Hereditary ataxias are a group of clinically and genetically heterogeneous disorders. In general, they are characterized by slowly progressive aphasia and incoordination of gait, hand, and eye movements. Ataxia, dysarthria, dysmetria, and intention tremor are also common symptoms.^1,2 Cerebellar degeneration is often seen on brain imaging studies, along with lesions in the spinal cord, and peripheral sensory loss.²

An important reason to distinguish hereditary ataxia from acquired ataxia is because acquired forms of ataxia may be treatable. In addition, a recurrence risk exists for hereditary ataxias. Acquired causes of ataxia include: alcoholism, vitamin deficiency, Multiple sclerosis, vascular disease, primary or metastatic tumors, and paraneoplastic syndromes associated with occult carcinoma of the ovary, breast, or lung.² A detailed family history, physical examination, neuroimaging studies, and genetic assays are all useful tools in the complete diagnosis of hereditary ataxia.

Figure 1. Spinocerebellar ataxia type 6 Midline sagittal MRI of the brain of a patient with spinocerebellar ataxia type 6 demonstrating cerebellar atrophy without brainstem (pons or medulla) atrophy.

Provided courtesy of www.medlink.com .

Hereditary ataxia can be associated with all modes of inheritance (autosomal dominant, autosomal recessive, X-linked, and mitochondrial).² In order to provide accurate genetic counseling and recurrence risks to the relatives of patients with hereditary ataxia, it is important to identify the molecular basis of the disorder in an affected family member. SCA types 1, 2, 3, 6, 7, 8, and 10 all fall into the category of autosomal dominant cerebellar ataxia (ADCA). There is a 50% chance that the children of an individual with an ADCA mutation will inherit the mutation and be affected with the particular disorder. (Please note that this is a general principle of autosomal dominant inheritance; when providing genetic counseling to families it is critical to take into account additional factors such as anticipation and penetrance, which are variable depending on the SCA subtype.)

Another commonly accepted clinical classification system separates the ADCAs into three groups (Type I, II, III) according to the presence or absence of symptoms such as brain-stem signs or retinopathy.^1,3 See Table 1, below.

 

	SCA1	SCA2	SCA3	SCA4	SCA5	SCA6	SCA7	SCA10
Cerebellar ataxia
Ophthalmoparesis
Slow saccades
Pyramidal tract signs
Extrapyramidal tract signs
Dementia
Peripheral neuropathy
Optic neuropathy
Deafness
Retinopathy
Macular degeneration
Generalized motor seizures
ADCA Type	I	I, II	I	I	III	I, III	II	I, III

An additional hereditary movement disorder, dentatorubral-pallidoluysian atrophy (DRPLA), can also be confirmed by molecular testing. DRPLA was first described in a patient with ataxia, choreoathetotic movements and dentatorubral and pallidluysian degeneration. The highest incidence of DRPLA is in individuals of Japanese heritage. DRPLA has also been reported as the "Haw River Syndrome"; a phenotypic variant named for the North Carolina locale where it has been described in an African-American community.⁴

SCA10 is characterized by a unique combination of pure cerebellar ataxia and generalized motor seizure. Gait and limb ataxia, dysarthria, gaze nystagmus in all directions, and impaired smooth pursuit are also cardinal signs in these individuals.³

In one study of a large Mexican family, 67% of the individuals affected with SCA10 had a history of generalized motor seizures, which began in the third to fifth decade (average age of onset was 36 +/- 6 years and ranged from 26-45 years of age).³ Two family members experienced episodes of complex partial seizures with or without secondary generalization. Patients generally presented with ataxia (upper and lower limb dysmetria) and dysdiadochokinesia. In addition, the researchers described a wide-based gait without a positive Romberg sign.³

SCA10 is caused by an unstable expansion (meaning the expansion can change in size upon transmission to offspring) of an ATTCT pentanucleotide repeat in the SCA10 gene on chromosome 22.⁴ Anticipation, the phenomenon of increased severity and younger age of onset in subsequent generations, is observed in many of the ADCAs and tends to occur in SCA10 when the expansion is inherited from the father, although a larger number of transmissions need to be studied to clarify this pattern.¹ (A summary of the genotype and phenotype of SCA10 can be found in the Summary section.)

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary movement disorder associated with chorea, myoclonus, seizures, ataxia, and dementia. Due to an overlap of symptoms, DRPLA may be included in a differential diagnosis with Huntington's disease (HD). Molecular testing and pathological examination are often used to distinguish HD from DRPLA because of the overlapping symptoms. Patients with an HD phenotype that test negative for an HD allele should be considered for testing for DRPLA.⁵

DRPLA progressively affects the cerebellar and pallidal outflow pathways.⁶ Tissue specificity seems to be directly related to particular gene products in HD and DRPLA. For example, in DRPLA neuronal loss occurs prominently in the dentate nucleus, rubrum, globus pallidus and Luys' body, while in HD the loss of neurons is most commonly found in the caudate and putamen.⁶

The age of onset in DRPLA patients ranges from less than 10 years of age to 70 years of age with an average age of onset of 30 years.⁷ Juvenile-onset DRPLA usually progresses rapidly, compared to late-onset cases.⁸ Patients with an early age of onset often present similarly to those with progressive myoclonus epilepsy and exhibit a variable degree of mental retardation or dementia.⁷ In contrast, adult onset DRPLA more closely resembles HD and typically presents with cerebellar ataxia, choreoathetosis, and dementia.⁷

Patients with onset of DRPLA after the age of 20 years tend to develop cerebellar ataxia, choreoathetosis, dementia, or mental retardation, and psychiatric disturbances, making DRPLA occasionally difficult to differentiate from Huntington's disease or other spinocerebellar ataxias. In some patients, involuntary movements and dementia mask the presence of ataxia.⁵

DRPLA is an autosomal dominant disorder that is caused by an unstable CAG triplet (trinucleotide) repeat expansion on chromosome 12 encoding a polyglutamine track (trinucleotide expansions are associated with several other disorders including spinal bulbar muscular atrophy, fragile X syndromes, myotonic dystrophy, Huntington's disease, and several types of spinocerebellar ataxia).⁶

Like SCA10 and other ataxias, inheritance of DRPLA is associated with anticipation (younger age of onset and increased severity of symptoms due to expansion of the trinucleotide repeat on transmission from parent to child). Male DRPLA patients are typically more severely affected than female patients and anticipation tends to be more pronounced through the paternal line.⁸ Characteristics of the autosomal dominant inheritance of DRPLA, such as anticipation and gender-influenced anticipation, are akin to those seen with HD and SCA1.⁸ In the general population, repeat sizes range from 7-23. In affected individuals, the expanded allele ranges from 49-75 repeats. The genetic test for DRPLA can be useful in establishing a diagnosis when a patient presents with an HD-like picture, but tests negative for HD in a genetic assay.⁵ (A summary of the genotype and phenotype of DRPLA can be found in the Summary section.)

Evidence of the [DRPLA] CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.⁹

A phenotypic variation of DRPLA, the Haw River Syndrome (HRS), has been described in five successive generations of an African-American family. DRPLA and HRS are caused by the same CTG-B37 expansion on chromosome 12, despite the significant clinical and ethnic variation between the two disease populations. Although DRPLA and HRS are clinically the same disease (both presenting with ataxia, chorea, mental retardation, and psychiatric disease) they have variations in presentation. HRS is characterized by several features, such as demyelination of the subcortical white matter, calcification in the basal ganglia, and neuroaxonal dystrophy. Further, HRS does not present with myoclonic seizures. In addition, the age of onset of HRS is usually between 15 and 30 years of age, a shorter range of onset than DRPLA. HRS typically leads to death 15-20 years after symptoms develop.¹⁰

Genetic counseling is a critical component of genetic testing. Through counseling, patients and their families can be educated about genetic testing options, the significance of test results, inheritance patterns, and recurrence risk. This information empowers patients and families to make informed medical and personal decisions. It also gives physicians and counselors the opportunity to gather valuable family history information and learn more about their patients' expectations and attitudes towards genetic testing.

SCA10, DRPLA, and HD have overlapping symptoms, which can make a clinical diagnosis difficult. Identification of SCA10 and DRPLA can improve the diagnosis of these patients and facilitate our understanding of the molecular mechanisms that cause these hereditary ataxias. Already, convincing evidence that expanded polyglutamine tracts in the protein products of SCA1, SCA2, SCA3, and DRPLA cause lethal functions has been eluciated.³ Genetic testing for hereditary movement disorders, such as SCA10, DRPLA, and HD can help clarify a clinical picture and provide a definitive diagnosis for the physician and the patient. A molecular diagnosis for these disorders can also help provide a more accurate prognosis and lead to improved patient management.

 

	SCA10	DRPLA	Huntington's Disease	Haw River Syndrome (phenotypic variant of DRPLA)
Clinical Features	Pure cerebellar ataxia and generalized motor seizure	Combinations of chorea, myoclonus, seizures, ataxia, and dementia	Chorea and psychiatric disease	Ataxia, chorea, mental retardation, and psychiatric disease
Pathology	Prominent cerebellar degeneration	Prominent neuronal loss in the dentate nucleus, rubrum, globus pallidus and subthalamic nucleus	Prominent neuronal loss in the caudate and putamen	Demyelination of the subcortical white matter, calcification in the basal ganglia, and neuroaxonal dystrophy
Inheritance Pattern	Autosomal dominant	Autosomal dominant	Autosomal dominant	Autosomal dominant
Genetics	ATTCT pentanucleotide repeat expansion in the SCA10 gene on chromosome 22	CAG triplet repeat expansion in the DRPLA gene on chromosome 12	CAG expansion in the IT15 gene on chromosome 4	CAG triplet repeat expansion in the DRPLA gene on chromosome 12
Anticipation	Yes	Yes	Yes	Yes
Age Range of Onset	26 to 45 years	10 to 70 years	2 to 80 years	15 to 30 years

 

 

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