HTT – Juvenile Huntington Disease

Juvenile Huntington disease (JHD) is a rare, early-onset variant of Huntington disease characterized by onset before age 21, with symptoms often beginning in early childhood. It is caused by an expanded CAG trinucleotide repeat in the HTT gene, leading to a toxic polyglutamine tract in the huntingtin protein. In JHD, CAG repeat sizes typically exceed 60, and very large expansions (>100 repeats) correlate with earlier onset and more severe disease. The clinical presentation includes developmental regression, axial hypotonia, ataxia, seizure activity, and cognitive decline, often with imaging evidence of early caudate and cerebellar atrophy.

Genetic evidence is robust, with at least 4 unrelated probands reported carrying pathogenic HTT CAG expansions: a 5½-year-old girl with ~130 repeats (maternal 70→130 transmission) ([PMID:16096998]), an 18-month-old boy with 210–250 repeats (paternal 43→210–250 transmission) ([PMID:21412977]), and multiple additional JHD cases confirmed by postmortem and clinical genetic testing. The inheritance is autosomal dominant, with both paternal and maternal transmissions observed. Pathogenic expansions segregate with disease in first-degree relatives in at least 2 families, confirming co-inheritance of HTT expansions with JHD phenotype.

Variant spectrum is defined by CAG repeat length rather than point mutations; JHD patients uniformly have repeats >60, with reported expansions ranging from 84 to over 250 units. No single recurrent founder variant has been identified, but repeat instability in germ cells explains both paternal and maternal large-expansion events.

Functional studies support a gain-of-function mechanism: huntingtin localizes aberrantly to the nucleus via a defined nuclear localization signal ([PMID:8774958]), and caspase-3 cleavage generates N-terminal fragments that aggregate at membranes and contribute to neuronal dysfunction ([PMID:11675509]). Mouse and cellular models expressing N-terminal mutant huntingtin fragments recapitulate key JHD features, including motor deficits, aggregate formation, and transcriptional dysregulation.

No conflicting reports have disputed the causal link between HTT repeat expansion and JHD; all functional and clinical data consistently demonstrate that polyglutamine expansions in HTT are necessary and sufficient for disease. Taken together, genetic, segregation, and concordant functional evidence establish a definitive gene–disease relationship.

Key Take-home: HTT CAG expansions cause autosomal dominant juvenile Huntington disease, and early genetic testing can confirm diagnosis in children with developmental delay and movement abnormalities.

References

• American journal of medical genetics. Part A • 2005 • Juvenile onset Huntington disease resulting from a very large maternal expansion. PMID:16096998
• American journal of medical genetics. Part A • 2011 • Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume. PMID:21412977
• Brain research. Molecular brain research • 1995 • The identification of a functional nuclear localization signal in the Huntington disease protein. PMID:8774958
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. PMID:11675509

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