ataxia

CONGENITAL ATAXIAS

Pathogenesis and Pathophysiology.

Cerebellar malformations are often part of complex malformation syndromes that affect diverse structures in the central

nervous system (CNS). In addition, some cerebellar malformations are more or less limited to the cerebellum. In these latter forms, congenital ataxia is often a

prominent clinical feature, although it may be associated with other symptoms such as mental retardation, spasticity, and seizures. In some cases of severe cerebellar

malformation, ataxia is surprisingly mild.

The etiology of congenital ataxia is poorly understood. The occasional appearance of congenital ataxia in siblings suggests that congenital ataxia may be inherited in

an autosomal recessive manner. The molecular genetic basis of congenital ataxia, however, has been incompletely explored. Sporadic cases of congenital ataxia

outnumber familial

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cases by far. Whether sporadic cases are also due to recessive mutations or whether they have other causes is unknown. Animal experimental studies show that a

variety of exogenous factors such as toxins, viral infection, hypoxia, and irradiation may lead to cerebellar malformations. [

16]

Epidemiology and Risk Factors. Congenital ataxia due to cerebellar malformation is a rare condition. Precise information on the epidemiology of congenital ataxia is

not available.

Clinical Features and Associated Disorders. Cerebellar aplasia seldom occurs alone. It is characterized by complete or near complete absence of the cerebellum.

The clinical picture of patients with cerebellar aplasia is variable. The life expectancy of patients with this disorder ranges from a few weeks to a normal life span. In

general, patients with cerebellar agenesis have profoundly impaired motor development and persistent motor deficits. However, there are reports of patients with

subtotal cerebellar aplasia who learned to stand, walk, and run. Compensation appears to be best if intelligence is normal. [

17]

Vermian aplasia is often associated with a reduction in the size of the cerebellar hemispheres and anomalies of the cerebellar and olivary nuclei. As in cerebellar

aplasia, survival ranges from a few weeks to a normal life span. The clinical picture of patients with vermian aplasia is not uniform. It may be associated with a

nonprogressive cerebellar syndrome but may also be completely asymptomatic. If vermian aplasia is associated with other malformations, a neurological syndrome

with no features of cerebellar dysfunction may be present.

Joubert's syndrome is an autosomal recessive disorder with a distinctive clinical picture. It comprises episodes of hyperpnea alternating with apnea, abnormal eye

movements, ataxia, and mental retardation. Most patients die before the age of 3 years. Neuropathologically, complete or partial vermian aplasia is found along with

changes in the cerebellar cortex and dentate nucleus. [

18]

Cerebellar hypoplasia is characterized by reduced size of the entire cerebellum or parts of it. Cerebellar hypoplasia may be detected by chance in neurologically

healthy individuals. Often, however, it is associated with congenital ataxia. In affected children, motor milestones are delayed. When the child begins to walk, the gait

is ataxic, and falls are frequent. Limb movements and speech may also be affected. [

19]

The Dandy-Walker malformation is a complex malformation of the CNS characterized by partial or complete aplasia of the cerebellar vermis associated with a large

posterior fossa cyst. Other abnormalities include enlargement of the posterior fossa, abnormally high placement of the tentorium, and elevation of the transverse

sinuses. The Dandy-Walker malformation is almost always associated with hydrocephalus. The clinical syndrome accompanying this malformation is related to the

extent of the hydrocephalus. Despite the presence of vermian aplasia, congenital ataxia is not a typical feature of the Dandy-Walker malformation (see Chapter 28 ).

Chiari malformations consist of caudal herniation of parts of the cerebellum and brain stem into the upper cervical canal. Although these malformations affect the

cerebellum, they do not lead to congenital ataxia (see Chapter 28 ). Differential Diagnosis and Evaluation. Congenital ataxia can be distinguished from other types of early-onset ataxias by the nonprogressive nature of the disorder.

Clinical distinctions among the various cerebellar malformations underlying

congenital ataxia are impossible. MRI is the method of choice for the evaluation of patients

with congenital ataxia because it clearly shows the size of the cerebellum and the presence of any associated anomalies such as cysts and hydrocephalus. [ 20]

Electrophysiological investigations do not reveal consistent abnormalities. Management, Prognosis, and Future Perspectives. There is no specific treatment for congenital ataxia. If cerebellar malformations occur in combination with

hydrocephalus, surgical shunting is required. Congenital ataxia itself is a nonprogressive and benign condition. Children with normal intelligence can compensate for

cerebellar defects particularly well. However, the cerebellar malformations that underlie congenital ataxia are often associated with other malformations of the CNS.

These may lead to mental retardation, epilepsy, disorders of breathing, and noncerebellar motor symptoms. The prognosis in children affected by complex malformation syndromes is poor, and many of them die in the first weeks of life.

EARLY-ONSET CEREBELLAR ATAXIA WITH RETAINED TENDON REFLEXES Pathogenesis and Pathophysiology. Early-onset cerebellar ataxia with retained tendon reflexes (EOCA) denotes a type of degenerative ataxia with disease onset

before age 25 that is distinguished from FRDA in that patients with EOCA retain tendon reflexes. [

21] The occurrence of EOCA in siblings suggests an autosomal

recessive disorder. Segregation analysis performed in EOCA patients, however, yielded segregation ratios that were lower than the expected value of 0.25 for

autosomal recessive inheritance, suggesting that genetic heterogeneity exists among EOCA patients. [

7] Other cases appear to be nonhereditary and idiopathic. The

high proportion of male patients in most series of EOCA patients suggests the possibility that inheritance is based on the X chromosome in some cases. The molecular genetic basis of EOCA is unknown. The major neuropathological abnormality in EOCA is diffuse cerebellar atrophy. Occasionally, additional degeneration

of brain stem nuclei and medial cerebellar peduncles occurs, suggesting the presence of OPCA.

Epidemiology and Risk Factors. The prevalence of EOCA has been reported to be 0.5 to 2.3 per 100,000. [

4] As in other recessive hereditary disorders, birth from a

consanguineous marriage is a risk factor for EOCA. In families in which one child is affected by EOCA, the remaining children have an increased risk of

developing

the disorder. However, this risk appears to be smaller than the estimated risk of 25 percent for an autosomal recessive disorder.

Clinical Features and Associated Disorders. By definition, EOCA starts before the age of 25 years. On average, disease onset occurs at the age of 17 years. All

EOCA patients suffer from a progressive cerebellar syndrome marked by ataxia of gait and stance, ataxia of limb movements, dysarthria, and cerebellar oculomotor

abnormalities (gaze-evoked nystagmus, saccade hypermetria,

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broken smooth pursuit, reduced optokinetic nystagmus, and impaired suppression of vestibulo-ocular reflexes by fixation). About half of the patients have an impaired

vibration or position sense. Other noncerebellar symptoms, such as pyramidal tract signs, skeletal muscle atrophy, pale optic discs, cardiomyopathy, diabetes

mellitus, and skeletal deformities, are rare or absent. [

7] , [

21]

Differential Diagnosis. There are a number of rare types of early-onset cerebellar ataxia of unknown etiology that resemble EOCA in many respects but have

characteristic additional features. These disorders include early-onset cerebellar ataxia with hypogonadism (Holmes' syndrome), with optic atrophy and spasticity

(Behr's syndrome), with cataract and mental retardation (MarinescoSjogren's syndrome), with retinal degeneration and deafness( Hallgren's syndrome), with spasticity,

amyotrophy, and bladder dysfunction (autosomal recessive spastic ataxia Charlevoix-Saguenay), and with myoclonus in the absence of severe epilepsy and dementia

(Ramsay Hunt syndrome).

Evaluation. EOCA can be distinguished clinically from FRDA by the presence of tendon reflexes. In addition, the oculomotor abnormalities in FRDA and EOCA

patients are different, and EOCA patients usually do not have cardiomyopathy. On MRI, EOCA patients are found to have cerebellar atrophy, whereas FRDA patients

have isolated cervical spinal cord atrophy. Nevertheless, the differentiation of FRDA and EOCA may be difficult in exceptional cases of FRDA with retained tendon

reflexes. In these cases, a molecular genetic test for FRDA must be performed.

EOCA may be confused with other early-onset disorders associated with ataxia, such as ataxia telangiectasia, abetalipoproteinemia, Refsum's disease, ataxia with

isolated vitamin E deficiency, juvenile and adult forms of GM 2 -gangliosidosis, adrenoleukodystrophy, and mitochondrial encephalomyopathies. To exclude these

disorders, the workup of an EOCA patient should include determination of the serum levels of alpha-fetoprotein, serum lipids, phytanic acid, vitamin E, hexosaminidase A, and very long chain fatty acids. In addition, cerebrospinal fluid (CSF) lactate levels should be measured. In some cases, a muscle and skin biopsy

may be helpful to exclude mitochondrial encephalomyopathies and lipid storage diseases.

Nerve conduction studies show evidence of axonal neuropathy in the majority of EOCA patients. Nerve conduction velocity (NCV) is usually normal or mildly reduced.

However, there are exceptional cases in which the NCV is as low as 20 m/sec. Cortical potentials of SEPs are absent or moderately delayed. Abnormal BAEPs are

found in more than half of EOCA patients. The abnormalities include loss of waves I, III, and V and delay of waves III and V, suggesting pathology of the auditory

nerve and the central auditory pathways. MRI usually shows cerebellar atrophy. In some cases, the brain stem is also atrophic, suggesting the presence of OPCA.

Spinal cord atrophy is not a typical feature of EOCA. [

7]

Management, Prognosis, and Future Perspectives. At present, there is no specific treatment for EOCA. As in FRDA, 5-hydroxytryptophan, amantadine, or

buspirone may be tried, although there are no controlled trials that clearly demonstrate the efficacy of these drugs in relieving ataxia. Physical therapy is recommended. Many EOCA patients become dependent on canes or wheelchairs within years after the onset of disease. EOCA is a progressive disorder; however, it

progresses more slowly than FRDA. On average, EOCA patients become wheelchair-bound about 20 years after disease onset. Reliable data concerning survival in

EOCA are not available.

Autosomal Dominant Disorders

AUTOSOMAL DOMINANT CEREBELLAR ATAXIA WITHOUT RETINAL DEGENERATION Autosomal dominant cerebellar ataxias (ADCAs) without retinal degeneration comprise a heterogeneous group of dominantly inherited neurodegenerative diseases in

which ataxia is the leading symptom. In most families, additional extracerebellar symptoms (saccade slowing, ophthalmoplegia, optic atrophy, pyramidal signs,

amyotrophy, basal ganglia symptoms, dementia: ADCA-I) are present, whereas families with a pure cerebellar syndrome (ADCA-III) are less frequent. [

22]

The genetic heterogeneity of ADCA has been established. In ADCA-I, the disease loci have been assigned to chromosome 6p (spinocerebellar ataxia type 1 [SCA1]),

12q (SCA2), 14q (SCA3), and 16q (SCA4). [

23] [

24] [

25] [

26] In an ADCA-III family with an almost pure cerebellar phenotype, a linkage with a marker on chromosome 11cen

was demonstrated (SCA5). A novel locus, SCA6, has been identified on 19p (see Table 35-2 ).[

27]

Machado-Joseph disease (MJD) is a dominantly inherited ataxic disorder in which there is great phenotypical variation. MJD was first described in patients of Azorean

descent. Later, the MJD phenotype was also observed in families of

non-Azorean origin. Although MJD patients may have some clinical features, such as prominent

eyes, severe dystonia, and amyotrophy, which are less frequently seen in North American and European ADCA families, there is no convincing clinical evidence to

separate MJD from ADCA-I.[

22] The gene locus of Japanese MJD families has been mapped to chromosome 14q, coincident with the localization of SCA3. Subsequent

work has shown that the same mutation causes MJD in Japanese families and ADCA in European and North American SCA3 families. [

28]

Spinocerebellar Ataxia Type 1

Pathogenesis and Pathophysiology. The SCA1 locus in this autosomal dominant disorder was found on chromosome 6p in both Japanese and American families

using serological markers of the human leukocyte antigen (HLA) system. In 1993, Orr and colleagues isolated the SCA1 gene and showed that the mutation was an

unstable CAG trinucleotide repeat expansion within a translated region of the gene. [

24] Although the repeat length in normals varies from 6 to 39 trinucleotides,

SCA1

patients have one allele within a range of 40 to 81 repeat units. The mutated SCA1 genes contain uninterrupted CAG stretches. In contrast, normal alleles have a

midstream CAT interruption.[

29] Repeat length and the presence or absence of the interruption appear to be critical factors in the stability of trinucleotide repeats.

Repeats in the normal size range containing a CAT interruption are stable in parent-to-offspring transmission.

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Expanded uninterrupted repeats in SCA1 patients are unstable and have a tendency to expand further during meiosis, particularly during spermatogenesis. This

mechanism leads to larger expansions in the offspring of affected males. Mitotic instability of the expanded repeats also occurs, leading to varying repeat lengths in

different body tissues.[

30]

In patients with SCA1 there is an inverse correlation between the length of the CAG repeat and the age of onset, the largest alleles occurring in patients with juvenile

disease onset. Because of the instability of expanded repeats during gametogenesis, the age of onset varies with features of anticipation. Anticipation is most

pronounced in the offspring of affected males. [

24]

The wild-type SCA1 gene encodes ataxin-1, a protein that contains a polyglutamine stretch of variable length. Normal ataxin-1 and its mutated form are expressed

ubiquitously within the body at comparable levels. The physiological function of ataxin-1 is unknown. It is also unknown how the trinucleotide repeat mutation causes

the SCA1 phenotype. Like

The mutation underlying SCA1 is an expansion of a CAG trinucleotide repeat, encoding a polyglutamine tract in the open reading frame of the SCA1 transcript (3). In the normal population, the repeat is polymorphic, with allele sizes ranging from 6 to 44 CAG units, and it is interrupted by at least one CAT triplet. Conversely, SCA1 chromosomes carry uninterrupted CAG tracts ranging in size from 40 to 83 repeat units (4,5). Although alleles in the normal size range are relatively stable on germline transmission, expanded alleles change size in the majority of the parent-to-offspring transmissions (4,5). This results in an earlier manifestation of the clinical symptoms in subsequent generations of SCA1 families, a phenomenon known as anticipation. There is an inverse correlation between the size of the expanded alleles and age of disease onset (3).

The SCA1 gene encodes a 100 kDa protein of unknown function termed ataxin-1, and is widely expressed in the central nervous system and peripheral tissues (6).

Immunohisto chemical studies showed that ataxin-1 localizes predominantly to the nucleus of neuronal cells and in the cytoplasm of other cell types (7). In SCA1 patients, ataxin-1 accumulates in single ubiquitin-positive nuclear inclusions which are present in affected neurons (8). Transgenic mice overexpressing an expanded human SCA1 cDNA under the control of the Purkinje cell-specific promoter, Pcp2, have been generated to

gain insight into the pathogenesis of the SCA1 mutation (9,10). One of these transgenic lines, named B05, overexpresses mutant ataxin-1 mRNA at ～50–100 times endogenous levels, only in Purkinje cells. These mice develop neuropathological changes limited to Purkinje cells and begin to show an ataxic phenotype at ～12 weeks of age (9,11). As in brain tissue from SCA1 patients, expanded ataxin-1 shows an altered distribution in the Purkinje cell nuclei of B05 mice where it forms ubiquitin-positive inclusions (8).

In order to study the effects of the expression of a mutant form of ataxin-1 under the control of its own promoter, we designed a knock-in strategy aimed to insert an expanded CAG trinucleotide repeat into the mouse Sca1 locus. These mice would allow study of the effects of the pathogenicity of mutant ataxin-1 when expressed at endogenous levels in a spatial and temporal pattern that parallels the human condition. Also, introducing the expansion into the genomic locus might provide insight into the repeat instability. Here we describe the generation of the Sca1 knock-in mice that carry 78 CAG repeats in the Sca1 locus, and their phenotypic and neuropathological analyses.

Huntington's disease, it is assumed that the pathogenetic mechanism is not loss of the physiological function of ataxin-1 but rather gain of a

new toxic function.

Neuropathological findings in SCA1 vary. In most cases, OPCA is found as well as degeneration of the ascending spinal pathways with minor degeneration of the

pyramidal tract.[

31] In the cerebellar cortex, Purkinje cells are primarily affected.

At the pathological level, the most frequent and severe alterations seen in SCA1 patients are the loss of Purkinje cells in the cerebellar cortex, and degeneration of neurons in the inferior olivary nuclei, the cerebellar dentate nuclei and the red nuclei. Nuclei of the third, tenth and twelfth cranial nerves also have variable involvement, with the hypoglossal nuclei being the most frequently and severely affected

Epidemiology and Risk Factors.The prevalence of ADCA has been reported to be 1.2 in 100,000 with large regional variations due to founder effects. [ 32] In a recent

nationwide study a frequency of 3 percent of SCA1 among 149 ADCA families was reported. [

33] SCA1 is a genetically determined disorder with no known

environmental risk or precipitation factors. Children of an SCA1 patient have a 50 percent risk of developing the disease.

Clinical Features and Associated Disorders. The onset of SCA1 occurs at any time from adolescence to late adulthood with features of anticipation. On average,

the disease starts at around the age of 35 years. All SCA1 patients suffer from a progressive cerebellar syndrome marked by ataxia of gait and stance, ataxia of limb

movements, dysarthria, and cerebellar oculomotor abnormalities

(gaze-evoked nystagmus, saccade hypermetria, broken-up smooth pursuit, reduced optokinetic

nystagmus, and impaired suppression of vestibulo-ocular reflex by fixation). In the majority of patients additional noncerebellar symptoms are present. Pyramidal tract

signs, skeletal muscle atrophy, and pale optic discs are found in more than 50 percent of SCA1 patients. Gaze palsy, slow saccades, decreased vibration sense, and

bladder dysfunction occur less frequently, and basal ganglia symptoms and dementia are rare symptoms. Dysphagia is a typical feature of the late stages of disease.

[31] , [

34] , [

35] A recent study performed in a large Siberian SCA1 kindred suggests that the severity of associated symptoms such as dysphagia and muscle atrophy increases with CAG repeat length.[

36]

Differential Diagnosis and Evaluation. SCA1 should be differentiated from other hereditary cerebellar ataxias as well as from symptomatic ataxias. The diagnosis of

SCA1 is made by the demonstration of CAG repeat expansion at the SCA1 locus. Clinically, SCA1 cannot be distinguished with certainty from other forms of ADCA-I.

However, the presence of pyramidal tract signs, pale optic discs, and dysphagia is suggestive of SCA1 because these symptoms are less frequently found in other

mutations leading to ADCA.

NCVs are in the normal range or moderately reduced. SNAPs are reduced in almost all patients, suggesting the presence of sensory axonal neuropathy. Patients with

widespread atrophy of the skeletal muscles demonstrate chronic neurogenic electromyographic (EMG) features. MEPs in response to transcranial magnetic

stimulation are abnormal in almost all SCA1 patients; the loss of responses or increased CMCT indicates pyramidal tract involvement. SEPs due to tibial nerve

stimulation are usually delayed or absent. Similarly, visual evoked potentials (VEPs) are abnormal in almost all SCA1 patients, who show a loss or delay of P100.

Abnormalities of BAEPs, with delays in peaks I, III, and V and increased interpeak latencies, are found in about half of SCA1 patients. MRI shows diffuse cerebellar

atrophy, brain stem atrophy, and shrinkage of the cervical spinal cord. [

35]

Management. At present, there is no specific treatment for SCA1. As in the other ataxias, a trial with 5-hydroxytryptophan, amantadine, or buspirone may be

undertaken, although there are no controlled trials that clearly demonstrate the efficacy of these drugs in relieving ataxia. Physical therapy is recommended. Many

SCA1 patients become dependent on canes or wheelchairs within years after disease onset. Patients with severe dysphagia should be fed by means of gastric tubing

to avoid undernourishment and aspiration.

Prognosis and Future Perspectives. SCA1 is a progressive disorder. On

average, SCA1 patients become wheelchair-bound about 13 years after the disease

begins, and median survival after disease onset is 18 to 20 years. SCA1 is caused by an expansion of a CAG repeat within the translated region of a gene of

unknown function. CAG repeat expansions have been also found in paptiens with SCA3, Huntington's disease, and dentatorubral-pallidoluysian atrophy (DRPLA),

suggesting that these disorders share common pathogenetic mechanisms. It remains to be established in future molecular biological studies how expanded CAG

repeats lead to regional specific neurodegeneration. Recently, transgenic mice have been generated that overexpress an expanded SCA1 allele in their Purkinje

cells.[

37] It is hoped that this animal model will be helpful in elucidating the pathogenesis of SCA1 and other CAG repeat disorders.

Spinocerebellar Ataxia Type 2

Pathogenesis and Pathophysiology. SCA2 is an autosomal dominant hereditary disorder. Genetic analysis of a large Cuban founder population led to the mapping

of the SCA2 locus on chromosome 12q.[

23] Recently, a protein containing a polyglutamine expansion was detected in the brain of an SCA2 patient, suggesting that

SCA2 is caused by a CAG repeat expansion.[

38] Subsequent molecular studies confirmed that SCA2 is caused by a CAG repeat mutation, with expanded alleles

ranging from 35 to 39 repeats.

Neuropathological examinations of SCA2 patients have consistently revealed OPCA, characterized by a marked reduction in Purkinje cells and degeneration of the

inferior olives, pontine nuclei, and pontocerebellar fibers. In most cases, additional degeneration of the posterior columns and

686

spinocerebellar pathways is evident, as well as cell loss in the substantia nigra. [

39]

Epidemiology and Risk Factors. The incidence and prevalence of SCA2 are unknown. There are large regional variations due to founder effects. Large SCA2

families have been found in Cuba, Tunisia, Martinique, Austria, Germany, and Italy. SCA2 is a genetically determined disorder with no known environmental risk or

precipitation factors. Children from SCA2 patients have a 50 percent risk of

developing the disease.

Clinical Features and Associated Disorders. SCA2 can begin at any time from early childhood to late adulthood with features of anticipation. On average, the

disease starts around the age of 35 years. All SCA2 patients suffer from a progressive cerebellar syndrome marked by ataxia of gait and stance, ataxia of limb

movements, and dysarthria. Saccade slowing is a highly characteristic feature that is observed in the majority of SCA2 patients. About half the patients have vertical

or horizontal gaze palsy. Cerebellar oculomotor abnormalities are rarely found in SCA2 patients. Typically, tendon reflexes are absent or decreased. Pyramidal tract

signs are present in less than 20 percent of the patients. Vibration sense is decreased in most patients, but sensation is otherwise normal. Dementia, basal ganglia

symptoms, pale optic discs, and bladder dysfunction are usually absent. [

35] , [

39] , [

40]

Differential Diagnosis and Evaluation. Diagnosis of SCA2 is made by the demonstration of the CAG repeat expansion at the SCA2 locus. Clinically, SCA2 cannot

be distinguished with certainty from other forms of ADCA-I. However, the presence of slow saccades, axonal neuropathy, and severe OPCA on MRI is suggestive of

SCA2.

Evaluation. Nerve conduction findings are similar to those seen in SCA1 with low-amplitude SNAPs and normal or slightly reduced NCVs. In contrast to SCA1, MEPs

in response to transcranial magnetic stimulation and VEPs are usually normal in SCA2. BAEPs are abnormal in less than half of SCA2 patients. SEPs after tibial

nerve stimulation are usually abnormal. MRI shows diffuse cerebellar atrophy with marked brain stem atrophy, suggesting the presence of OPCA. In addition, the

cervical spinal cord is atrophic in most patients( Fig. 35-2 ). [

35]

Management. At present, there is no specific treatment for SCA2. Principles of symptomatic and palliative therapy are identical to those described for SCA1. Prognosis and Future Perspectives. SCA2 is a progressive disorder. On average, these patients become wheelchair-bound about 15 years after disease onset.

Median survival after disease onset is approximately 25 years. Patients in

whom the disease begins in childhood appear to have a worse prognosis. Future studies

must explore the mechanisms by which the SCA2 mutation leads to the regional specific pattern.

Spinocerebellar Ataxia Type 3--Machado-Joseph Disease

Pathogenesis and Pathophysiology. SCA3, or Machado-Joseph disease (MJD), is an autosomal dominant disorder. The SCA3-MJD locus on chromosome 14q was

found in Japanese families with the MJD phenotype and in European ADCA families. Subsequently, the gene was isolated, and the mutation was shown to be an

unstable trinucleotide CAG repeat expansion present within the coding region of the gene. [

26] The repeat length in normals varies between 14 and 40 trinucleotides,

but SCA3-MJD patients have one allele with 62 to 84 repeat units. Both the normal and mutated SCA3 genes contain uninterrupted CAG stretches. Expanded SCA3

alleles display intergenerational instability and show a tendency toward further expansion. Repeat lengths vary in different body tissues due to the mitotic instability of

the expanded repeats.

In SCA3 there is an inverse correlation between the length of the CAG repeat and the age of onset, the largest alleles occurring in patients with juvenile disease

onset. Because of the intergenerational instability of the expanded repeats, the age of onset varies from generation to generation with features of anticipation. In

contrast to patients with SCA1, there is no paternal effect on age of onset. [ 26] , [

31]

Neuropathologically, SCA3 is characterized by degeneration of the spinocerebellar tracts, vestibular nuclei, and dentate nucleus. The cerebellar cortex and the

inferior olives are spared. In most cases, the pontine base is only moderately affected. The substantia nigra and the subthalamopallidal connections are frequently

involved.[

31]

Epidemiology and Risk Factors. The prevalence of ADCA has been reported to be 1.2 in 100,000, with large regional variations due to founder effects. [

32] In a recent

nationwide study SCA3 was found to occur in 21 percent of a population of 149 ADCA families. [

33] SCA3 is a genetically determined disorder with no known

environmental risk or precipitation factors. Children of SCA3 patients have a 50 percent risk of developing the disease.

Clinical Features and Associated Disorders. SCA3 begins at any time between early childhood and late adulthood with features of anticipation. On average, the

disease starts around the age of 40 years. The clinical picture of SCA3-MJD is characterized by a wide range of clinical manifestations, the precise nature of which

depends partly on the CAG repeat length. All SCA3-MJD patients suffer from a progressive syndrome marked by ataxia of gait and stance, ataxia of limb movements,

and dysarthria. Vertical or horizontal gaze palsy is a frequent additional finding that occurs independently of age of onset. Saccade velocity is usually normal. Dementia, basal ganglia symptoms, pale optic discs, and bladder dysfunction are absent in most cases. In patients with a repeat length of more than 74, the disease

begins early, usually before the age of 30 years, and clinical features of pyramidal tract and basal ganglia involvement are evident. Most of these patients have

increased tendon reflexes, extensor plantar responses, spasticity, and dystonia. In patients with an intermediate repeat length of 71 to 74 units, the disease begins in

middle age; clinical signs include mainly ataxia and gaze palsy. In patients with a repeat length of less than 71, the disease begins later, and they show signs of

peripheral neuropathy with loss of tendon reflexes, amyotrophy, and decreased vibration sense. However, the boundaries between these clinical syndromes are

vague, and the clinical phenotype of an individual may change as the disease progresses. Therefore, we do not advocate dividing SCA3-MJD patients into clinical

subtypes. [

28] , [

31] , [

34] , [

35] , [

41]

Differential Diagnosis and Evaluation. Diagnosis of SCA3 is made by demonstration of the CAG repeat expansion at the SCA3 locus. Clinically, SCA3 cannot be

distinguished with certainty from other forms of ADCA-I. The

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presence of dystonia is suggestive for SCA3. However, even in patients with

SCA3, dystonia is infrequent and occurs mainly in those with an early disease onset.

Absence of cerebellar atrophy on MRI is typical of SCA3 and may help to distinguish SCA3 from other mutations leading to ADCA.

Evaluation. The results of electrophysiological investigations resemble those in patients with SCA2, with evidence of peripheral axonal neuropathy and posterior

column involvement; MEPs in response to transcranial magnetic stimulation and VEPs are normal in most patients. On MRI, the cerebellum and brain stem appear

normal or only moderately shrunken. As in patients with SCA1 and SCA2, the cervical spinal cord is atrophic in most patients(see Fig. 35-2 ). Management. At present, there is no specific treatment for SCA3. Principles of symptomatic and palliative therapy are identical to those described for patients with

SCA1. Patients with generalized dystonia may respond to anticholinergics. Prognosis and Future Perspectives. SCA3 is a progressive disorder. On average, these patients become wheelchair-bound about 15 years after disease onset.

Median survival is 25 to 30 years. Progression is faster in patients with long repeats and early disease onset. The SCA3 mutation is an expanded CAG repeat that is

similar to the mutations found in Huntington's disease, SCA1, and dentatorubral-pallidoluysian atrophy (DRPLA). Future studies must explore the mechanisms by

which the SCA3 mutation leads to the regional specific pattern of neurodegeneration in this disorder.

Spinocerebellar Ataxia Type 5

Pathogenesis and Pathophysiology. SCA5 is an autosomal dominant hereditary disorder that has been described in a large American ADCA-III family with an

almost pure cerebellar phenotype. Using linkage analysis, the SCA5 locus has been mapped to chromosome 11cen. The SCA5 gene has not yet been cloned, and

the mutation is unknown.

Epidemiology and Risk Factors. To date, SCA5 has been described in a single American ADCA-III family. Information on the incidence and prevalence of SCA5 is

not available. In our experience, ADCA-III families account for less than 25 percent of all ADCA families. SCA5 is a genetically determined disorder with no known

environmental risk or precipitation factors. Children from SCA5 patients have a 50 percent risk of developing the disease.

Clinical Features and Associated Disorders. SCA5 begins at any time

between childhood and late adulthood with features of anticipation. The most dramatic

examples of decreasing age at onset are observed with maternal transmission. On average, the disease starts at about the age of 30 years. The clinical syndrome is

predominantly cerebellar and is marked by ataxia of gait and stance, ataxia of limb movements, dysarthria, and cerebellar oculomotor disturbances. Bulbar involvement has been noted in only two patients in whom the disease had an early onset. [

27]

Differential Diagnosis and Evaluation. Since the SCA5 gene has not yet been isolated, a test that allows a molecular diagnosis of SCA5 in individual patients is not

available. In appropriate families, a diagnosis of SCA5 can be made by linkage analysis with markers closely linked to the SCA5 locus on chromosome 11cen. Clinically, SCA5 can be distinguished from other types of ADCA by its predominantly cerebellar syndrome and its slower rate of progression. Information about the electrophysiological characteristics of SCA5 is lacking. In patients with ADCA-III, nerve conduction and evoked potential studies produce normal

results. MRI of SCA5 patients shows cerebellar atrophy with no evidence of brain stem involvement.

Management, Prognosis, and Future Perspectives. At present, there is no specific treatment for patients with SCA5. Symptomatic and palliative therapy is similar

to that described for SCA1. Although SCA5 is disabling, the disease progresses slowly, and life expectancy is not shortened. Quantitative data about the rate of

progression in SCA5 are not available. At present, the chromosomal localization of the SCA5 gene is known. To further understand the pathogenesis of SCA5 and to

develop diagnostic tests, the SCA5 gene must be cloned and the mutation identified.

Other Degenerative Ataxias The ADCAs without retinal degeneration and with additional extracerebellar symptoms (ADCA-I) are a heterogeneous group of

autosomal dominant diseases, some of which are due to mutations at the SCA1, SCA2, or SCA3 locus. An additional locus, SCA4, has been mapped to chromosome

16q in an American family characterized clinically by cerebellar ataxia, pyramidal tract signs, and sensory neuropathy. Detailed information about SCA4, however, is

lacking.[

25] The SCA6 locus maps to chromosome 19p. The mutation has been

identified as a small CAG repeat expansion in a gene that codes for the alpha 1A

voltage-dependent calcium channel subunit. Clinically, SCA6 families have an almost pure cerebellar phenotype.

AUTOSOMAL DOMINANT CEREBELLAR DISORDERS WITH RETINAL DEGENERATION Pathogenesis and Pathophysiology. ADCA with retinal degeneration is an autosomal dominant disorder that is distinct from other types of ADCA in that it has the

constant additional feature of retinal degeneration. ADCA with retinal degeneration has also been named ADCA-II. [

22] The gene locus of ADCA-II, SCA7, has been

mapped to chromosome 3p. [

50] , [

51] All available data suggest that ADCA-II is a genetically homogeneous disorder. Recently, a protein containing a polyglutamine

expansion was detected in the brains of patients with SCA7, suggesting that SCA7 is caused by a CAG repeat expansion. [

38] The clinical observation of marked

anticipation in ADCA-II families also points toward an unstable mutation. Neuropathological examinations of ADCA-II patients have consistently revealed the presence

of OPCA. All patients have primarily macular degeneration, which then spreads to involve the retina. There is often secondary atrophy of the optic nerve.

Epidemiology and Risk Factors. ADCA-II has been described in a small number of families. Information about the incidence and prevalence of ADCA-II is not

available. ADCA-II is a genetically determined disorder with no known environmental risk or precipitation factors. Children

688

Figure 35-2 T1-weighted MRIs of infratentorial brain structures and cervical spinal cord in different types of degenerative ataxia. The images show the posterior fossa in the midsagittal u p p la p n er e l e(ft) and axial slices at the level of the middle cerebellar

peduncles (upper right), inferior olive complex l(ower left), and dens axis (lower right). A, Normal. B, SCA2. There is severe cerebellar and brain stem shrinkage, suggesting the presence of OPCA. In additiona, the cervical spinal cord is

atro C ph, iScC. A3. There is

only mild cerebellar vermal atrophy with additional involvement of the spinal co D r,d I.D CA-P/MSA. There is severe cerebellar and brain stem shrinkage, suggesting the presence of OPCA. The cervical spinal cord has normal size. from ADCA-II patients have a 50 percent risk of developing the disease. Clinical Features and Associated Disorders. ADCA-II begins at any time between childhood and late adulthood with features of anticipation. Anticipation is greater

when the disease is transmitted by males. On average, ADCA-II begins around the age of 25 years. The clinical picture and the course of the disease depend

on the

age of onset. In patients with late disease onset (after the age of 40 years), cerebellar ataxia is always the first symptom. There are some exceptional patients who

never develop visual problems. In most patients, however, ataxia is followed by progressive loss of vision. In about half the patients with late disease onset, there is

no evidence of retinal degeneration

689

or optic atrophy, suggesting that retinopathy affects only the macula. All patients in whom the disease begins earlier (before the age of 40 years) have visual

problems, starting either prior to or at the same time as the appearance of cerebellar ataxia. The majority of these patients have retinal degeneration, and some also

have optic atrophy. Tendon reflexes are usually absent. A number of additional symptoms occur in less than half the patients and tend to be more frequent in patients

with a long disease duration. These symptoms include gaze palsy, dysphagia, hearing loss, and muscle weakness. Dementia and basal ganglia symptoms are not

typical features of ADCA-II. [

52] , [

53]

Differential Diagnosis and Evaluation. The diagnosis of ADCA-II is based on the clinical observation of ataxia

690

in combination with progressive visual loss and a positive family history suggesting autosomal dominant inheritance. In selected families, the diagnosis can be further

substantiated by demonstration of linkage to the SCA7 locus. Autosomal dominant retinitis pigmentosa is clearly distinct from ADCA-II in that ataxia is not a feature of

this disorder. Sporadic cases involving ataxia and retinal degeneration may pose considerable diagnostic problems, particularly if reliable information about the family

history is lacking. The differential diagnosis of these cases includes

early-onset cerebellar ataxia with retinal degeneration (Hallgren's syndrome), Refsum's disease,

abetalipoproteinemia, and neuronal ceroid lipofuscinosis.

MRI shows cerebellar and brain stem atrophy, suggesting the presence of OPCA. The electrophysiological features of ADCA-II have not been systematically studied.

Electroretinography may be used to detect retinal degeneration early. There is

no specific treatment for SCA7.

Prognosis and Future Perspectives. ADCA-II is a progressive disorder, and it progresses more rapidly in patients with early disease onset. On average, patients in

whom the disease begins in childhood die 5 years after disease onset, whereas adult patients survive for about 15 years after onset. At present, the chromosomal

localization of SCA7 is known. Immunocytochemical studies suggest that the mutation is an expanded CAG repeat. To further clarify the pathogenesis of SCA2 and to

develop a diagnostic test for SCA7, the SCA7 gene must be cloned and the mutation identified.

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY

Pathogenesis and Pathophysiology. DRPLA is an autosomal dominant disease that occurs mainly in Japan. The DRPLA gene is localized on chromosome 12p.

DRPLA patients show an unstable expanded CAG repeat within a coding region of the gene. Whereas the repeat length in normals varies between 7 and 23

trinucleotides, in DRPLA patients there is one allele within a range of 49 to 79 repeat units. As in other trinucleotide repeat disorders, DRPLA alleles display intergenerational instability and show a tendency toward further expansion. Larger expansions frequently occur with paternal transmission. There is an inverse

correlation between the length of the CAG repeat and the age of onset, the largest alleles occurring in patients with juvenile disease onset. Because of the intergenerational instability of expanded repeats, the age of onset varies with features of anticipation. [

42]

DRPLA is also observed as an apparently sporadic disease. Molecular analysis in such patients has revealed expanded alleles of the DRPLA gene, showing that the

molecular basis of inherited and sporadic DRPLA is the same. [

43] The gene product encoded by the DRPLA gene, atrophin, is a 190-kD protein of unknown function

that has been detected in various body tissues. In the brain, the DRPLA gene product is localized in the cytoplasm of neurons. An additional 205-kD protein has been

found in DRPLA patients that probably represents the mutated protein with an elongated polyglutamine stretch. [

44]

The degenerative pathological changes seen in DRPLA mainly affect the dentate nucleus with its projection to the red nucleus and the external pallidum with its

projection to the subthalamic nucleus. Usually the dentatorubral system is more severely affected. Atrophy may also be seen in other basal ganglia nuclei, the

thalamus, and the inferior olives. In several cases, degeneration of the posterior columns and spinocerebellar tracts has been described. Involvement of the pontine

tegmentum has been found also, and this appears to correlate with oculomotor abnormalities.

Epidemiology and Risk Factors. DRPLA has been predominantly reported in Japan, but diseases with similar features have been occasionally observed in non-Japanese families. It has recently been shown that the Haw River syndrome, a hereditary disease occurring in an African-American family, is genetically identical

with DRPLA.[

45] In Japan, the prevalence rate of DRPLA has been estimated to be 0.1 per 100,000. [

46]

Clinical Features and Associated Disorders. Onset of DRPLA occurs at any time from infancy to late adulthood with features of anticipation. On average, clinical

features begin to appear at about the age of 30 years. The clinical picture of DRPLA is characterized by a wide range of manifestations, the precise nature of which

depends on the age of onset and the length of the CAG repeat. The most constant clinical findings in DRPLA are cerebellar ataxia, dysarthria, and progressive

dementia. These features are present in almost all patients regardless of age of onset and repeat length. Patients in whom the disease begins before the age of 21

years and who have large expansions show the clinical syndrome of progressive myoclonus epilepsy. Some of them have opsoclonus. In patients with a later disease

onset and shorter expansions, myoclonus and seizures are less prominent. Instead, many of these patients have involuntary choreic or dystonic movements and

psychiatric abnormalities including personality changes, hallucinations, and delusional ideas. Various oculomotor disturbances have been described including

gaze-evoked nystagmus, broken-up smooth pursuit, square-wave jerks, and vertical gaze palsy. [

43]

Differential Diagnosis and Evaluation. The diagnosis of DRPLA is made by demonstration of an expanded CAG repeat at the DRPLA locus. The differential