Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes?

Abstract

Seventy-seven families with autosomal dominant cerebellar ataxia were analyzed for the CAG repeat expansions causing spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22% of German ataxia families. Seven of 27 SCA6 patients had no family history of ataxia. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of one CAG unit on onset age was different for each SCA subtype. We compared clinical, electrophysiological, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. However, overlap between the four SCA subtypes was broad.

Hereditary ataxias: overview

“…Table 1 indicates a few distinguishing clinical features for each type. [4][5][6][7][8] Scales for rating symptoms and signs of ataxia have been published. 9 Often the autosomal dominant ataxias cannot be differentiated by clinical or neuroimaging studies; they are usually slowly progressive and often associated with cerebellar atrophy, as seen from brain imaging studies (Figure 1).…”

Trinucleotide repeats and neuropsychiatric disorders

“…A genetic heterogeneity has been identified with six different loci (SCA1,2,3,4,6 and 7). A pathological expansion of a CAG sequence has been identified in SCA1,2,3, 6 and 7 (9). SCA type 1 is caused by unstable expansion of a CAG repeat in the protein coding region of a gene located on chromosome 6p23.…”

A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6

“…In Japan, SCA6 seems to be either the most common or second most common subtype of the SCAs (Matsumura et al 1997;Watanabe et al 1998;Sasaki et al 2000;Maruyama et al 2002), but its prevalence is lower in Western Europe and North America (Geschwind et al 1997;Scho¨ls et al 1997Scho¨ls et al , 1998Stevanin et al 1997). In contrast, other dominantly inherited pure cerebellar ataxias seem to be infrequent in Japan, including SCA5 (Holmberg et al 1995), SCA10 (Zu et al 1999), SCA11 (Worth et al 1999), SCA14 , SCA15 (Knight et al 2003), SCA16 (Miyoshi et al 2001), and SCA22 (Chung et al 2003).…”

“…The main clinical feature of SCA6 is slowly progressive cerebellar ataxia, but extracerebellar symptoms, such as pyramidal tract signs, abnormal involuntary movements, parkinsonism, hyporeflexia, intellectual impairment, and urinary incontinence, have also been reported (Geschwind et al 1997;Gomez et al 1997;Ikeuchi et al 1997;Matsumura et al 1997;Scho¨ls et al 1997;Stevanin et al 1997;Watanabe et al 1998;Yabe et al 1998). The induction of vertigo and oscillopsia by changes of the head position can also occur in SCA6 patients.…”