Clinical features and genetic characteristics of homozygous spinocerebellar ataxia type 3

Abstract

Background Homozygous spinocerebellar ataxia type 3 (SCA3) patients, which have an expanded cytosine‐adenine‐guanine (CAG) repeat mutation in both alleles of ATXN3, are extremely rare. Clinical features and genetic characteristics of them were seldom studied. Methods We analyzed seven newly homozygous SCA3 patients from five families and 14 homozygotes reported previously. An additional cohort of 30 heterozygous SCA3 patients were analyzed to compare age at onset (AAO). Results Two out of seven SCA3 homozygotes had the minimum CAG repeats reported so far (55/56 and 56/58). Five patients appeared peripheral neuropathy and two had mild cognitive impairment. The AAO was significantly inversely correlated with both the large and small expanded CAG repeats (r = −.7682, p < .0001). The AAO was significantly earlier in homozygous SCA3 than heterozygous ones (32.81 ± 11.86 versus. 49.90 ± 9.73, p < .0001). In addition, the AAO of our seven homozygotes is elder compared to those reported previously (41.29 years vs. 28.57 years), which may be related to the fewer CAG repeats in our seven patients. Conclusion Gene dosage effect may play an important role in the AAO and severity of disease, and homozygosity for ATXN3 enhances phenotypic severity. Our findings expand clinical features and genetic characteristics of homozygous SCA3 patients.

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

“…[ 19,24,27, 28 ] Expansion in both alleles in SCA3, SCA6, and DRPLA has been proven to be associated with phenotypic severity and earlier age of onset. [ 18,25,26,20 ] No bi‐allelic CAG expansion in SCA7 is reported so far.…”

Homozygous spinocerebellar ataxia type 3 in China: a case report

“…Genetically confirmed patients with homozygous SCA3 are scarce, with only 21 cases reported in the literature before this report. [3][4][5][6][7][8][9][10] We reviewed the genetic and clinical features of all 22 patients with homozygous SCA3, including our own. Most homozygote SCA3 carriers had the characteristic symptoms of progressive cerebellar ataxia, including gait or limb ataxia.…”

“…An inverse relationship between the age at onset (AAO) and the number of CAG repeats in the pathogenic allele has been widely reported. 3 , 4 …”

“…An inverse relationship between the age at onset (AAO) and the number of CAG repeats in the pathogenic allele has been widely reported. 3,4 To date, few studies have recorded homozygous cases among patients with SCA3. [3][4][5][6][7][8][9][10] Homozygous individuals carrying both expanded ATXN3 alleles present with an earlier AAO and more severe clinical symptoms than heterozygotes, which may result from an effect of gene dosage.…”

“…3,4 To date, few studies have recorded homozygous cases among patients with SCA3. [3][4][5][6][7][8][9][10] Homozygous individuals carrying both expanded ATXN3 alleles present with an earlier AAO and more severe clinical symptoms than heterozygotes, which may result from an effect of gene dosage. 10 The intergenerational CAG repeat instability can explain the clinical phenotypes more generally; 11 however, the repeat instability of homozygous individuals' transmission is rarely reported, with only one known case carrying all expanded CAG repeats of uniform length.…”