Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: A case report

Abstract

BackgroundThe autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington’s disease.Case presentationWe report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype.ConclusionsThe current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

Cognitive Changes in the Spinocerebellar Ataxias Due to Expanded Polyglutamine Tracts: A Survey of the Literature

“…As such, its clinical presentation may overlap that of Huntington’s disease or DRPLA (vide infra). Larger repeats usually present in early to mid-life with ataxia plus psychiatric features and cognitive impairment, followed by dementia (in about 90% of cases), with various combinations of parkinsonism, chorea and/or dystonia and spasticity ensuing ibid [ 94 , 95 , 96 , 97 , 98 ]. Indeed, the clinical presentation varies considerably even within the same family [ 99 ].…”

“…Clinical progression was fairly slow (approximately 30 years) with cerebellar signs emerging followed by extrapyramidal signs, and myoclonus and epilepsy appearing later. A case report by Neilsen et al [ 98 ] points out the diagnostic challenge of neurodegenerative disorders such as SCA 17 in their discussion of a male referred at 44 years with rapid progression of personality changes and cognitive impairment over 1½ years. There was rapid deterioration in motor abilities and movement coordination with fine postural tremor of the hands, reduced speed of finger tapping, hand diadochokinesia, lower limb ataxia, and mildly broad-based gait.…”

The Pathogenic Role of Low Range Repeats in SCA17

“…Current evidence, which suggests a pathologic role for SCA17 with low expansions, is mostly based on case descriptions showing movement disorders or psychiatric symptoms accompanied by CAG expansions in TBP. [ 10 – 13 ] Because the statistical analysis between the normal controls and patients with low expansion repeats failed to show any differences so far, we must consider that clinical cases with low expansion repeats could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low-expansions(41–42).…”

“…[ 6 , 10 ] Furthermore, there have been case reports of patients with even 41 repeats: one presenting with late onset progressive cerebellar ataxia [ 11 ]; one with late onset chorea and psychiatric symptoms;[ 12 ] and one with a rapidly progressing cognitive phenotype. [ 13 ] On the other hand, healthy controls with more than 42 repeats have been reported including 44 [ 6 ] and 45 repeats [ 7 ].…”

Spinocerebellar ataxia 17: Inconsistency between phenotype and neuroimage findings

“…[ 1 ] Nielsen et al ., reported a patient carrying with 43 CAG repeat presented with rapid cognitive decline, but the MRI scan revealed mild atrophy of the cerebellum. [ 8 ] The patients carrying with 55 CAG repeats presented in the third decade with obviously gait ataxia and dementia, whose MRI findings indicated diffuse cortical and cerebellar atrophy. [ 2 ] Compared to these affected individuals with full blown disease state, the case had mild phenotype, but the cerebellar atrophy was noticeable.…”