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Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype
C S Benton1, R de Silva, S L Rutledge
1Department of Molecular and Human Genetics, Baylor College of Medicine and Howard Hughes Medical Institute, Houston, TX 77030, USA.
Insights
This study identified the SCA-7 mutation in 10 autosomal dominant cerebellar ataxia (ADCA) families, revealing a wide range of clinical symptoms and defining an infantile phenotype. The findings highlight the genetic basis of spinocerebellar ataxia type 7 (SCA-7).
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Autosomal dominant cerebellar ataxia (ADCA) is a group of inherited neurodegenerative disorders.
- Spinocerebellar ataxia type 7 (SCA-7) is a distinct form of ADCA characterized by cerebellar ataxia and progressive pigmentary macular dystrophy.
- SCA-7 is caused by an unstable CAG repeat expansion in a novel gene on chromosome 3p12-13.
Purpose of the Study:
- To screen for the SCA-7 mutation in families with ADCA.
- To investigate genotype/phenotype correlations in SCA-7 patients.
- To characterize the clinical spectrum of SCA-7.
Main Methods:
- Screened 51 ADCA kindreds for the SCA-7 mutation after excluding SCA-1, SCA-2, SCA-3, and SCA-6.
- Utilized primers to specifically amplify the SCA-7 CAG repeat.
- Analyzed CAG repeat lengths and correlated them with clinical phenotypes.
Main Results:
- Identified the SCA-7 mutation in 10 independent families.
- Observed normal alleles ranging from 7-16 CAG repeats and expanded alleles from 41-306 repeats.
- Documented a wide spectrum of clinical features including visual loss, dementia, hypoacusis, severe hypotonia, and auditory hallucinations. Juvenile SCA-7 showed variable inheritance patterns, while infantile SCA-7 occurred only with paternal transmission. An infant with the largest expansion (306 repeats) presented with severe hypotonia, cardiac and cerebral abnormalities, and visual loss.
Conclusions:
- The study demonstrates a broad spectrum of phenotypic abnormalities associated with SCA-7.
- An infantile phenotype linked to the largest reported CAG repeat expansion in SCA-7 has been defined.
- These findings contribute to understanding the genetic basis and clinical variability of spinocerebellar ataxia type 7.
Objective:
To screen for the SCA-7 mutation in autosomal dominant cerebellar ataxia (ADCA) families and study genotype/phenotype correlations.
Background:
The association of cerebellar ataxia and progressive pigmentary macular dystrophy clinically defines a distinct form of ADCA classified as SCA-7. SCA-7 is caused by expansion of a highly unstable CAG repeat that lies in the coding region of a novel gene on chromosome 3p12-13.
Methods:
We screened 51 ADCA kindreds, in which SCA-1, SCA-2, SCA-3, and SCA6 mutations had been excluded, for the SCA-7 mutation using primers that specifically amplify the SCA-7 CAG repeat.
Results:
The SCA-7 mutation was identified in 10 independent families. Normal alleles ranged from 7 to 16 repeats; expanded alleles ranged from 41 to 306 repeats. One allele with 36 repeats was found in an asymptomatic individual carrying an at-risk haplotype. SCA-7 presents a wide spectrum of clinical features including visual loss, dementia, hypoacusia, severe hypotonia, and auditory hallucinations. Juvenile SCA-7 occurs on maternal and paternal transmission of the mutation, whereas the infantile form occurs only on paternal transmission. An infant of African American descent carried the largest SCA-7 expansion (306 CAG repeats) and had severe hypotonia, congestive heart failure, patent ductus arteriosus, cerebral and cerebellar atrophy, and visual loss.
Conclusion:
These data show a wide spectrum of phenotypic abnormalities in SCA-7 and define an infantile phenotype caused by the largest CAG repeat expansion described to date.