Spinocerebellar Degenerations

Ataxia, or disturbance of coordination of movements and of gait and balance, tremor of the extremities and head, dysarthric speech, and disorders of eye movement, are distinctive clinical features of cerebellar and spinocerebellar degenerations. This group encompasses inherited and sporadic diseases (Table 5.15).

Sporadic cerebellar ataxias are the olivopontocere-bellar atrophy (see the section Multiple System Atrophy) and the idiopathic cerebellar ataxias of midlife.

Inherited cerebellar and spinocerebellar ataxias (ICSCA) occur from infancy to adulthood. The clinical presentation is manifold. The ataxia is associated with combinations of various symptoms and signs relating to the cranial nerves and to the pyramidal, extrapyramidal, and sensory systems. Systemic manifestations are characteristic for some. The pattern of inheritance is autosomal recessive or autosomal dominant (see Table 5.15). Notably, several diseases are trinucleotide repeat disorders caused by expanding cytosine-adenine-guanine

(CAG) repeats that code for polyglutamine tracts, hence the name polyglutamine diseases (Table 5.16). An expansion of the repeats from the normal range of 10 to 30 to over 40 to 90 results in diseases (Table 5.17). Longer repeats cause an earlier age of onset and greater severity of the disease in offspring, a feature referred to as genetic anticipation.

Diagnostic evaluation is aimed first at eliminating sporadic degenerative ataxias and cerebellar diseases with specific causes, and second, at differentiating between various forms of inherited cerebellar ataxias (Table 5.18). Molecular genetic tests are available to detect and measure triplet expansion.

The pathology is widespread. The cerebellum, brainstem, and spinal cord are usually affected. Additional lesions occur in various subcortical gray structures and peripheral nerves. The presence of neuronal nuclear inclusions that derive from aggregations of expanded polyglutamine-containing proteins are characteristic of triplet-repeat diseases.

TABLE 5.17.

Genetic Features of Trinucleotide Repeat Diseases

TABLE 5.17.

Genetic Features of Trinucleotide Repeat Diseases

Disease

Gene Product

Chromosome

Repeats

Abnormal Length

Normal Length

FA

Frataxin

9

GAA

66-1700

9-55

DRPLA

Atrophin 1

12

CAG

34-79

7-23

SCA 1

Ataxin 1

6

CAG

42-81

16-36

SCA 2

Ataxin 2

12

CAG

35-64

15-34

SCA 3/MJD

Ataxin 3

14

CAG

68-79

13-36

SCA 6

CACNA1A

19

CAG

20-33

4-181

HD

Huntingtin

4

CAG

36-121

6-34

BSMA

Androgen receptor

X

CAG

38-62

9-34

FA, Friedreich's ataxia; DRPLA, dentatorubro-pallidoluysial atrophy; SCA, spinocerebellar ataxia; MJD, Machado-Joseph disease; GAA, guanine-adenine-adenine; CAG, cytosine-adenine-guanine; HD, Huntington's disease; BSMA, bulbospinal muscular atrophy (Kennedy's disease)

FA, Friedreich's ataxia; DRPLA, dentatorubro-pallidoluysial atrophy; SCA, spinocerebellar ataxia; MJD, Machado-Joseph disease; GAA, guanine-adenine-adenine; CAG, cytosine-adenine-guanine; HD, Huntington's disease; BSMA, bulbospinal muscular atrophy (Kennedy's disease)

TABLE 5.18.

Etiologies of Cerebellar Diseases

Primary Degenerative

Acquired

Vascular Infection Toxin

Alcohol, phenytoin, Barbiturate, lithium, Mercury, lead, Thallium, solvents Myelin diseases Paraneoplastic Heat stroke, hypoxia, Metabolic

Hypothyroidism Neoplasm

Inherited Metabolic

Lysosomal diseases Mitochondrial diseases Hartnup disease Aminoacidurias

Acanthocytosis (Abetalipoproteinemia)

Prion Diseases

Sporadic Creutzfeldt-Jakob disease Gerstmann-Sträussler-Scheinker disease

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