Objective: RAREST-JHD (Juvenile Huntington Disease) is an initiative to study young HD subjects’ clinics, genetics and imaging to identify markers to transfer into clinics and to disclose mechanisms causing JHD

Background: JHD variant with infantile age at onset (£10 years) are generally associated with very large mutations even above 70-80 CAG repeats, paternally transmitted and extremely rare. Because of their rarity, the difficulty in evaluating sick children and the missing specific clinical scales, no experimental therapies can be planned in these cases

Methods: We retrospectively selected infantile JHD (i-JHD) patients with large CAG expansions (n=11). We obtained a total motor score (TMS, within the UHDRS assay) from all of them, in four cases with a 3-year follow-up and collected brain MRI scans from five of them (one with follow up). We obtained a total body MRI from one child and brain images of a post-mortem brain from another one. Finally, we established a IPSC line from an affected child with 85CAG repeats

Results: All i-JHD cases were paternally transmitted and manifested with either delay of psychic and motor development during the pre-scholar time or relevant learning difficulty during the primary school. They showed a variable age at onset of motor manifestations ranging between 1,5 and 10years (mean 5±3) with a CAG repeat expansion included between 73 and 120. First motor manifestation was frequently dystonia (60%), Westphal variant with onset parkinsonism in 20% cases. One case manifested with ataxia, one with motor tics. Dystonia and parkinsonism represented the most representative motor manifestation during the follow-up. Seven cases had epileptic seizures, two cases developed schizophrenia-like syndrome. For all children, brain MRI scans showed peculiar alterations in brain subcortical structures selectively affecting both the striata nuclei without any significant cortical involvement. We obtained induced pluripotent stem cells (iPSC) from fibroblasts of a young child with 85 CAG repeat mutation which we are reprogramming into neuronal cell lines

Conclusions: The careful JHD clinical and genetic stratification and the investigation of subjects with very large mutations and infantile onset may open clues on new mechanisms of HD, ie possibly contributing to developmental delay of some specific brain structures

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MDS Abstracts - https://www.mdsabstracts.org/abstract/large-cag-expansions-in-huntington-disease-children-the-rarest-jhd-initiative/