Objective: To investigate the clinical and molecular features of HD in homozygous versus heterozygous patients.

Background: Huntington’s disease (HD) is a neurodegenerative autosomal dominant disorder caused by a CAG expansion in the Huntingtin gene (HTT) with a threshold of 36.

Homozygotie in HD is very rare, and the relationship between the quantity of the mutated huntingtin (mHtt) and symptoms is therefore difficult to establish. Some studies suggest that, unlike most genetic diseases, HD is characterized by a complete penetrance. The homozygous and the heterozygous present the same symptoms. Other studies suggest on the contrary that for the homozygous, the progression of the disease is faster than for the heterozygous, but the age of onset is similar.

Due to the gain of function of the double-dose mutation, normally, homozygotes will have a more toxic effect of the Htt than the heterozygous.

Patients with biallelic mutations for HD are rare.

Method: From a cohort of 180 Tunisian patients, we investigate the clinical and molecular findings of 5 unrelated patients with homozygous alleles and compared the data with those of heterozygous patients.

Results: We present here five patients with homozygous alleles (2.77%). All five patients have a positive family history and three of them are from a consanguineous marriage. The age of onset ranged from 30 to 62 years, with a mean age of 44.8±11,14 years. One patient (30 years at onset) developed hypotonia after 3 years of evolution, this patient has 37/49 CAG. Only one patient (62 years at onset) presented with abnormal movement associated with behavior trouble and social isolation, he has 36/39 CAG. The CAG number ranges from 36-49 CAG with a mean of 42.6±3.32 CAG.

These results are similar to those of heterozygous patients. The largest allele (49 CAG for homozygous and heterozygous) are associated with early age at onset (EOHD) (30 years for homozygous and 33 years for heterozygous).

The smaller allele (36 CAG for homozygous and 38 CAGS for heterozygous) is correlated with late age at onset (LOHD) (62 and 74 years respectively).

The CAG number and the age at onset are inversely correlated for the homozygous (R²=0.670) and the heterozygous (R²=0.715).

Conclusion: Our study is the first in Tunisia, it extends the spectrum of patients with biallelic mutation and highlights the importance of genetic diagnosis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-molecular-features-of-tunisian-patients-with-biallelic-mutations-in-huntingtons-disease/