ClinVar Genomic variation as it relates to human health

Koide et al. (1999) described a sporadic case of a complex neurologic disorder with cerebellar ataxia, pyramidal signs, and severe intellectual impairment (SCA17; 607136) associated with expansion of the CAG repeat of the TBP gene. The gene encoded 63 glutamines, far exceeding the range in normal individuals (25 to 42 in Caucasians; 31 to 42 in Japanese). Zuhlke et al. (2001) described 2 German families with an autosomal dominant degenerative multisystem disorder with predominant ataxia and intellectual impairment but also involvement of the pyramidal, extrapyramidal, and possibly autonomic system (607136). Expanded (CAG)n alleles of the TBP gene ranged between 50 and 55 residues in affected individuals. In 1 family, 2 affected sisters differed by 1 trinucleotide repeat, and upon transmission from one of the sisters to her daughter the repeat was elongated by 2 units. This expansion may have contributed to the earlier age of onset in the daughter. In the other family, the (CAG)n element was combined with CAA interruptions, which had not been described for CAG expansions in other genes. Nakamura et al. (2001) identified a form of spinocerebellar ataxia- 17 in 4 Japanese pedigrees which was caused by an abnormal (CAG)n expansion in TBP to a range of 47 to 55 repeats. Age at onset ranged from 19 to 48 years, and symptoms included ataxia, bradykinesia, and dementia. Postmortem brain tissue from 1 patient exhibited shrinkage and moderate loss of small neurons with gliosis predominantly in the caudate nucleus and putamen, with similar but moderate changes in the thalamus, frontal cortex, and temporal cortex. Moderate Purkinje cell loss and an increase of Bergmann glia were seen in the cerebellum. Immunocytochemical analysis performed with anti-ubiquitin (191339) and anti-TBP antibodies showed neuronal intranuclear inclusion bodies, and most neuronal nuclei were diffusely stained with 1C2 antibody, which recognizes expanded polyglutamine tracts. In a total of 12 patients with a Huntington disease-like phenotype (607136), Stevanin et al. (2003), Bauer et al. (2004), and Toyoshima et al. (2004) identified expanded trinucleotide repeats, ranging from 44 to 52 repeats, in the TBP gene. Clinical features were indistinguishable from Huntington disease, including behavioral changes progressing to dementia, chorea, cerebellar gait, lower limb hyperreflexia, and pontocerebellar atrophy. Shatunov et al. (2004) described a 20-year-old patient who developed rapidly progressive cognitive decline and pronounced ataxia, a phenotype compatible with prion disease. No mutation was found in the PRNP gene (176640), and the patient was found to have a de novo increase of the trinucleotide repeat number in the coding region of the TBP gene. Susceptibility to Parkinson Disease In a patient with Parkinson disease (168600) from Taiwan, Wu et al. (2004) detected an abnormal trinucleotide repeat expansion (46 repeats) in the SCA17 gene. The patient presented with typical features of idiopathic PD: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. The authors noted that this was the first report describing PD in association with an expanded allele in the TBP gene. (less)

Koide et al. (1999) described a sporadic case of a complex neurologic disorder with cerebellar ataxia, pyramidal signs, and severe intellectual impairment (SCA17; 607136) associated with expansion of the CAG repeat of the TBP gene. The gene encoded 63 glutamines, far exceeding the range in normal individuals (25 to 42 in Caucasians; 31 to 42 in Japanese). Zuhlke et al. (2001) described 2 German families with an autosomal dominant degenerative multisystem disorder with predominant ataxia and intellectual impairment but also involvement of the pyramidal, extrapyramidal, and possibly autonomic system (607136). Expanded (CAG)n alleles of the TBP gene ranged between 50 and 55 residues in affected individuals. In 1 family, 2 affected sisters differed by 1 trinucleotide repeat, and upon transmission from one of the sisters to her daughter the repeat was elongated by 2 units. This expansion may have contributed to the earlier age of onset in the daughter. In the other family, the (CAG)n element was combined with CAA interruptions, which had not been described for CAG expansions in other genes. Nakamura et al. (2001) identified a form of spinocerebellar ataxia- 17 in 4 Japanese pedigrees which was caused by an abnormal (CAG)n expansion in TBP to a range of 47 to 55 repeats. Age at onset ranged from 19 to 48 years, and symptoms included ataxia, bradykinesia, and dementia. Postmortem brain tissue from 1 patient exhibited shrinkage and moderate loss of small neurons with gliosis predominantly in the caudate nucleus and putamen, with similar but moderate changes in the thalamus, frontal cortex, and temporal cortex. Moderate Purkinje cell loss and an increase of Bergmann glia were seen in the cerebellum. Immunocytochemical analysis performed with anti-ubiquitin (191339) and anti-TBP antibodies showed neuronal intranuclear inclusion bodies, and most neuronal nuclei were diffusely stained with 1C2 antibody, which recognizes expanded polyglutamine tracts. In a total of 12 patients with a Huntington disease-like phenotype (607136), Stevanin et al. (2003), Bauer et al. (2004), and Toyoshima et al. (2004) identified expanded trinucleotide repeats, ranging from 44 to 52 repeats, in the TBP gene. Clinical features were indistinguishable from Huntington disease, including behavioral changes progressing to dementia, chorea, cerebellar gait, lower limb hyperreflexia, and pontocerebellar atrophy. Shatunov et al. (2004) described a 20-year-old patient who developed rapidly progressive cognitive decline and pronounced ataxia, a phenotype compatible with prion disease. No mutation was found in the PRNP gene (176640), and the patient was found to have a de novo increase of the trinucleotide repeat number in the coding region of the TBP gene. Susceptibility to Parkinson Disease In a patient with Parkinson disease (168600) from Taiwan, Wu et al. (2004) detected an abnormal trinucleotide repeat expansion (46 repeats) in the SCA17 gene. The patient presented with typical features of idiopathic PD: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. The authors noted that this was the first report describing PD in association with an expanded allele in the TBP gene. (less)