ATN1 – Dentatorubal-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene (ATN1). DRPLA is characterized by cerebellar ataxia, choreoathetosis, progressive myoclonic epilepsy, dementia, and variable anticipation across generations. The disease is catalogued as MONDO:0007435.

Inherited in an autosomal dominant manner, pathogenic CAG repeat expansions in ATN1 beyond the normal range (6–35 repeats) have been reported in multiple populations including North American, Japanese, European, and Chinese cohorts (PMID:7847869, PMID:8866494). Age at onset inversely correlates with expansion size, with juvenile-onset cases often presenting with early progressive myoclonic epilepsy and rapid cognitive decline.

Segregation analysis across multi-generational pedigrees demonstrates robust co-segregation of expanded alleles with disease. A five-generation Danish family included 16 affected individuals spanning ages 13 to 60, with larger expansions in early-onset cases (PMID:8866494). Additionally, a founder Italian pedigree traced 51 affected subjects over four generations to a common ancestor (PMID:31755148).

The variant spectrum in ATN1 consists exclusively of CAG repeat expansions in exon 5. Reported expansion sizes range from borderline pathogenic to over 60 repeats, with founder mutations identified in Portuguese and Italian populations (PMID:14512972, PMID:10894992). A Chinese family study of six members confirmed a negative correlation between repeat length and age at onset, and a positive correlation with disease severity (PMID:37243799).

Functional studies reinforce the pathogenic mechanism of polyglutamine toxicity. Fluorodeoxyglucose positron emission tomography in preadolescent-onset DRPLA revealed bilateral striatal hypometabolism, correlating with severe juvenile presentation (PMID:26723987). Additionally, atrophin-1 directly interacts with IRSp53, implicating cytoskeletal dysregulation in disease pathogenesis (PMID:12884081).

Integration of extensive genetic and functional evidence supports a Definitive gene-disease relationship between ATN1 and DRPLA. Genetic testing for CAG expansions in ATN1 is clinically actionable for diagnosis, prognostication, and family planning. Key take-home: Detection of ATN1 CAG repeat expansions confirms DRPLA in patients presenting with ataxia, seizures, chorea, and cognitive decline, enabling definitive diagnosis and genetic counseling.

References

• Annals of neurology • 1995 • Molecular and clinical findings in a family with dentatorubral-pallidoluysian atrophy. PMID:7847869
• Movement disorders : official journal of the Movement Disorder Society • 1996 • Dentatorubral-pallidoluysian atrophy. Clinical features of a five-generation Danish family. PMID:8866494
• Movement disorders : official journal of the Movement Disorder Society • 2019 • The largest caucasian kindred with dentatorubral-pallidoluysian atrophy: A founder mutation in italy. PMID:31755148
• Acta neurologica Belgica • 2023 • The relationship between the number of CAG repeats and clinical manifestations: a survey of Chinese DRPLA family. PMID:37243799
• Journal of the neurological sciences • 2016 • Striatal glucose hypometabolism in preadolescent-onset dentatorubral-pallidoluysian atrophy. PMID:26723987
• Journal of human genetics • 2003 • Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein. PMID:12884081

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