ADULT-ONSET TAY-SACHS DISEASE

Although GM2 gangliosidosis usually is evident in early childhood, there are variant forms (adult-onset Tay-Sachs disease) that have a clinical phenotype resembling a lower motor neuropathy (47). Patients with this illness usually offer a history of lifelong motor incoordination. As young adults, they note the subtle onset of progressive proximal muscle weakness with features indicating lower motor neuron dysfunction (fasciculations, mild denervation atrophy, and electromyographic abnormalities). This may then evolve to frank leg weakness, sometimes with dysarthria. Some patients also show psychiatric manifestations (e.g., anxiety, subnormal attention span, or even psychotic episodes) (48). Some patients may reveal spasticity and Babinski signs as the illness progresses. Involvement of the central nervous system is indicated not only by the corticospinal signs but also some atrophy, particularly in the cerebellum. A salient pathologic finding is the presence of distended neurons with periodic acid-Schiff-positive inclusions (49).

The underlining defect in this disease is an accumulation of GM2 ganglioside, which is normally metabolized by yV-acetyl-hexosaminidases A and B (Hex A and B); these are dimeric enzymes made up of two polypeptides. An alpha and beta subunit are combined in HEX A, and HEX B has two beta subunits. The activity of both enzymes is augmented by GM2 activator protein, which enhances access of substrate to the enzyme. The genes for the alpha and beta subunits are encoded on chromosomes 15q and 5q (50). The GM2 activator protein may be encoded on chromosome 5 (51). Patient DNA analysis reveals mutations in the alpha and beta subunits and the GM2 activator protein (52,53).

X-LINKED SPINAL BULBAR ATROPHY

The hallmark of this disorder is a slowly progressive lower motor neuropathy arising in adult males (54). Unlike the situation in ALS, pathology in X-linked spinal bulbar atrophy is confined to lower motor neurons. Moreover, the time course is slower than in ALS. In X-linked spinal bulbar atrophy, there may be gynecomastia and testicular atrophy with reduced fertility. LaSpada et al. (55) discovered that the molecular defect in X-linked spinal bulbar atrophy is an expansion of a CAG repeat in the first exon of the androgen receptor gene. This expands a polyglutamine tract within the receptor. It is apparent that as the length of the tract of CAGs increases, the illness becomes more severe (56). It is not clear how this molecular lesion causes motor neuron disease. However, important insights have come from the discoveries that there are diverse inherited neurodegenerative diseases associated with CAG repeat expansions, including Huntington's disease and several of the spinocerebellar ataxias; in each of these, there is a predicted polyglutamine expansion; and in each, careful ultramicroscopy and analysis with antibodies to expanded glutamine tracts document the presence of intranuclear inclusions of protein consisting in part of polyglutamine (57). That these are abnormal is indicated in part by their aggregation within nuclei and in part by the fact that they are ubiquitinated (57).

SPINAL MUSCULAR ATROPHY

The spinal muscular atrophies are discussed in detail in Chapter 30. Briefly, this family of disorders characterized by progressive degeneration of motor neurons in the brainstem and spinal cord is caused by deficiencies of a survival motor neuron or SMN protein. Recent studies indicate that SMN is important in the formation and function of spliceosomes and thus is important in the processes of splicing of nuclear and nucleolar RNA (58,59).

FAMILIAL SPASTIC PARAPLEGIA

Familial spastic paraplegia (FSP) is an autosomal dominant disorder characterized by slowly worsening spastic weakness that typically starts in the distal legs (60,61). Although the age at onset is variable, in a large preponderance of families the disease begins in the third or fourth decade. Many patients live several decades with this illness. Sphincter disturbance and weakness of the upper extremities are uncommon but may be seen late in the course. By the same token, minor sensory loss may be evident in late-stage FSP. The most prominent pathologic feature in FSP is degeneration of the corticospinal tracts (62). Rarely, FSP is associated with involvement of other regions of the nervous system (63) and thus may entail amyotrophy, mental retardation, optic atrophy, and sensory neuropathy. Although these complex forms of the disease attest to the difficulty in classifying subtypes of FSP, it seems likely that genetic and molecular studies will clarify these nosologic issues. For example, in only the last 5 years, loci for FSP have been identified on chromosomes 2p (64), 14q (65), and 15q (66). X-linked and recessive forms of FSP are also encountered; the latter is more common in regions with consanguinity (67). Atypical FSP has been associated with mutations in genes encoding the proteolipid protein (68) and the cell adhesion protein LI CAM (69). A form of adrenoleukodystrophy (adrenomyeloneuropathy) can resemble FSP (70,71).

REFERENCES

An extensive reference list can be found in Motor Disorders, edited by David S. Younger, MD, Lippincott Williams & Wilkins, 1999, pgs. 360-361.

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