A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis

Abstract

Clinical revaluation and genetic analysis of six Indian pedigrees, segregating autosomal dominant cerebellar ataxia, slow saccades and peripheral neuropathy, has been undertaken, and expansion at the spinocerebellar ataxia 2 (SCA2) locus was confirmed in 14 affected family members. These families became available from 31 phenotypically similar families seen over the years. In common with other neurodegenerative disorders resulting from expansion of a CAG trinucleotide repeat motif, an inverse correlation between repeat size and age at onset and severity is observed, although the size range (36-45 repeat units) for the expanded alleles is comparatively limited. Saccadic velocity was reduced in all our patients, even in the early stages of the disease. The observation of slow saccades in affected individuals has been proposed previously as an important diagnostic criterion serving to distinguish the SCA2 phenotype. This is now confirmed in a retrospective study of the clinical literature, facilitated by the cloning of the SCA2 gene and the subsequent genetic analysis of families segregating this phenotype. We therefore argue that the clinical appraisal of 'ophthalmoplegia' be subject to more precise definition, as differentiation between the various types of ocular dysfunction can be an important adjunct to diagnosis.

Professor Wadia’s contributions to neurology and spinocerebellar ataxia type 2

“…This work was carried out at a time when not only had the advanced genetics techniques available to us today not been developed, but also there was not even an adequate system for classifying the various entities that were being discovered. The most important contribution by Prof. Wadia was the identification, for the first time, of spinocerebellar ataxia with slow eye movements, nowadays defined as SCA 2 [4][5][6][7] .…”

“…The presence of cerebellar atrophy was suggested but not confirmed because a pathological study was not carried out and the only imaging examination available at the time was pneumoencephalography 4 . His interest in the disease, which was later called SCA 2, led to the publication, in 1975, of a model of an ocular subsystem based on his findings in these same patients 6,7 . In the following years he was able to establish a correlation between clinical findings up to that time and olivopontocerebellar atrophy 7 .…”

“…His interest in the disease, which was later called SCA 2, led to the publication, in 1975, of a model of an ocular subsystem based on his findings in these same patients 6,7 . In the following years he was able to establish a correlation between clinical findings up to that time and olivopontocerebellar atrophy 7 . In the subsequent decade he made two important contributions to our understanding of SCA 2: he showed the importance of correct characterization of patterns of eye movement abnormalities when there is a suspected clinical diagnosis of SCA 2 8 , and he made progress in the field of genetics by suggesting that the populations affected by SCA 2 in Cuba, England, Japan and India had a common ancestor 9 .…”

Eye Movement Abnormalities in Spinocerebellar Ataxias

“…This feature called attention to Wadia and Swami when made the first report of SCA2 in 1971, so that they described the disease as "a new form of heredofamilial spinocerebellar degeneration with slow eye movements" (Wadia & Swami, 1971). Several clinical and epidemiological studies have confirmed the high frequency of this saccadic alteration in more than 80% of cases (Velazquez-Pérez et al, 2009a;Orozco et al, 1989;Cancel et al, 1997, Wadia et al, 1998Schmitz-Hübsch, et al, 2008).…”

Genetic testing for Spinocerebellar Ataxias (SCA) in Parkinsonism

“…Recently Takano et al 12 have reported that the general prevalence of SCA1 and SCA2 is significantly higher among white SCA pedigrees (15% and 14%, respectively) than in the Japanese (3% and 5% respectively), whereas relative prevalence of SCA3 is higher in the Japanese pedigrees (43%) than in whites (30%). Also, SCA6 appear to be less frequent in white populations (5%) than in Japanese populations (11%) respectively 12 It has been reported that SCA2 is exclusively responsible for all ataxia cases in the Indian population 13 . In a study of six Indian SCA2 pedigrees, Wadia et al 13 observed CAG repeat expansion in 14 affected family members at the SCA2 locus.…”