F004 Intermediate allele CAG expansion in an early adulthood onset Huntington´s disease

<h3>Background</h3> Huntington’s disease (HD) is a hereditary neurodegenerative condition caused by an abnormal expansion of CAG trinucleotides in the HTT gene. Patients with manifest HD typically present 36 or more CAG repeats, whereas individuals with intermediate alleles (IA) are characterized by expansions ranging from 27 to 35 CAG repeats. We present a patient with a progressive choreic syndrome with a molecular HD test with the presence of an allele in the intermediate range repeat expansion. Materials and <h3>Methods</h3> A 39-year-old woman presented with a progressive choreic syndrome, characterized by distal choreic movements in both hands that worsened to generalized chorea. She had a history of schizophrenia, epilepsy, type 2 diabetes, and Sudek syndrome. Her family history (figure 1) was notable for a maternal uncle with a history of suicide and several members affected by depression. The patient‘s neurological examination revealed normal cognition, mild generalized choreic movements, bilateral bradykinesia and rigidity in upper limbs, distal dystonic posture in lower limbs, and a short steps gait. <h3>Result</h3> Laboratory tests, including peripheral blood smear, CPK, ASTO, and antiphospholipid antibodies, were normal. Brain MRI and EMG/somatosensitive evoked potential tests were also normal. Genetic testing revealed a CAG expanded allele in an intermediate range, with 35 repeats. Segregation studies of both parents showed the mother had an intermediate-range CAG expanded allele, while the father had normal-range CAG in both alleles. <h3>Conclusion</h3> The patient‘s symptoms and family history strongly suggest Huntington’s disease (HD), despite the presence of an intermediate allele (IA). The age of onset in HD is influenced by multiple factors, with only about 60% of the variation explained by the size of the expanded CAG repeat. The loss of the CAA interruption could act as a cis-acting modifier of the age of onset in HD patients, which could explain the early onset symptoms in the patient. Additionally, genetic modifier loci and DNA maintenance genes can influence the age of onset, and the instability of CAG expansions can generate variability in repeat sequences during intergenerational transmission, resulting in somatic mosaicism. <h3>References</h3> Ainhi D Ha, Christopher A Beck, Joseph Jankovic. Intermediate CAG Repeats in Huntington’s Disease: Analysis of COHORT, 2012, Tremor and Other Hyperkinetic Movements. http://www.tremorjournal.org. Ferdinando Squitieri, Joseph Jankovic. Huntington’s Disease: How Intermediate are Intermediate Repeat Lengths?.<i> Movement Disorders</i>, 2012;<b>27</b>:14. Justus L Groen, Rob MA de Bie, Elisabeth MJ Foncke, Raymund AC Roos, Klaus L Leenders, Marina AJ Tijssen. Late-onset Huntington disease with intermediate CAG repeats: true or false?. <i>J Neurol Neurosurg Psychiatry</i> 2010;<b>81</b>:228e230. doi:10.1136/jnnp.2008.170902 Killoran Annie, Biglan Kevin M, Joseph Jankovic. Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS- Neurology 80 May 28, 2013. Reyes M, Yañez R, Lopez-Ibor M. Juvenile Huntington Disease: a case report and literature review.<i> Actas Esp Psiquiatr</i> 2010;<b>38</b>(5):285–294. Roos R. Huntington´s Disease: a clinical review. <i>Orphanet Journal of Rare Diseases.</i> 2010;<b>5:</b>40. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. <i>Clin Genet</i> 2006;<b>70</b>:283–294. Goldberg YP, Kremer B, Andrew SE, <i>et al</i>. Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. <i>Nat Genet</i> 1993;<b>5</b>:174–179. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. <i>Cell</i> 2019;<b>178</b>:887–900 August 8, 2019 ª 2019 The Authors. Published by Elsevier https://doi.org/10.1016/j.cell.2019.06.036.