Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38)

IntroductionSCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified.ObjectiveThe present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38.MethodsWe extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation.ResultsAge at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease.ConclusionsSCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions.     

Clinical study of large kindreds with autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) of late onset

Six families with SCA1 were studied. The clinical data on 35 patients are reported. Cerebellar and pyramidal system involvement was invariably found in association with brainstem, spinal cord and/or peripheral nervous system disorders. In our patients the clinical features appeared concordant when the patients with the same disease duration were compared. Previous reports of SCA1 families had shown great variability in clinical phenotype both interfamilial and intrafamilial. We suggest that the phenotype might appear more homogeneous if disease duration is taken into account.

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Sommario Sono state studiate 6 famiglie con atassia spinocerebellare autosomica domiinante ad esordio tardivo, in linkage con l'HLA e con il marker D6S89 (SCA1). I dati clinici su 35 pazienti hanno permesso di stabilire che la malattia è caratterizzata da deficit cerebellari e piramidali associati a segni di interessamento del tronco dell'encefalo, del midollo spinale e del sistema nervoso periferico. Nella valutazione clinica dei pazienti si è tenuto conto della durata della malattia e ciò ha permesso di evidenziare un fenotipo clinico abbastanza omogeno nei differenti stadi della malattia. è possibile che la variabilità intra- e inter-familiare nel fenotipo di altre famiglie SCA1 sia da attribuire al fatto di confrontare soggetti in fasi diverse della malattia.

     

A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1.

OBJECTIVE: To characterize a distinct form of autosomal dominant cerebellar ataxia (ADCA) clinically and genetically. BACKGROUND: ADCAs are a clinically, pathologically, and genetically heterogeneous group of neurodegenerative disorders. Nine responsible genes have been identified for SCA-1, -2, -3, -6, -7, -8, -10, and -12 and dentatorubral-pallidoluysian atrophy (DRPLA). Loci for SCA-4, -5, -11, -13, and -14 have been mapped. METHODS: The authors studied a four-generation Japanese family with ADCA. The 19 members were enrolled in this study. The authors performed the mutation analysis by PCR and a genome-wide linkage analysis. RESULTS: Nine members (five men and four women) were affected. The ages at onset ranged from 20 to 66 years. All affected members showed pure cerebellar ataxia, and three patients also had head tremor. Head MRI demonstrated cerebellar atrophy without brain stem involvement. The mutation analysis by PCR excluded diagnoses of SCA-1, -2, -3, -6, -7, -8, and -12 and DRPLA. The linkage analysis suggested linkage to a locus on chromosome 8q22.1-24.1, with the highest two-point lod score at D8S1804 (Z = 3.06 at theta = 0.0). The flanking markers D8S270 and D8S1720 defined a candidate region of an approximately 37.6-cM interval. This candidate region was different from the loci for SCA-4, -5, -10, -11, -13, and -14. CONCLUSION: The family studied had a genetically novel type of SCA (SCA-16).     

Clinical features and diagnosis of spinocerebellar ataxia

In the past decade, a great progress has been made in understanding genetic basis of the spinocerebellar ataxia. Based upon the genotypes, more then 20 subgroups of autosomal dominant spinocerebellar ataxia have been identified with different gene mutations. Neither the pathomechanism nor the function of these genes is fully understood. In these disorders the main clinical sign is ataxia. Other symptoms may be present as well, but no specific clinical feature is known for differentiating subgroups. Specific diagnosis can be made by genetic tests. In this review we summarize the clinical features and genetic backgrounds of the most common spinocerebellar ataxias.     

Recent progress in spinocerebellar ataxia type-10 (SCA10)

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited ataxia caused by expansion of ATTCT pentanucleotide repeat in intron 9 of a novel gene, E46L, on chromosome 22q13.3. SCA10 is a complex neurodegenerative condition. Initial studies characterized SCA10 as pure cerebellar ataxia associated with seizures. Recent identification of new SCA10 families revealed more diverse phenotypes, including polyneuropathy, pyramidal signs, cognitive and neuropsychiatric impairment. Moreover, several families manifest with ataxia without seizures. Thus a complete clinical spectrum is emerging. Progress has also been made in understanding the molecular and genetic mechanisms of pathogenesis. The length of expanded ATTCT repeats is variable in different tissues and highly unstable during paternal transmission, revealing complex genetic and pathogenetic processes. Under torsional stress, ATTCT repeats form unpaired DNA structure and may serve as an erroneous DNA replication origin, potentially contributing to repeat instability and aberrant cell cycle entry. E46L is a cytoplasmic protein with unknown function. Reduced expression of E46L in primary neuronal cultures from cerebellum and cortex by small interfering RNAs (siRNAs) caused increased apoptosis, raising the possibility that reduced expression of E46L might also play an important role in SCA10 pathogenesis.     

Clinical,psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19)

The SCA19 locus on chromosome 1p21-q21 was identified in a Dutch family in 2002. Affected individuals displayed a lateonset slowly progressive mild cerebellar ataxia, hyporeflexia, and signs of frontal lobe dysfunction. A postural head tremor and myoclonic movements were observed occasionally. Before the SCA19 locus was identified, the SCA22 symbol had been assigned to a locus on 1p21-q23 following a linkage study of a Chinese family with spinocerebellar ataxia. Although both SCA19 and SCA22 are linked to 1p21-q21, the clinical features are slightly different. While it cannot be excluded that the genes lie in close approximation at this locus, it is more likely that the same gene is mutated in both the Dutch and Chinese families, and that SCA19 and SCA22 represent the same condition.     

Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population.

Dominant ataxias show wide geographic variation. We analyzed 108 dominant families and 123 sporadic ataxia patients from Mexico for mutations causing SCA1-3, 6-8, 10, 12, 17 and DRPLA. Only 18.5% of dominant families remained undiagnosed; SCA2 accounted for half (45.4%), followed by SCA10 (13.9%), SCA3 (12%), SCA7 (7.4%), and SCA17 (2.8%). None had SCA1, 6, 8, 12 or DRPLA. Among sporadic cases, 6 had SCA2 (4.9%), and 2 had SCA17 (1.6%). In the SCA2 patients we identified 6 individuals with the rare (CAG)(33) allele, 2 of whom showed early onset ataxia. The distribution of dominant ataxia mutations in Mexicans is distinct from other populations.     

Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6)

SCA6 is an autosomal dominant spinocerebellar ataxia (SCA) caused by a small CAG repeat expansion of the gene encoding an α-1a-voltage-dependent Ca channel gene subunit on chromosome 19p13. A Japanese woman with SCA6, with a 7-year history of progressive pure cerebellar ataxia, died of malignant lymphoma. Systematic neuropathological examination showed that neuronal degeneration was confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without any involvement of other central nervous system structures. Such pathological selectivity correlates with the localized expression of the responsible gene, and coincides with the neurological manifestation. These findings might contribute to establishing the phenotype of the SCA6 via comparison with other dominant ataxias. Received: 7 July 1997 / Revised, accepted: 14 August 1997     

Molecular and genetic analysis of spinocerebellar ataxia type 10 (SCA10)

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative disease caused by expansion of the ATTCT pentanucleotide repeat in intron 9 of a novel gene, ATXN10, on chromosome 22q13.3. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. The length of the expanded ATTCT repeats is highly unstable on paternal transmission and shows a variable degree of somatic and germline instabilty, revealing complex SCA10 genetic mechanisms. Moreover, the purity of the expanded repeat element may be a disease modifier. ATTCT repeats have been recently shown to form unpaired DNA structure and may serve as an aberrant DNA replication origin, potentially contributing to repeat instability and cell death. How this untranslated ATTCT expansion leads to neurodegeneration has been still controversial. We discuss several possible pathogenic mechanisms for SCA10, and growing number of evidence indicates a gain-of-function RNA mechanism, similar to the myotonic dystrophies caused by non-coding CTG or CCTG repeat expansions.     

Autosomal dominant spinocerebellar ataxia]

The modern classification is presented based on genetic criteria of the group of degenerative nervous system diseases inherited as autosomal dominant trait and called collectively spinocerebellar ataxia (SCA). They belong mostly to the class of diseases of similar mutation mechanism in which amplification is present of the trinucleotide sequence (CAG)n. Clinical picture and neuropathological changes in various SCA types are compared.     

Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.

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Sommario Riportiamo it caso di una famiglia affetta da atassia autosomica dominante, in cui numerosi membri presentavano anche microcitemia. L'analisi genetica dimostrava una espansione CA G net locus SCA1 in cinque membri, mentre tutti i soggetti con microcitemia erano portatori di una sostituzione C-T al codone 39 del gene delta beta-globina. La malattia neurologica era caratterizzata nelle prime fasi da una sindrome cerebellare pura con prevalente atassia delta marcia. Il quadro completo della malatia includeva anche disartria, disfagia e segni di danno assonale ai nervi periferici. Non veniva mai osservata oftalmoplegia. La coesistenza di degenerazione spinocerebellare ereditaria ed eritropatie o emoglobinopatie è già stata descritta precedentemente. Discutiamo i possibili legami tra queste due patologie.

     

Contributions to the study of spinocerebellar ataxia type 38 (SCA38)

Journal of Neurology - To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38). Five family members spanning two generations developed gait ataxia and...