Brain, Vol. 126, No. 4, 946-955,
April 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg077
Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course
1 Neurogenetics Unit, IRCCS INM Neuromed, Pozzilli (IS), 2 Division of Biochemistry and Genetics, Neurological Institute IRCCS ‘C. Besta’, Milan, 3 Division of Neurology, ‘Fornaroli’ Hospital, Magenta (MI), Italy, 4 Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, 5 Department of Medical Genetics, Grampian University Hospitals Trust, Aberdeen, UK, 6 Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada, 7 Department of Haematology and Genetic Pathology, School of Medicine, Flinders University, Adelaide, 8 Victorian Clinical Genetics Services, The Murdoch Institute, Royal Children’s Hospital, Melbourne, Australia, 9 Faculté de Medicine, Paris and 10 Service de Neurologie, Hôpital Henri Mondor, Créteil, France
Correspondence to: Dr Ferdinando Squitieri, Neurogenetics Unit, IRCCS INM Neuromed, Località Camerelle, 86077 Pozzilli (IS), Italy or Dr Stefano Di Donato, Division of Biochemistry and Genetics, Neurological Institute IRCCS ‘C. Besta’, Milan, Italy E-mail: neurogen{at}neuromed.it or didonato{at}istituto-besta.it
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.
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