Objective: To explore the clinical and molecular findings of two Tunisian patients with LOHD and carriers of an IA.

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG in Huntingtin gene (HTT). Symptoms of HD usually appear in adulthood, around the age of 40. However, in rare cases, the disease can manifest itself after the age of 70 (LOHD).

An allele with > 36 CAG is considered pathological, while an allele with < 26 CAG is normal and without risk of developing Huntington’s Disease. Generally, IA (27-35 CAG) does not confer the disease phenotype but is always unstable and may expand when transmitted to the next generation. Therefore, offspring are likely to inherit an expanded allele of ≥36 CAG. Few cases have been reported with IA and clinical manifestation of HD.

Several studies have shown that IAs are associated with apathy, cognitive performance, and increased chorea with age.

Recent studies suggested that IA could be involved in the pathogenesis of Alzheimer’s Disease (AD).

Method: Two male patients were selected from a cohort of 180 HD Tunisian patients and admitted to the Mongi Ben Hmida National Institute of Neurology.

Patients’ clinical were obtained from individual case report forms. Genetic testing was carried out by Triplet-primed PCR for HD, HDL2, SCA17, and DRPLA, and analysis with Genemapper Software v 4.1.

Results: we report two patients with intermediate alleles admitted to our institute for clinical and genetic management.

Both patients have a late age of onset of 70 and 78 years, an intermediate allele of respectively 34 and 31, and a negative family history. Case 1 with 20/34 CAG only developed memory impairment at age 70 years. Genetic testing for HDL2, DRPLA, and SCA17 revealed normal alleles.

Patient 2 with 15/31 CAG developed choreic movement, behavior disturbance, and the onset of dementia syndrome at the age of 78 years. After a year of disease, he developed generalized hypotonia. A molecular study of HDL2, DRPLA, and SCA17 showed normal alleles.

Conclusion: These findings may have significant implications for genetic counseling.

This study strengthens previous studies that showed that individuals with IA should be considered at risk for developing HD.

Further research on environmental factors and modifier genes would be needed for understanding the pathological mechanisms behind the correlation between IA and HD or other neurodegenerative disorders such as AD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/huntingtons-disease-patients-with-intermediate-allele-in-tunisia/