This session is provided courtesy of Stefan-M. Pulst, M.D., Dr. med.,
Carmen and Louis Warschaw Chair, Division of Neurology, Professor of Neurobiology
and Medicine, UCLA School of Medicine.
Ataxias are characterized by variable degrees of dysfunction and degeneration of systems involved in motor coordination. Although many of these disorders lead to dysfunction of Purkinje cells, others involve the deep cerebellar nuclei, brainstem nuclei and spinal sensory, and spinocerebellar tracts. Prominent neuronopathy or neuropathy may further contribute to imbalance and incoordination.
The phenotypic classification of the ataxias has been confusing for many decades.1 Few of the designations given to specific ataxias have withstood the test of time as disease entities. Phenotypic overlap among the different spinocerebellar ataxias (SCAs) is significant. A complicating factor is that some of the SCAs may not initially present with prominent ataxia. One of the few phenotypic classifications that has withstood the test of time is Friedreich ataxia (FRDA), but the phenotypic spectrum has undergone revision and expansion. It now includes patients that, in the absence of genotypic testing, would not have entered the differential diagnosis of FRDA 10 years ago.
Autosomal dominant cerebellar ataxias (ADCAs) make up a complex group of neurodegenerative disorders characterized by adult onset (although rare infantile and juvenile cases are reported), a progressive disease course, and pathologic features involving specific neuronal groups in the cerebellum and the brainstem. Harding proposed a phenotypic classification of ADCAs, distinguishing three types (see Table 1). SCA10 may represent a fourth type that includes ataxia and epilepsy. This phenotype may also be seen in some patients with dentatorubro-pallidoluysian atrophy (DRPLA) and rarely in SCA17, although in DRPLA and SCA17 it is usually accompanied by other non-cerebellar neurologic signs.
As shown in Table 1, each phenotype can be associated with mutations in multiple genes, and a mutation in a specific gene can give rise to different ADCA phenotypes, depending on the mutation, disease duration, genetic background and environmental effects.
Table 1: Modified Harding ADCA Classification
| Phenotype | Genotype | ||||
| Most Common | Somewhat Common | Less Common | Rare | ||
| ADCA I | Ataxia plus degeneration of other neuronal systems ± neuropathy | SCA1, 2, 3 | SCA12, 17 | SCA4, 8, 10, 13, DRPLA | SCA6, 7 |
| ADCA II | ADCA I phenotype plus retinal degeneration | SCA7 | SCA2 | ||
| ADCA III | Pure cerebellar ataxia, often late onset | SCA6 | SCA11, 14, 15, 16 | SCA4, 5, 8, 10 | SCA3 |
| ADCA IV | Cerebellar ataxia with seizures | SCA10 | SCA17, DRPLA | ||
Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by expansion of CAG repeats coding for polyglutamine stretches. Gait ataxia and dementia, progressing over several decades to include bradykinesia, dysmetria, dysdiadochokinesis, hyperreflexia and paucity of movement, characterize the clinical presentations of SCA17.
SCA17
represents the most recent addition to the ever-growing list of ataxias
for which genetic testing is available. It was identified in an individual
patient as an abnormality in a gene that had been cloned several years
earlier. In 1999, Koide3 described a 14-year-old Japanese female who developed
gait disturbance and intellectual deterioration from the age of six years.
At age nine, she showed truncal ataxia, spasticity and muscle weakness,
as well as a few episodes of atypical absence. The symptoms were slowly
progressive, and she became confined to a wheelchair at age 13.
Through the identification of the genes for SCA1, 2, and 3, it became evident by 1996 that many of the ADCAs were caused by expansion of CAG repeats. The TATA-Binding Protein (TBP) represented a good candidate, because it contained a long CAG repeat in its normal form (wildtype or normal allele). Indeed, the aforementioned patient was found to have 63 CAG repeats in the TBP gene; the range of CAG repeats in normal Japanese individuals is 25 to 42. For several years, this case remained the only one identified worldwide, and it was not evident whether the DNA sequence variation in the TBP gene was causative or merely associated with the phenotype.
The TBP is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D (TFIID). This multisubunit complex is crucial for the expression of most genes.
While expansion of the CAG repeat of the TBP gene has recently been described, pathophysiologic mechanisms of neurodegeneration caused by expanded CAG repeats remain to be elucidated. Expanded polyglutamine stretches of TBP may affect the function of TBP as a general transcriptional initiator factor. Alternatively, the expanded polyglutamine stretches may exert toxic functions in neurons similar to the effects of other polyQ proteins in other ADCAs.
In 2001, three groups reported expansions in the TBP gene in familial cases.4,5,6 In four Japanese pedigrees, CAG repeats in the TBP gene were expanded to 47-55 repeat units.5 The mode of inheritance was autosomal dominant with incomplete penetrance. The age of onset ranged from 19 to 48 years, with the mean age of onset of 33.2 years. Including the above-described case with de novo expansion of the CAG repeat, a strong inverse correlation between the age of onset and the size of expanded CAG repeats was observed. The clinical presentations were characterized by gait ataxia and dementia that progressed over several decades to include bradykinesia, dysmetria, dysdiadochokinesis, hyperreflexia and paucity of movement. The first symptom (ataxia, dementia or parkinsonism) varied with the patients.
SCA17
is not restricted to Japanese patients. Zühlke6 screened
469 sporadic and 135 familial cases with ataxia and gait disturbances
without known SCA mutations and found repeat expansion in the TBP gene
in four individuals. These patients belonged to two families of northern
German origin with autosomal dominant inheritance of ataxia, dystonia,
intellectual decline and a marked intra- and interfamilial phenotypic
variability. One patient presented with a focal dystonia (writer's cramp)
at age 20, and developed cerebellar dysfunction three years later. Elongated
polyglutamine stretches between 50 and 55 residues were demonstrated in
the four patients. Normal alleles in the German population ranged from
27 to 44 CAG repeats, the most common alleles with 37 and 38 repeats.
Fujigasaki4 identified one index case after screening 162 ADCA families for expansion in the TBP gene. This individual belonged to a family with six affected individuals segregating a phenotype that varied from ataxia and dementia to psychosis.
It is still too early to determine how common SCA17 mutations will be in the US. In contrast to DRPLA, which is predominantly found in the Japanese population, SCA17 appears to be at least as common in Europeans. Even the small number of SCA17 patients identified worldwide suggests that there will be significant phenotypic variability.
Magnetic resonance imaging (MRI) shows prominent cerebellar atrophy, and mild cerebral atrophy.3,4,5
As the phenotypic variability of SCA17 patients indicates, neuropathologic involvement is not restricted to cerebellar structures. Atrophy and loss of small neurons are seen in the caudate nucleus and putamen. Similar, but moderate, changes can be detected in the thalamus, frontal cortex and temporal cortex. Moderate Purkinje cell loss and an increase of Bergmann glia can be seen in the cerebellum. Neuronal intranuclear inclusions are seen at autopsy.4,5
Although the number of SCA17 pedigrees described in literature is limited, it can be expected that very long normal alleles or short pathologically expanded alleles are likely associated with reduced penetrance or late and very late onset.
The diagnosis of SCA17 is made by DNA analysis. Affected individuals demonstrate an abnormal expansion of the TBP gene of 47 - 63 repeats. The phenotype within and between different families can be highly variable and can overlap with other ADCAs, or even with neuropsychiatric and dystonic disorders.
SCA17 is the most recent addition to the list of ataxias for which genetic testing is available. While the cause of SCA17 has been identified as CAG repeats in the TBP gene, the pathophysiologic mechanisms of neurodegeneration caused by the expanded repeats are not yet understood.
Genetic testing for SCA17, as well as for the other spinocerebellar ataxias, 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.
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A 47-year-old woman presented with a 13-year history of slowly progressive ataxia, dystonic posturing of the feet, mood and personality changes, and mild deterioration of intellectual function. Over the past year, she also developed marked spasticity of all four extremities, an akinetic-rigid parkinsonian syndrome following haloperidol therapy, urinary incontinence, and most recently, complete cessation of speech production. Early milestones and general health were normal up to the age of 34 years. The patient is married and has three daughters, aged 16, 21, and 23 years. The eldest daughter was also diagnosed with a neurological syndrome. According to her father, the second daughter was noted to develop torticollis at age 20, while the youngest daughter appeared unaffected (both unavailable for neurological examination). The index patient's mother was affected by an unexplained gait disorder (by history), and her sister is affected by cerebellar ataxia. On her most recent neurologic examination, the patient was awake but mute, showed saccadic gaze, marked cerebellar ataxia, and spasticity of all four extremities, which were held in a flexed posture with beginning contractures. Reflexes were brisk bilaterally, but Babinski sign was negative. The patient was bedridden and could not sit, stand or walk. The sensory system appeared normal. Laboratory results were unremarkable. A brain CT scan showed generalized cerebral atrophy, most pronounced in the cerebellar region. Molecular genetic testing for known CAG repeat expansions was negative. Subsequent molecular genetic testing identified an abnormal CAG expansion in the TATA-binding protein, thus confirming a novel spinocerebellar ataxia, SCA 17.6 |
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