Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course

Abstract

Huntington disease is caused by a dominantly transmitted CAG repeat expansion mutation that is believed to confer a toxic gain of function on the mutant protein. Huntington disease patients with two mutant alleles are very rare. In other poly(CAG) diseases such as the dominant ataxias, inheritance of two mutant alleles causes a phenotype more severe than in heterozygotes. In this multicentre study, we sought differences in the disease features between eight homozygotes and 75 heterozygotes for the Huntington disease mutation. We identified subjects homozygous for the Huntington disease mutation by DNA testing and compared their clinical features (age at onset, symptom presentation, disease severity and disease progression) with those of a group of heterozygotes, who were assessed longitudinally. The age at onset of symptoms in the homozygote cases was within the range expected for heterozygotes with the same CAG repeat lengths, whereas homozygotes had a more severe clinical course. The observation of a more rapid decline in motor, cognitive and behavioural symptoms in homozygotes was consistent with the extent of neurodegeneration as available at imaging in three patients, and at the post-mortem neuropathological report in one case. Our analysis suggests that although homozygosity for the Huntington disease mutation does not lower the age at onset of symptoms, it affects the phenotype and the rate of disease progression. These data, once confirmed in a larger series of patients, point to the possibility that the mechanisms underlying age at onset and disease progression in Huntington disease may differ.

Longitudinal Evaluation of theHdh(CAG)150Knock-In Murine Model of Huntington's Disease

“…Positron emission tomography imaging studies indicate that more advanced HD is accompanied by loss of nigrostriatal dopaminergic innervation Bohnen et al, 2000). The more severe pathological findings in HOM mutants is consistent with data indicating that HD homozygotes and SCA3 homozygotes have more aggressive disease than HET patients (Lang et al, 1994;Sobue et al, 1996;Squitieri et al, 2003).…”

Systemic delivery of P42 peptide: a new weapon to fight Huntington¿s disease

“…Our approach is based on the observation that the ratio between normal and mutant Huntingtin is a crucial factor in the onset and progression of the disease [1,[16][17][18][19][20][21][22]. In a previous work, we confirmed the protective role of wild-type N-terminus Htt [22].…”

“…The quantification shows that NP42T reduces astrogliosis in the cortex (C) and the striatum (D), but the recovery is not significant. Data represent means +/−SEM (n = 4-7 per group), and were analysed using one way ANOVA: GFAP in the cortex (F (3,19) = 4.9, p < 0.01) and GFAP in the striatum (F (3,18) microemulsion formulation technology (Medesis-Pharma) to deliver the fusion peptide. P42-TAT was formulated in the water-in-oil microemulsion, allowing per mucosal administrations and providing efficient delivery.…”

Detection of mutations by flow cytometric melting point analysis of PCR products

“…Among them, Huntington's chorea is caused by the expanded repetition of the CAG triplet localized in Exon 1 of the Huntingtin gene (also called IT15/HTT/HD). There are four categories based on the number of CAG-repetitions: healthy (\27 CAG), intermediate (27)(28)(29)(30)(31)(32)(33)(34)(35), those with reduced penetrance (35)(36)(37)(38)(39), and those of the diseased phenotype (>40 CAG) (15)(16)(17). For diagnosis, the length of genomic DNA fragments carrying the CAG-repeats are to be compared; typically this is performed after PCR amplification, sometimes following restriction enzyme digestion and ligation to adaptors (18) and the products are analyzed in a standard way by agarose or polyacrylamide gel electrophoresis (17,19,20), with capillary gel electrophoresis (17,21,22), or by sequencing.…”