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.

Table 592-1 NEUROMETABOLIC CONDITIONS ASSOCIATED WITH DEVELOPMENTAL REGRESSION

AGE AT ONSET (yr)	CONDITIONS	COMMENTS
<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

Jennifer M. Kwon

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.

Figure 592-1 Sphingolipid degradation pathway showing the sites of enzyme deficiencies and their associated disorders. Sphingolipids are composed of a ceramide backbone with oligosaccharide side chains.

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.

Figure 592-2 A cherry red spot in a patient with GM₁ gangliosidosis. Note the whitish ring of sphingolipid-laden ganglion cells surrounding the fovea.

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.

Krabbe Disease (Globoid Cell Leukodystrophy)

Krabbe disease (KD) is a rare autosomal recessive neurodegenerative disorder characterized by severe myelin loss and the presence of globoid bodies in the white matter. The gene for KD (GALC) is located on chromosome 14q24.3-q32.1. The disease results from a marked deficiency of the lysosomal enzyme galactocerebroside β-galactosidase. KD is a disorder of myelin destruction rather than abnormal myelin formation. Normally, myelination begins in the 3rd trimester, corresponding with a rapid increase of galactocerebroside β-galactosidase activity in the brain. In patients with KD, galactocerebroside cannot be metabolized during the normal turnover of myelin because of deficiency of galactocerebroside β-galactosidase. When galactocerebroside is injected into the brains of experimental animals, a globoid cell reaction ensues. It has been postulated that a similar phenomenon occurs in humans; nonmetabolized galactocerebroside stimulates the formation of globoid cells that reflect the destruction of oligodendroglial cells. Because oligodendroglial cells are responsible for the elaboration of myelin, their loss results in myelin breakdown, thus producing additional galactocerebroside and causing a vicious circle of myelin destruction.

The symptoms of KD become evident in the 1st few months of life and include excessive irritability and crying, unexplained episodes of hyperpyrexia, vomiting, and difficulty feeding. In the initial stage of KD, children are often treated for colic or “milk allergy” with frequent formula changes. Generalized seizures may appear early in the course of the disease. Alterations in body tone with rigidity and opisthotonos and visual inattentiveness due to optic atrophy become apparent as the disease progresses. In the later stages of the illness, blindness, deafness, absent deep tendon reflexes, and decerebrate rigidity constitute the major physical findings. Most patients die by 2 yr of age. MRI and magnetic resonance spectroscopy are useful for evaluating the extent of demyelination in Krabbe disease. Umbilical cord blood (stem cell) transplantation from unrelated donors in asymptomatic babies may favorably alter the natural history but will not help patients who already have neurologic symptoms.

Late-onset KD has been described beginning in childhood or adolescence. Patients present with optic atrophy and cortical blindness, and their condition may be confused with adrenoleukodystrophy. Slowly progressive gait disturbances, including spasticity and ataxia, are prominent. As with classic KD, globoid cells are abundant in the white matter, and leukocytes are deficient in galactocerebroside β-galactosidase. An examination of the cerebrospinal fluid (CSF) shows an elevated protein content, and the nerve conduction velocities are markedly delayed due to segmental demyelination of the peripheral nerves. The VEPs decrease gradually in amplitude with no response in the late stages of the disease, and the ABRs are characterized by the presence of only waves I and II. CT scans and MRI studies highlight the marked decrease in white matter, especially of the cerebellum and centrum semiovale, with sparing of the subcortical U fibers. Prenatal diagnosis is possible by the assay of galactocerebroside β-galactosidase activity in chorionic villi or in cultured amniotic fluid cells.

Metachromatic Leukodystrophy (MLD)

This disorder of myelin metabolism is inherited as an autosomal recessive trait and is characterized by a deficiency of arylsulfatase A (ARSA) activity. The ARSA gene is located on chromosome 22q13-13qter. The absence or deficiency of arylsulfatase A leads to accumulation of cerebroside sulfate within the myelin sheath of the central nervous system (CNS) and peripheral nervous system due to the inability to cleave sulfate from galactosyl-3-sulfate ceramide. The excessive cerebroside sulfate is thought to cause myelin breakdown and destruction of oligodendroglia. Prenatal diagnosis of MLD is made by assaying of ARSA activity in chorionic villi or cultured amniotic fluid cells. Cresyl violet applied to tissue specimens produces metachromatic staining of the sulfatide granules, giving the disease its name. Some individuals with low enzyme ARSA activity are clinically normal and have a pseudodeficiency state that can only be confirmed by additional genetic or biochemical tests. Those affected with MLD are generally classified according to age of onset: late infantile, juvenile, and adult.

Late infantile MLD begins with insidious onset of gait disturbances between 1 and 2 yr of age. The child initially appears awkward and frequently falls, but locomotion is gradually impaired significantly and support is required in order to walk. The extremities are hypotonic, and the deep tendon reflexes are absent or diminished. Within the next several months, the child can no longer stand, and deterioration in intellectual function becomes apparent. The speech is slurred and dysarthric, and the child appears dull and apathetic. Visual fixation is diminished, nystagmus is present, and examination of the retina shows optic atrophy. Within 1 yr from the onset of the disease, the child is unable to sit unsupported, and progressive decorticate postures develop. Feeding and swallowing are impaired due to pseudobulbar palsies, and a feeding gastrostomy is required. Patients ultimately become stuporous and die of aspiration or bronchopneumonia by age 5-6 yr. Neurophysiologic evaluation shows slowing of peripheral nerve conduction velocities (NCVs) and progressive changes in the VEPs, ABRs, and somatosensory-evoked potentials (SSEPs). CT and MRI images of the brain indicate diffuse symmetric attenuation of the cerebellar and cerebral white matter, and examination of the CSF shows an elevated protein content. Bone marrow transplantation is a promising experimental therapy for the management of late infantile MLD. As with Krabbe disease, favorable outcomes have been reported only in patients treated very early in the course of the disease.

Juvenile MLD has many features in common with late infantile MLD, but the onset of symptoms is delayed to 5-10 yr of age. Deterioration in school performance and alterations in personality may herald the onset of the disease. This is followed by incoordination of gait, urinary incontinence, and dysarthria. Muscle tone becomes increased, and ataxia, dystonia, or tremor may be present. In the terminal stages, generalized tonic-clonic convulsions are prominent and are difficult to control. Patients rarely live beyond mid-adolescence.

Adult MLD occurs from the 2nd to 6th decade. Abnormalities in memory, psychiatric disturbances, and personality changes are prominent features. Slowly progressive neurologic signs, including spasticity, dystonia, optic atrophy, and generalized convulsions, lead eventually to a bedridden state characterized by decorticate postures and unresponsiveness.

Bibliography

Boomkamp SD, Butters TD. Glycosphingolipid disorders of the brain. Subcell Biochem. 2008;49:441-467.

592.2 Neuronal Ceroid Lipofuscinoses

Jennifer M. Kwon

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by visual loss, progressive dementia, seizures, motor deterioration, and early death. The NCLs are so named because of the intracellular accumulation of fluorescent lipopigments, ceroid and lipofuscin. They comprise a genetically and phenotypically heterogeneous group of disorders (the current number of NCL types is 10) that have traditionally been subclassified by age of onset, among other clinical features. They differ from one another in the associated ultrastructural patterns of the inclusions as seen by electron microscopy. Evaluation of neuronal biopsies (either brain, rectal, conjunctival, or skin) was once required for diagnosis (see Table 592-1). With the advent of enzymatic and molecular testing methods, clinicians can make specific NCL diagnoses using less invasive methods (Table 592-2).

Table 592-2 CLINICAL AND GENETIC CHARACTERISTICS OF THE NCLs*

Infantile type (INCL, Haltia-Santavuori) begins in the 1st yr of life with myoclonic seizures, intellectual deterioration, and blindness. Optic atrophy and brownish discoloration of the macula are evident on examination of the retina, and cerebellar ataxia is prominent. The electroretinogram (ERG) typically shows small-amplitude or absent waveforms. Death occurs during childhood. The infantile form is caused by recessive mutations of the gene for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) on chromosome 1p32. A number of cell types in INCL patients show characteristic intracellular fine granular osmiophile deposits (GRODs) discernible by electron microscopy.

A subset of children with PPT1 enzyme deficiency has a much less severe course with clinical features resembling those of the juvenile-onset NCL patients. Clinically, these “variant INCL” patients have a course that is often quite distinct from the typical, classic rapidly degenerating infantile form. Yet they have PPT1 deficiency and GRODs on pathology. There is no clear CLN1 genotype that predicts severity of phenotype.

Late infantile type (LINCL, Jansky-Bielschowsky) generally presents with myoclonic seizures beginning between 2 and 4 yr of age in a previously normal child. Dementia and ataxia are combined with a progressive loss of visual acuity and microcephaly. Examination of the retina shows marked attenuation of vessels, peripheral black “bone spicule” pigmentary abnormalities, optic atrophy, and a subtle brown pigment in the macular region. The ERG and VEP are abnormal early in the course of disease. The autofluorescent material is deposited in neurons, fibroblasts, and secretory cells. Electron microscopic examination of the storage material in skin or conjunctival biopsy material typically shows curvilinear profiles. LINCL can be caused by autosomal recessive mutations of several different genes: CLN2 gene, which codes for a tripeptidyl peptidase-1 (TPP1) that is essential for the degradation of cholecystokinin-8, as well as the CLN5, CLN6, and CLN8 genes that code for membrane proteins that have not been completely characterized. CLN8 is also known as the locus of Northern epilepsy syndrome, which is often called progressive epilepsy with mental retardation (EPMR).

Juvenile type (JNCL, Spielmeyer-Vogt or Batten disease) is the most common form of NCL disease and is generally caused by autosomal recessive mutations in CLN3. (Patients who present clinically with JNCL but have PPT1 or TPP1 deficiency are said to have variant INCL or LINCL, respectively.) Children affected with JNCL tend to develop normally for the 1st 5 yr of life. Their initial symptom is usually progressive visual loss and their retinal pigmentary changes often results in an initial diagnosis of retinitis pigmentosa. The funduscopic changes are similar to those for the late infantile type. After disease onset, there may be rapid decline with changes in cognition and personality, motor incoordination, and seizures. Myoclonic seizures are not as prominent as in LINCL, but parkinsonism can develop and impair ambulation. Patients die in their late twenties to early thirties. In JNCL caused by CLN3, the electron microscopy of tissues show deposits called “fingerprint profiles,” and routine light microscopy of a peripheral blood smear may show lymphocyte vacuoles.

Bibliography

Kohlschütter A, Schulz A. Towards understanding the neuronal ceroid lipofuscinoses. Brain Dev. 2009;31:499-502.

592.3 Adrenoleukodystrophy

Jennifer M. Kwon

See Chapter 80.2.

The adrenoleukodystrophies consist of a group of CNS degenerative disorders that are often associated with adrenal cortical insufficiency and are inherited by X-linked recessive transmission. Classic adrenoleukodystrophy (ALD), also called cerebral ALD (CERALD) is considered to be the most common leukodystrophy. Boys present between 5 and 15 yr of age with evidence of academic difficulties, behavioral disturbances, and gait abnormalities. ALD is caused by accumulation of very long chain fatty acids in neural tissue and adrenals due to mutations in the ABCD1 gene coding for the ALD protein, an adenosine triphosphate (ATP)-binding cassette half transporter on Xq28.

The incidence of ALD approximates 1/20,000 boys. In 40% of male hemizygotes, the disease presents in its classic form, CERALD, as an inflammatory demyelinating disease. Generalized seizures are common in the early stages. Upper motor neuron signs include spastic quadriparesis and contractures, ataxia, and marked swallowing disturbances secondary to pseudobulbar palsy. These dominate the terminal stages of the illness. Hypoadrenalism is present in approximately 50% of cases, and adrenal insufficiency characterized by abnormal skin pigmentation (tanning without exposure to sun) may precede the onset of neurologic symptoms. CT scans and MRI studies of patients indicate periventricular demyelination beginning posteriorly; this advances progressively to the anterior regions of the cerebral white matter. ABRs, VEPs, and SSEPs may be normal initially but ultimately show prolonged latencies and abnormal waveforms. Death occurs within 10 yr of the onset of the neurologic signs.

Bone marrow transplant can prevent the progression of the disease when done at an early stage before clinical signs develop. Lorenzo’s oil (LO), a mixture of glyceryl trioleate and glyceryl trierucate, lowers very long chain fatty acid (VLCFA) levels by inhibiting synthesis. While LO has not been shown to effectively reverse or slow neurologic deterioration in CERALD boys, it may be effective in slowing onset of cerebral disease when given to asymptomatic boys with no clinical or MRI findings.

Adrenomyeloneuropathy occurs in another 40% of boys with X-linked ALD and presents as a more chronic disorder of the spinal cord and peripheral nerves. It begins with a slowly progressive spastic paraparesis, urinary incontinence, and onset of impotence during the 3rd or 4th decade, even though adrenal insufficiency may have been present since childhood. Cases of typical ALD have occurred in relatives of those with adrenomyeloneuropathy. One of the most difficult problems in the management of X-linked ALD is the common observation that affected individuals in the same family may have quite different clinical courses. For example, in 1 family, 1 affected boy had severe classic ALD culminating in death by age 10 yr; another affected male (a brother) had late-onset adrenomyeloneuropathy, and a 3rd had no symptoms at all. A panel of brain neuroimaging studies, which can provide quantitative information about the progression of adrenoleukodystrophies, aids the selection of patients for bone marrow therapy, and has improved counseling for these disorders.

Neonatal ALD is characterized by marked hypotonia, severe psychomotor retardation, and early onset of seizures. It is inherited as an autosomal recessive condition. Visual inattention is secondary to optic atrophy. Results of adrenal function tests are normal, but adrenal atrophy is evident postmortem. Correction of adrenal insufficiency is ineffective in halting neurologic deterioration.

The diagnosis of ALD is frequently made on the basis of characteristic clinical features that raise suspicion; an MRI that demonstrates posterior leukoencephalopathy; and serum studies that demonstrate abnormally elevated very long chain fatty acids. In classical and late-onset ALD, the male child is affected, but the carrier mother may show spasticity of spinal cord origin.

592.4 Sialidosis

Jennifer M. Kwon

Sialidosis is the result of lysosomal sialidase deficiency, secondary to autosomal recessive mutations in the sialidase (α-neuraminidase, NEU1) gene on chromosome 6p21.3. The accumulation of sialic acid–oligosaccharides with markedly increased urinary excretion of sialic acid–containing oligosaccharides is associated with clinical presentations that range from the milder sialidosis type I to the more severe sialidosis type II associated with both neurologic and somatic features.

Sialidosis type I, the cherry red spot myoclonus syndrome (CRSM), usually presents in the 2nd decade of life, when a patient complains of visual deterioration. Inspection of the retina shows a cherry red spot, but, unlike patients with TSD, visual acuity declines slowly in individuals with CRSM. Myoclonus of the extremities is gradually progressive and often debilitating and eventually renders patients nonambulatory. The myoclonus is triggered by voluntary movement, touch, and sound and is not controlled with anticonvulsants. Generalized convulsions responsive to antiepileptic drugs occur in most patients.

Sialidosis type II patients present at a younger age and have cherry red spots and myoclonus, as well as somatic involvement, including coarse facial features, corneal clouding (rarely), and dysostosis multiplex, producing anterior beaking of the lumbar vertebrae. Type II patients may be further subclassified into congenital and infantile (childhood) forms, depending on the age at presentation. Examination of lymphocytes shows vacuoles in the cytoplasm, biopsy of the liver demonstrates cytoplasmic vacuoles in Kupffer cells, and membrane-bound vacuoles are found in Schwann cell cytoplasm, all attesting to the multiorgan nature of sialidosis type II. No distinctive neuroimaging findings or abnormalities in electrophysiologic studies are noted in this group of disorders. Patients with sialidosis have been reported to live beyond the 5th decade.

Some cases of what appears to be sialidosis type II are the result of combined deficiencies of β-galactosidase and α-neuraminidase due to deficiency of “protective protein/cathepsin A” (PPCA) that prevents premature intracellular degradation of these two enzymes. These patients have galactosialidosis and they are clinically indistinguishable from those with sialidosis type II. Therefore patients who have features of sialidosis type II with marked urinary excretion of oligosaccharides should be tested for PPCA deficiency as well as sialidase deficiency.

592.5 Miscellaneous Disorders

Jennifer M. Kwon

Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder characterized by nystagmus and abnormalities of myelin. PMD is caused by mutations in the proteolipid protein (PLP1) gene, on chromosome Xq22, which is essential for CNS myelin formation and oligodendrocyte differentiation. Mutations in the same gene can cause familial spastic paraparesis (progressive spastic paraparesis type 2, SPG2). PLP1 mutations causing disease include point mutations, deletions, gene duplications, and other gene dosage changes.

Clinically, classic PMD is recognized by nystagmus and roving eye movements with head nodding during infancy. Developmental milestones are delayed; ataxia, choreoathetosis, and spasticity ultimately develop. Optic atrophy and dysarthria are associated findings, and death occurs in the 2nd or 3rd decade. The major pathologic finding is a loss of myelin with intact axons, suggesting a defect in the function of oligodendroglia. An MRI scan shows a symmetric pattern of delayed myelination. Multimodal-evoked potential studies demonstrate early in the course a pattern consisting of loss of waves III-V on the ABR. This finding is useful in the investigation of nystagmus in infant boys. VEPs show prolonged latencies, and SSEPs show absent cortical responses or delayed latencies. It is now recognized that a broad spectrum of phenotypes, including SPG2 and peripheral nerve abnormalities, can also result from mutations in the PLP1 gene.

Recently, individuals with a clinical and radiologic phenotype like PMD including hypomyelinating leukodystrophy, have been identified with autosomal recessive mutations of gap junction protein alpha 12 (GJA12, or connexin 47).

Alexander Disease

This is a rare disorder that causes progressive macrocephaly and leukodystrophy. Alexander disease is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, on chromosome 17q21 and cases are usually sporadic in their families. Pathologic examination of the brain discloses deposition of eosinophilic hyaline bodies called Rosenthal fibers in astrocyte processes. These accumulate in a perivascular distribution throughout the brain. In the classic infantile form of Alexander disease, degeneration of white matter is most prominent frontally. Affected children develop progressive loss of intellect, spasticity, and unresponsive seizures causing death by 5 yr of age. However, there are milder forms that present later in life and that may not have the characteristic frontal predominance or megalencephaly.

Metabolic and degenerative disorders can present with significant cerebral white matter changes, such as some mitochondrial disorders (Chapters 80.1 and 591.2) and glutaric aciduria type 1 (Chapter 79). In addition, the broader use of MRI has brought to light new leukodystrophies. One example is vanishing white matter disease or childhood ataxia with central nervous system hypomyelination (VWM/CACH) characterized by ataxia and spasticity. Some patients also have optic atrophy, seizures, and cognitive deterioration. The age of presentation and the rapidity of decline can be quite variable. In the early-onset forms, decline is usually rapid and followed quickly by death; in the later-onset forms, mental decline is usually slower and milder. Interestingly, acute demyelination in these disorders can be triggered by fever or fright. The diagnosis of VWM/CACH is based on clinical findings, characteristic abnormalities on cranial MRI, and autosomal recessive mutations in 1 of 5 causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the 5 subunits of the eucaryotic translation initiation factor, eIF2B.

Menkes Disease

Menkes disease (kinky hair disease) is a progressive neurodegenerative condition inherited as a X-linked recessive trait. The Menkes gene codes for a copper-transporting, P-type ATPase, and mutations in the protein are associated with low serum copper and ceruloplasmin levels as well as a defect in intestinal copper absorption and transport. Symptoms begin in the 1st few months of life and include hypothermia, hypotonia, and generalized myoclonic seizures. The facies are distinctive, with chubby, rosy cheeks and kinky, colorless, friable hair. Microscopic examination of the hair shows several abnormalities, including trichorrhexis nodosa (fractures along the hair shaft) and pili torti (twisted hair). Feeding difficulties are prominent and lead to failure to thrive. Severe mental retardation and optic atrophy are constant features of the disease. Neuropathologic changes include tortuous degeneration of the gray matter and marked changes in the cerebellum with loss of the internal granule cell layer and necrosis of the Purkinje cells. Death occurs by 3 yr of age in untreated patients.

Copper-histidine therapy may be effective in preventing neurologic deterioration in some patients with Menkes disease, particularly when treatment is begun in the neonatal period or, preferably, with the fetus. These presymptomatic children are currently identified because of a family history of an affected brother. Copper is essential in the early stages of CNS development, and its absence probably accounts for the neuropathologic changes. In presymptomatic neonatally diagnosed patients the dosage regimen is copper histidine, 250 µg by subcutaneous injection twice daily to 1 yr of age and 250 µg once daily thereafter. Optimal response to copper-injection treatment appears to occur only in patients who are identified in the newborn period and whose mutations permit residual copper-transport activity.

The occipital horn syndrome, a skeletal dysplasia caused by different mutations in the same gene as that involved in Menkes disease, is a relatively mild disease. The 2 diseases are often confused, because the biochemical abnormalities are identical. Resolution of the uncertainty about treatment of patients with Menkes disease will require careful genotype-phenotype correlation, along with further clinical trials of copper therapy.

Rett Syndrome (RS)

This syndrome is not strictly speaking a degenerative disease, but a disorder of early brain development marked by a period of developmental regression and deceleration of brain growth after a relatively normal neonatal course. It occurs predominantly in girls. The frequency is ≈1/15,000-1/22,000. RS is caused by mutations in MeCP2, a transcription factor that binds to methylated CpG islands and silences transcription. Development may proceed normally until 1 yr of age, when regression of language and motor milestones and acquired microcephaly become apparent. An ataxic gait or fine tremor of hand movements is an early neurologic finding. Most children develop peculiar sighing respirations with intermittent periods of apnea that may be associated with cyanosis. The hallmark of Rett syndrome is repetitive hand-wringing movements and a loss of purposeful and spontaneous use of the hands; these features may not appear until 2-3 yr of age. Autistic behavior is a typical finding in all patients. Generalized tonic-clonic convulsions occur in the majority and are usually well controlled by anticonvulsants. Feeding disorders and poor weight gain are common. After the initial period of neurologic regression, the disease process appears to plateau, with persistence of the autistic behavior. Cardiac arrhythmias may result in sudden, unexpected death at a rate that is higher than the general population. Generally girls survive into adulthood.

Postmortem studies show significantly reduced brain weight (60-80% of normal) with a decrease in the number of synapses, associated with a decrease in dendritic length and branching. The phenotype may be related to failure to suppress expression of genes that are normally silent in the early phases of postnatal development. Although very few males survive with the classic RS phenotype, genotyping of boys without the classic RS phenotype but with mental retardation and other atypical neurologic features has detected a significant number with mutations in MeCP2. Mutations in MeCP2 have been demonstrated in normal female carriers, females with Angelman syndrome, and in males with fatal encephalopathy, Klinefelter (47 XXY) syndrome, and familial X-linked mental retardation.

Some girls have an atypical Rett phenotype associated with severe myoclonic seizures in infancy, slowing of head growth, and developmental arrest and have mutations in another X-linked gene encoding for cyclin-dependent kinase–like 5 (CDKL5), which may interact with MeCP2 and other proteins regulating gene expression.

Subacute Sclerosing Panencephalitis

This is a rare, progressive neurologic disorder caused by persistent measles virus infection of the CNS (Chapter 238). The number of reported cases has decreased dramatically to 0.06 cases/million population, paralleling the decline in reported measles cases. The initial clinical manifestations include personality changes, aggressive behavior, and impaired cognitive function in individuals who have been exposed to natural measles virus in early childhood. Myoclonic seizures soon dominate the clinical picture. Later, generalized tonic-clonic convulsions, hypertonia, and choreoathetosis become evident, followed by progressive bulbar palsy, hyperthermia, and decerebrate postures. Funduscopic examination early in the course of the disease reveals papilledema in approximately 20% of the cases. Optic atrophy, chorioretinitis, and macular pigmentation are observed in most patients. The diagnosis is established by the typical clinical course and 1 of the following: (1) measles antibody detected in the CSF, (2) a characteristic electroencephalogram consisting of bursts of high-voltage slow waves interspersed with a normal background that occur with a constant periodicity in the early stages of the disease, and (3) typical histologic findings in the brain biopsy or postmortem specimen. Treatment with a series of antiviral agents has been attempted without success. Death occurs usually within 1-2 yr from the onset of symptoms.

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