Sialic acid levels in urine are increased 100-fold, confirming the diagnosis. Failure of feedback inhibition of UDP-N-acetylglucosamine 2-epimerase by CMP-neuraminic acid is responsible. Mutations have been identified in the gene, GNE.

Distinctly different mutations in GNE are associated with the autosomal recessive disorder, hereditary inclusion body myopathy, another example of different disorders arising from mutations in the same gene.109-112 This disorder has been described in multiple ethnic groups, but predominantly in Jewish individuals of Persian descent. The principal clinical features occur in adulthood as a slowly progressive lower extremity myopathy with sparing of the quadriceps accompanied by vacuolar, filamentous inclusions in muscle.

Neuroimaging Assessment

Neuroimaging is particularly useful in the assessment of the leukodystrophies (Table 24-3).1,2 The principal CT finding is a decrease in density of white matter with later appearance of atrophy. In general, the later-onset forms have milder abnormalities. For example, the decrease in density is diffuse and symmetrical in the late infantile and juvenile types of sulfatide lipidosis, whereas the adult form may mainly show central and cortical atrophy, with variable and focal decrease in white matter density. Galactosylceramide lipidosis (Krabbe disease) may be distinguished from the others by the appearance of increased density in the cerebellum, thalami, caudate nuclei, brainstem, and corona radiata. These areas show markedly shortened T1 and T2 values by MRI, whereas the areas of decreased density in white matter show increased T1 and T2 values and appear similar to plaques in multiple sclerosis. This finding is particularly relevant in light of the proposed cytotoxic effect of psychosine.

Cranial CT is also helpful in the diagnosis of adrenoleukodystrophy, revealing attenuation in the periventricular white matter posteriorly with contrast enhancement at the periphery of the low-density lesions and a pattern of posterior-to-anterior progression. Enhancement decreases or disappears as the disease process progresses. Atypical findings noted on CT include low-density, non-enhancing frontal lesions and unilateral lesions with suggestion of mass effect. Adrenomyeloneuropathy, by contrast, has either normal findings or mild ventricular dilatation. MRI readily demonstrates demyelination in X-ALD and detects abnormal white matter in the cerebrum, pons, and spinal cord of adrenomyeloneuropathy despite a normal pattern by CT. The neonatal form, in comparison, demonstrates diffuse and symmetrical white matter lucencies with central contrast enhancement.

Cranial imaging is not of particular help in the diagnosis or differentiation of the neuronal storage disorders, including the sphingolipidoses, GM1- and GM2-gangliosidoses, the neuronal ceroid lipofuscinosis, and the sialidoses/sialuria complex.

Clinical Neurophysiologic Assessment

Clinical neurophysiologic assessments of the peripheral and central pathways in the inherited neurodegenerative disorders provide powerful tools. The information in Table 24-4 represents the collation of individual cases as well as in-depth studies of specific disorders.1,2

The electroretinogram (ERG) is particularly useful in the diagnosis of the neuronal ceroid lipofuscinosis, as responses range from small amplitude to absent. In few of the other entities is the response sufficiently reduced to confuse the diagnosis. Although ERG and VER responses may be markedly diminished in neonatal adrenoleukodystrophy, this disorder should be differentiated on clinical findings (see Table 24-1).

Visual evoked responses (VER) may also be extremely helpful. In Tay-Sachs disease, the VERs are lost in a progressive fashion. The VER is also abnormal in the neuronal ceroid lipofuscinoses, but the difference in the ERG response should be differentiating. Within the NCL group, the late infantile type demonstrates enlarged or exaggerated VERs, whereas the infantile and juvenile types display small to absent responses.

It is possible to discriminate between the leukodystrophies based on auditory brainstem responses (ABR) and nerve conduction velocities. Nerve conduction velocities are markedly reduced in both the early forms of galactosylceramide lipidosis and sulfatide lipidosis, whereas such studies are generally normal in disorders of the adrenoleukodystrophy complex, at least during the beginning stages of the disorder.

ABRs reveal abnormalities in disorders of white matter that range from prolonged interwave intervals to an absence of response after wave 1. White matter diseases have abnormal ABRs together with high-amplitude irregular delta activity on EEG, whereas gray matter disease is characterized by normal to minimally abnormal ABRs and EEGs that consist of paroxysmal sharp waves and spike-and-wave activity, in addition to diffuse slowing and progressive voltage reduction. Freeman and McKhann113 promulgated the concept of gray versus white matter differentiation in the expression of the inherited neurodegenerative diseases to direct strategies for clinical diagnosis. Clinical neurophysiology assessments provide support for this concept.

Chemical and Biochemical Assays

The clinical presentation of neurodegenerative disorders and the results of cranial imaging and clinical neurophysiology should allow the clinician to tailor specific diagnostic laboratory studies, in many instances focusing the diagnostic approach to a specific entity (Table 24-2).

For the sphingolipidoses and sialidoses, specific enzyme assays will confirm the diagnosis. For the adrenoleukodystrophy complex, measurements of very-long-chain fatty acids must be made in plasma or cultured skin fibroblasts. For the sialuria group, sialic acid can be measured in urine or in cultured skin fibroblasts. For the neuronal ceroid lipofuscinoses, specific enzymatic or molecular testing is possible. The use of conjunctival, skin, or nerve biopsies for ultrastructural analysis is less often employed because of its low yield and, more importantly, the availability of more precise and specific biochemical and molecular testing.

Carrier Identification and Prenatal Diagnosis

Carrier identification and prenatal diagnosis are now feasible for many of the inherited neurodegenerative diseases.114,115 Despite recent advances in molecular genetic diagnosis, analysis of the specific enzyme deficiency or detection of the relevant metabolite remains the gold standard in most instances. The number of different mutations in most of these disorders makes DNA analysis impractical on a broad scale. In families with known mutations, molecular testing should offer the most specific information.

Careful consideration should be given to medical, social, and ethical consequences of carrier identification and prenatal diagnosis including the outcome analysis of these programs. One must be aware of the possibility of revealing non-paternity with carrier identification.

Therapy

For most inherited neurodegenerative and neurometabolic diseases, treatment remains problematic (Table 24-5).116 Established strategies for some have been effective including dietary (PKU) and enzyme replacement (storage diseases).117-122 Enzyme replacement in Gaucher disease and Fabry disease has proved effective but costly. Bone marrow transplantation has also been beneficial in neuronopathic (type III) Gaucher disease, but of uncertain benefit in many other storage diseases involving the CNS.123

Molecular advances offer the opportunity to replace specific genes. Alternatively, multipotent neural progenitor cells (stem cells) have been engineered to express specific genes whose products would then supply deficient cells.

Alternative strategies have also been considered involving manipulation of substrate load through the use of chemical inhibitors or through the use of molecular chaperones designed to protect or stabilize enzyme function.124-129 This approach has been applied specifically to the sphingolipidoses. To date, the results have been relatively modest in terms of reducing substrate load; however, in combination with enzyme replacement therapy, this remains an approach warranting further study.

Evaluation of effective therapies requires the development of objective outcome data. This includes measurable motor, cognitive, and behavioral endpoints. Aiding this process is the implementation of quantitative measures of specific metabolites using techniques such as magnetic resonance spectroscopy.

This work was supported in part by the Civitan International Research Center and National Institutes of Health grant HD38985 (Mental Retardation Research Center).

The author has nothing to disclose beyond that noted above.