Neurodegenerative Disorders of Childhood

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Chapter 592 Neurodegenerative Disorders of Childhood

Neurodegenerative disorders of childhood encompass a large, heterogeneous group of diseases that result from specific genetic and biochemical defects, chronic viral infections, and varied unknown causes. Children with suspected neurodegenerative disorders were once subjected to brain and rectal (neural) biopsies, but with modern neuroimaging techniques and specific biochemical and molecular diagnostic tests, these invasive procedures are rarely necessary. The most important component of the diagnostic investigation continues to be a thorough history and physical examination. The hallmark of a neurodegenerative disease is regression and progressive deterioration of neurologic function with loss of speech, vision, hearing, or locomotion, often associated with seizures, feeding difficulties, and impairment of intellect. The age of onset, rate of progression, and principal neurologic findings determine whether the disease affects primarily the white or the gray matter. Upper motor neuron signs and progressive spasticity are the hallmarks of white matter disorders; convulsions, intellectual, and visual impairment that occur early in the disease course are the hallmarks of grey matter disorders. A precise history confirms regression of developmental milestones, and the neurologic examination localizes the process within the nervous system. Although the outcome of a neurodegenerative condition is usually fatal and available therapies are often limited in effect, it is important to make the correct diagnosis so that genetic counseling may be offered and prevention strategies can be implemented. Bone marrow transplantation and other novel therapies may prevent the progression of disease in certain presymptomatic individuals. For all conditions in which the specific enzyme defect is known, prevention by prenatal diagnosis (chorionic villus sampling or amniocentesis) is possible. Carrier detection is also often possible by enzyme assay. Table 592-1 summarizes selected inherited neurodegenerative and metabolic disorders by their age of onset.


<2, with hepatomegaly Fructose intolerance Vomiting, hypoglycemia, poor feeding, failure to thrive (when given fructose)
Galactosemia Lethargy, hypotonia, icterus, cataract, hypoglycemia (when given lactose)
Glycogenosis (glycogen storage disease) types I-IV Hypoglycemia, cardiomegaly (type II)
Mucopolysaccharidosis types I and II Coarse facies, stiff joints
Niemann-Pick disease, infantile type Gray matter disease, failure to thrive
Tay-Sachs disease Seizures, cherry red macula, edema, coarse facies
Zellweger syndrome Hypotonia, high forehead, flat facies
Gaucher disease (neuronopathic form) Extensor posturing, irritability
Carbohydrate-deficient glycoprotein syndromes Dysmyelination, cerebellar hypoplasia
<2, without hepatomegaly Krabbe disease Irritability, extensor posturing, optic atrophy and blindness
Rett syndrome Girls with deceleration of head growth, loss of hand skills, hand wringing, impaired language skills, gait apraxia
Maple syrup urine disease Poor feeding, tremors, myoclonus, opisthotonos
Phenylketonuria Light pigmentation, eczema, seizures
Menkes kinky hair disease Hypertonia, irritability, seizures, abnormal hair
Subacute necrotizing encephalopathy of Leigh White matter disease
Canavan disease White matter disease, macrocephaly
Neurodegeneration with brain iron accumulation disease White matter disease, movement disorder
2-5 Niemann-Pick disease types III and IV Hepatosplenomegaly, gait difficulty
Wilson disease Liver disease, Kayser-Fleischer ring; deterioration of cognition is late
Gangliosidosis type II Gray matter disease
Neuronal ceroid lipofuscinosis Gray matter disease
Mitochondrial encephalopathies (e.g., myoclonic epilepsy with ragged red fibers [MERRF]) Gray matter disease
Ataxia-telangiectasia Basal ganglia disease
Huntington disease (chorea) Basal ganglia disease
Neurodegeneration with brain iron accumulation syndrome Basal ganglia disease
Metachromatic leukodystrophy White matter disease
Adrenoleukodystrophy White matter disease, behavior problems, deteriorating school performance, quadriparesis
5-15 Adrenoleukodystrophy Same as for adrenoleukodystrophy in 2 to 5 yr olds
Multiple sclerosis White matter disease
Neuronal ceroid lipofuscinosis, juvenile and adult (Spielmeyer-Vogt and Kufs disease) Gray matter disease
Schilder disease White matter disease, focal neurologic symptoms
Refsum disease Peripheral neuropathy, ataxia, retinitis pigmentosa
Sialidosis II, juvenile form Cherry red macula, myoclonus, ataxia, coarse facies
Subacute sclerosing panencephalitis Diffuse encephalopathy, myoclonus; may occur years after measles

From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier/Saunders, p 542.

592.1 Sphingolipidoses

The sphingolipidoses are characterized by intracellular storage of lipid substrates resulting from defective catabolism of the sphingolipids comprising cellular membranes (Fig. 592-1). The sphingolipidoses are subclassified into 6 categories: Niemann-Pick disease, Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease, and metachromatic leukodystrophy. Niemann-Pick disease and Gaucher disease are discussed in Chapter 80.4.

Gangliosidoses (Chapter 80.4)

Gangliosides are glycosphingolipids, normal constituents of the neuronal and synaptic membranes. The basic structure of GM1 ganglioside consists of an oligosaccharide chain attached to a hydroxyl group of ceramide and sialic acid bound to galactose. The gangliosides are catabolized by sequential cleavage of the sugar molecules by specific exoglycosidases. Abnormalities in catabolism result in an accumulation of the ganglioside within the cell. Defects in ganglioside degradation can be classified into 2 groups: the GM1 gangliosidoses and the GM2 gangliosidoses.

GM1 Gangliosidoses

The 3 subtypes of GM1 gangliosidoses are classified according to age at presentation: infantile (type 1), juvenile (type 2), and adult (type 3). The condition is inherited as an autosomal recessive trait and results from a marked deficiency of acid β-galactosidase. This enzyme may be assayed in leukocytes and cultured fibroblasts. The acid β-galactosidase gene has been mapped to chromosome 3p14.2. Prenatal diagnosis is possible by measurement of acid β-galactosidase in cultured amniotic cells.

Infantile GM1 gangliosidosis presents at birth or during the neonatal period with anorexia, poor sucking, and inadequate weight gain. Development is globally retarded, and generalized seizures are prominent. The phenotype is striking and shares many characteristics with Hurler syndrome. The facial features are coarse, the forehead is prominent, the nasal bridge is depressed, the tongue is large (macroglossia), and the gums are hypertrophied. Hepatosplenomegaly is present early in the course as a result of accumulation of foamy histiocytes, and kyphoscoliosis is evident because of anterior beaking of the vertebral bodies. The neurologic examination is dominated by apathy, progressive blindness, deafness, spastic quadriplegia, and decerebrate rigidity. A cherry red spot in the macular region is visualized in approximately 50% of cases. The cherry red spot is characterized by an opaque ring (sphingolipid-laden retinal ganglion cells) encircling the normal red fovea (Fig. 592-2). Children rarely survive beyond age 2-3 yr, and death is due to aspiration pneumonia.

Juvenile GM1 gangliosidosis has a delayed onset beginning about 1 yr of age. The initial symptoms consist of incoordination, weakness, ataxia, and regression of language. Thereafter, convulsions, spasticity, decerebrate rigidity, and blindness are the major findings. Unlike the infantile type, this type is not usually marked by coarse facial features and hepatosplenomegaly. Radiographic examination of the lumbar vertebrae may show minor beaking. Children rarely survive beyond 10 yr of age. Adult GM1 gangliosidosis is a slowly progressive disease consisting of spasticity, ataxia, dysarthria, and a gradual loss of cognitive function.

GM2 Gangliosidoses

The GM2 gangliosidoses are a heterogeneous group of autosomal recessive inherited disorders that consist of several subtypes, including Tay-Sachs disease (TSD), Sandhoff disease, juvenile GM2 gangliosidosis, and adult GM2 gangliosidosis. Tay-Sachs disease is most prevalent in the Ashkenazi Jewish population and has an approximate carrier rate of 1/30. TSD is due to mutations in the HEXA gene located on chromosome 15q23-q24. Affected infants appear normal until ≈6 mo of age, except for a marked startle reaction to noise that is evident soon after birth. Affected children then begin to lag in developmental milestones and, by 1 yr of age, they lose the ability to stand, sit, and vocalize. Early hypotonia develops into progressive spasticity, and relentless deterioration follows, with convulsions, blindness, deafness, and cherry red spots in almost all patients (see Fig. 592-2). Macrocephaly becomes apparent by 1 yr of age and results from the 200- to 300-fold normal content of GM2 ganglioside deposited in the brain. Few children live beyond 3-4 yr of age, and death is usually associated with aspiration or bronchopneumonia. A deficiency of the isoenzyme hexosaminidase A is found in tissues of patients with TSD. Mass screening for prenatal diagnosis of TSD is a reliable and cost-effective method of prevention because the condition occurs most frequently in a defined population (Ashkenazi Jews). Targeted screening is responsible for the fact that currently, the rare children with TSD born in the USA are most commonly born to non-Jewish parents who are not routinely screened. An accurate and inexpensive carrier detection test is available (serum or leukocyte hexosaminidase A), and the disease can be reliably diagnosed by chorionic villus sampling in the 1st trimester of pregnancy in couples at risk (heterozygote parents).

Sandhoff disease is very similar to TSD in the mode of presentation, including progressive loss of motor and language milestones beginning at 6 mo of age. Seizures, cherry red spots, macrocephaly, and doll-like facies are present in most patients; however, children with Sandhoff disease may also have splenomegaly. The visual-evoked potentials (VEPs) are normal early in the course of Sandhoff disease and TSD but become abnormal or absent as the disease progresses. The auditory brainstem responses (ABRs) show prolonged latencies. The diagnosis of Sandhoff disease is established by finding deficient levels of hexosaminidase A and B in serum and leukocytes. Children usually die by 3 yr of age. Sandhoff disease is due to mutations in the HEXB gene located on chromosome 5q13.

Juvenile GM2 gangliosidosis develops in mid-childhood, initially with clumsiness followed by ataxia. Signs of spasticity, athetosis, loss of language, and seizures gradually develop. Progressive visual loss is associated with optic atrophy, but cherry red spots rarely occur in juvenile GM2 gangliosidosis. A deficiency of hexosaminidase is variable (total deficiency to near normal) in these patients. Death occurs around 15 yr of age.

Adult GM2 gangliosidosis is characterized by a myriad neurologic signs, including slowly progressive gait ataxia, spasticity, dystonia, proximal muscle atrophy, and dysarthria. Generally, visual acuity and intellectual function are unimpaired. Hexosaminidase A activity alone or hexosaminidase A and B activity is reduced significantly in the serum and leukocytes.