Objective: To clinically characterize a Huntington’s disease patient with two reduced penetrance alleles.

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder manifesting with motor, cognitive and psychiatric symptoms. A CAG triplet repeat expansion causes a pathological gain-of-function of the Huntingtin protein leading to neuronal death. The number of triplet repeats determines penetrance: 40 or more repeats cause full penetrance, 36 – 39 repeats reduced penetrance. Cases of homozygous CAG repeat expansions are rare and the link between homozygous genotype, disease severity and progression remains controversial.

Method: We report clinical characteristics of the patient and short-term follow-up investigations.

Results: This 58-year-old male of Polish descent presented to our clinic with severe depression, clumsiness of the hands, walking difficulties and weight loss of 30 kg. Symptoms had developed slowly over the course of 18 months. Family history was negative. Neurological examination at initial presentation revealed generalized chorea, bradykinesia and gait impairment (Unified Huntington’s Disease Rating Scale (UHDRS) 35). Psychiatric evaluation with the Beck Depression Inventory (BDI) indicated a major depression (BDI 39). MRI of the brain and laboratory investigations were normal. Of note, genetic testing showed CAG expansions with reduced penetrance on both alleles of the Huntingtin gene (38/39 triplet repeats). After five months, treatment with escitalopram and olanzapine had improved motor symptoms (UHDRS 28) and mood (BDI 12) markedly. In contrast, cognition worsened slightly (initial Montreal Cognitive Assessment (MoCA) 23; 19 at follow-up).

Conclusion: There is no evidence for increased disease severity associated with two reduced penetrance alleles in our patient. Long-term follow up investigations are necessary to assess the influence on disease progression. Evaluation of efficacy and safety of novel Huntingtin-lowering therapeutic approaches in homozygous HD patients will be of special interest in the future and need to be carefully investigated in clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/homozygous-huntingtons-disease-with-two-reduced-penetrance-alleles-a-case-report/