Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family

Abstract

Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree.

The evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease

“…These patients generally manifested typical PD phenotypes without motor neuron signs, cerebellar ataxia, or saccadic eye movement disorder, as was stated in previous reports (Furtado, et al, 2004,Klein, et al, 2009. A correlation between the association of AAO and polyQ repeat length was not clearly present or absent in our patients with repeat lengths of ATXN2 > 24, as previously observed (Furtado, et al, 2002,Furtado, et al, 2004,Payami, et al, 2003,Sun, et al, 2011. For example, in Family A, members of the 3 rd generation had earlier AAOs than did their mother.…”

“…This may be much lower than the threshold for ATXN2-related PD adopted by previous studies (Charles, et al, 2007), but it is possible that the cutoff for ATXN2 polyQ repeat length and its influence on PD may vary from population to population, as is the case for ALS, as indicated in a previous study (Lee, et al, 2011b). Such variation of the threshold would be consistent with the observation that previous reports of ATXN2-associated PD have mainly been from East Asian populations (Charles, et al, 2007,Klein, et al, 2009,Lu, et al, 2004b,Sun, et al, 2011,Wang, et al, 2009. Additional factors, such as cis-and trans-acting genetic elements, non-allelic genetic modifiers, and stochastic and environmental factors (Charles, et al, 2007,Pulst, et al, 2005, might have enhanced the toxicity of ATXN2…”

Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

“…At the same time, it is noteworthy to mention that few families having molecularly confirmed patients with other SCA mutations (SCA-2 and -3) demonstrated pure parkinsonism or parkinsonism predominant phenotype. SCA-2 family with six affected individuals showing pure parkinsonism phenotype was described by Sun et al 21 along with two other individuals with cerebellar ataxia.…”

“…They found further evidence that TGM6 mutations can cause SCA in human beings when they found another pathogenic missense variant cosegregating with the phenotype in an additional Chinese family with SCA. 21 This second singlenucleotide substitution mutation, D327G, was found to interfere with Ca 2þ binding at site 3 in structural remodeling and therefore may have compromised enzyme activation. But the mechanism by which the first mutation caused the deleterious effect remained obscure.…”

TGM6 variants in Parkinson's disease: clinical findings and functional evidence

“…However, there are a few reports of a pure parkinsonian phenotype in molecularly confirmed SCA patients, especially in patients with SCA2 and SCA3. The previous study describes a parkinsonismpredominant SCA2 family with six affected individuals showing typical parkinsonism and two showing cerebellar ataxia (Sun et al, 2011).…”