Presymptomatic testing in Huntington's disease and autosomal dominant cerebellar ataxias

OBJECTIVE: To report a 7-year experience of presymptomatic testing in persons at risk for Huntington disease (HD) and to compare their characteristics and outcomes with those of persons at risk for a less disabling condition, autosomal dominant cerebellar ataxias (ADCA). METHODS: The authors collected data on presymptomatic testing for HD (n = 712) and ADCA (n = 46) in 10 French centers. RESULTS: The characteristics of applicants were similar in HD and ADCA, revealing a predominance of women, a low rate of completing the presymptomatic testing program, and a high rate of follow-up. The frequency of serious events was low (2% for HD, 5% for ADCA), but such events were also found after favorable results. Family planning was a more frequent reason for seeking presymptomatic testing in ADCA than in HD. Prenatal diagnosis was performed in only half of the pregnancies in HD carriers (n = 35) but in all of those in ADCA carriers (n = 4). CONCLUSION: Counseling in multistep and multidisciplinary teams is important not only for presymptomatic testing in HD but also for less disabling diseases.     

Autosomal dominant cerebellar ataxias

Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.     

New autosomal recessive cerebellar ataxias with oculomotor apraxia

Autosomal recessive cerebellar ataxias (ARCAs) are a phenotypically and genetically heterogeneous group of diseases. Recently, a subgroup of ARCA associated with oculomotor apraxia (AOA) has been delineated. It includes at least four distinct genetic entities: ataxia-telangiectasia, ataxia-telangiectasia-like disorder, and ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2). The phenotypes share several similarities, and the responsible genes, ATM, MRE11, APTX, and SETX, respectively, are all implicated in DNA break repair. As in many other DNA repair deficiencies, neurodegeneration is a hallmark of these diseases. Recently, the genes for two new autosomal recessive cerebellar ataxias with oculomotor apraxia, AOA1 and AOA2, were identified. Here, we report the phenotypic characteristics, genetic characteristics, and the recent advances concerning AOA1 and AOA2.     

The clinical diagnosis of autosomal dominant spinocerebellar ataxias

The spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive ataxia diseases. Up to now, almost 30 different gene loci have been found. In 14 of them, the underlying mutations have been identified. The more common SCAs, SCA1, 2, 3 and 6 are due to translated CAG repeat expansions that code for an elongated polyglutamine tract within the respective proteins. These diseases belong to a larger group of polyglutamine disorders that also includes Huntington’s disease. Epidemiological studies conducted in different European regions found prevalence rates of SCAs ranging from 0.9 to 3.0:100,000. In all SCAs, ataxia is the prominent symptom. However, the majority have a complex phenotype in which ataxia is accompanied by varying non-ataxia symptoms. In all ataxia patients with proven or suspected autosomal dominant mode of inheritance, the available molecular genetic tests for SCA mutations should be performed. Depending on the geographical origin of the family, these tests will lead to positive diagnostic results in at least half of the families.     

A new autosomal dominant pure cerebellar ataxia.

A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.     

A comparative study of cardiac dysautonomia in autosomal dominant spinocerebellar ataxias and idiopathic sporadic ataxias

Objectives – Comparative evaluation of cardiac dysautonomia in spinocerebellar ataxias (SCA) and idiopathic sporadic ataxias (IA) not fulfilling the criteria of multiple system atrophy. Material and methods – Cardiac autonomic functions were evaluated in 14 SCA (SCA1 = 6, SCA2 = 5 and SCA3 = 3) and 10 IA patients, comparable for age, age at onset, duration and severity of illness. The results were categorized as early, definitive, or severe autonomic involvement (EI, DI and SI respectively) based on the degree of abnormalities on tests of parasympathetic and sympathetic pathways. Results – Cardiac autonomic dysfunction was present in all (EI = 25.0%, DI = 41.7% and SI = 33.3%), parasympathetic dysfunction being an early feature. SI was most often present in SCA3 (100%), followed by those with SCA1 (66.7%), and SCA2 (20%) and none in IA. Conclusions – Cardiac dysautonomia was common in both SCA and IA, although the severity was greater in SCA. Among SCAs, the severity was greatest in SCA3, followed by SCA2 and least in SCA1.     

Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders. The mutational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people. OBJECTIVES: To characterize the prevalence of SCA in the ethnic Chinese on Taiwan, and to specifically characterize Chinese patients with SCA6 in terms of clinical and molecular features. PATIENTS AND METHODS: Using a molecular approach, we investigated SCA in 74 Taiwanese families with dominantly inherited ataxias and in 49 Taiwanese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 12 patients from 8 families and in 2 sporadic cases. Furthermore, the intragenic polymorphic marker D19S1150 was amplified by polymerase chain reaction to analyze for linkage disequilibrium. RESULTS: Machado-Joseph disease-SCA3 was the most common type of autosomal dominant SCA in the Taiwanese cohort, accounting for 35 cases (47.3%), followed by SCA6 (8 [10.8%]), SCA2 (8 [10.8%]), SCA1 (4 [5.4%]), SCA7 (2 [2.7%]), dentatorubropallidoluysian atrophy (1 [1.4%]), and SCA8 (0%). The genes responsible for 16 (21.6%) of Taiwanese dominantly inherited SCA cases remain to be determined. Among the 49 patients with sporadic ataxias in the present series, 2 (4.1%) were found to harbor SCA6 mutations. In the families with SCA6, we found significant anticipation in the absence of genetic instability on transmission, indicating that some other mechanism might account for the anticipation. The same frequent allele of the intragenic DNA marker (D19S1150) was shared by 7 of 10 Taiwanese families with SCA6. CONCLUSIONS: Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.     

Clinical features and molecular genetics of autosomal recessive cerebellar ataxias

Among the hereditary ataxias, autosomal recessive spinocerebellar ataxias comprise a diverse group of neurodegenerative disorders. Clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathy, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal anomalies, and cutaneous disorders, among others. Molecular pathogenesis also ranges from disorders of mitochondrial or cellular metabolism to impairments of DNA repair or RNA processing functions. Diagnosis can be improved by a systematic approach to the categorisation of these disorders, which is used to direct further, more specific, biochemical and genetic investigations. In this Review, we discuss the clinical characteristics and molecular genetics of the more common autosomal recessive ataxias and provide a framework for assessment and differential diagnosis of patients with these disorders.     

Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia.

Slow saccades are often found in degenerative ataxia. Experimental studies have shown that horizontal saccades are generated in the paramedian pontine reticular formation and that lesions in this area produce slow saccades. Based on these findings, saccade slowing should be a frequent feature of olivopontocerebellar atrophy, a type of cerebellar degeneration with prominent involvement of the pons. To test this hypothesis, saccade velocity was measured in 31 patients with autosomal dominant cerebellar ataxia (ADCA) and 17 patients with idiopathic cerebellar ataxia (IDCA). Saccade velocity was reduced in most patients with ADCA whereas it was normal in IDCA although olivopontocerebellar atrophy occurred in both groups. Saccade velocities correlated with pontine size in ADCA but not in IDCA. The data disprove the hypothesis that saccadic slowing is a clinical hallmark of olivopontocerebellar atrophy. Instead, only patients with ADCA and morphological features of olivopontocerebellar atrophy have slow saccades.     

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis

Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.     

Falls in degenerative cerebellar ataxias.

We retrospectively and prospectively assessed the frequency and characteristics of falls in patients with degenerative cerebellar ataxias. The results show that falls occur very frequently in patients with degenerative cerebellar ataxias and that these falls are serious and often lead to injuries or a fear of falling. Clinicians should be aware of this problem in ataxia patients and should try to prevent falls.     

16q-linked autosomal dominant cerebellar ataxia: a clinical and genetic study

The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.     

Autosomal dominant cerebellar ataxias in ethnic Bengalees in West Bengal - an Eastern Indian state

BACKGROUND: Phenotypic and genotypic patterns of a hereditary disease in a large multiethnic country like India need to be studied in relation to geographical location and ethnicity of the population. The few reported studies from India on dominant ataxias (ADCA) have mostly been conducted on multiethnic populations and hence may not reflect the patterns observed in specific ethnic groups or geographical locations. The present study attempted to look into the patterns of ADCA amongst ethnic Bengalee patients hailing from the eastern Indian state of West Bengal. MATERIAL AND METHODS: Between mid-1996 and mid-2000, in a clinic based study, 37 cases (from 14 families) with ADCA were studied. This included 33 affected and four asymptomatic members with abnormal physical signs. Genotypic analyses were performed on more than one affected member from each family. Clinical, neuroradiological and electrophysiological aspects were studied. OBSERVATIONS: Genotype analysis revealed: two families with SCA-1,4 families with SCA2,5 families with SCA3 and three families with undetermined genotype. Of the latter, phenotypically 2 were of ADCA 1 and one of ADCA 2 type. No clear preponderance of one particular genotype over another was observed. We noted significant intra- and interfamily variations in phenotype within the same genotype form as well as overlapping of clinical signs between different genotypes. Slow saccadic eye movements and peripheral neuropathy were not seen consistently in our ethnic Bengalee subjects with SCA2 genotypes. Similarly, extrapyramidal features, ophthalmoplegias and distal amyotrophy were seen in some but not in all families with SCA3 mutation. A peculiar form of abduction lag during slow pursuit movement of eyes was observed in an asymptomatic girl in an SCA3 family. CONCLUSIONS: Although SCA2 has been claimed to be the commonest form of ADCA in India, this does not appear to be so in our ethnic Bengalee subjects. Phenotypic expression of the genotype also appears to be variable amongst families and individuals. Hence, phenotypic expression appears to be an inconsistent marker of the SCA genotype in our patients.