Huntington’s disease (HD) is a rare neurodegenerative disorder with autosomal dominant inheritance, characterized by involuntary movements (chorea), psychiatric disturbances and dementia. HD is caused by an elongated CAG repeat (36 repeats or more) in the Huntingtin gene (HTT), on the short arm of chromosome 4p16.3, with a prevalence of 5-10 per 100,000 in the Caucasian population. A positive family history is a sufficient indication for predictive testing, according to international guidelines (1). Alleles with 36-39 CAG repeats have reduced penetrance and can generate both a normal phenotype, alleles with >39 CAG copies show complete penetrance and inevitably cause, at some stage of life, the HD phenotype. Intermediate alleles (IAs) containing 27–35 CAG repeats does not confer an HD phenotype, however genetic, clinical and neuropathological implications has been recently discussed (2). As the CAG repeat expansion is the major determinant of age of onset (AO), here, we analyze the AO data in relation to CAG repeat number of 140 patients molecularly ascertained in our laboratory from 2005 to 2015. We divided the samples in two classes, in relationship with the CAG repeat number: the former was <39 and the latter was >40. The outcomes show an average age of 63.85±16.24 and 47.26±9.44, respectively. The analysis by paired t test confirmed that the length of the repeat is significantly and negatively correlated with AO (P<0.0022). Moreover, we describe the case of a young woman, 28 year old, with nervous anorexia, who inherited a normal allele from the father, HD affected, and an intermediate allele, 32 CAG repeats, from the mother, carrying both alleles of intermediate length (31 and 32 CAG), but apparently with no clinical impairments. This interesting case, among a few other (6 IAs in all cases identified in our laboratory), supports the recent consensus that a subtle phenotype with behavioral disturbances, including energy and metabolic impairments, can be due to subclinical HTT toxicity IAs-associated.
GENETIC, CLINICAL AND NEUROPATHOLOGICAL INSIGHTS INTO PATIENTS WITH ASCERTAINED DIAGNOSIS OF HUNTINGTON DISEASE
SELVATICI, Rita;RIMESSI, Paola;TRABANELLI, Cecilia;FABRIS, Marina;GUALANDI, Francesca;FERLINI, Alessandra;RAVANI, Anna
2015
Abstract
Huntington’s disease (HD) is a rare neurodegenerative disorder with autosomal dominant inheritance, characterized by involuntary movements (chorea), psychiatric disturbances and dementia. HD is caused by an elongated CAG repeat (36 repeats or more) in the Huntingtin gene (HTT), on the short arm of chromosome 4p16.3, with a prevalence of 5-10 per 100,000 in the Caucasian population. A positive family history is a sufficient indication for predictive testing, according to international guidelines (1). Alleles with 36-39 CAG repeats have reduced penetrance and can generate both a normal phenotype, alleles with >39 CAG copies show complete penetrance and inevitably cause, at some stage of life, the HD phenotype. Intermediate alleles (IAs) containing 27–35 CAG repeats does not confer an HD phenotype, however genetic, clinical and neuropathological implications has been recently discussed (2). As the CAG repeat expansion is the major determinant of age of onset (AO), here, we analyze the AO data in relation to CAG repeat number of 140 patients molecularly ascertained in our laboratory from 2005 to 2015. We divided the samples in two classes, in relationship with the CAG repeat number: the former was <39 and the latter was >40. The outcomes show an average age of 63.85±16.24 and 47.26±9.44, respectively. The analysis by paired t test confirmed that the length of the repeat is significantly and negatively correlated with AO (P<0.0022). Moreover, we describe the case of a young woman, 28 year old, with nervous anorexia, who inherited a normal allele from the father, HD affected, and an intermediate allele, 32 CAG repeats, from the mother, carrying both alleles of intermediate length (31 and 32 CAG), but apparently with no clinical impairments. This interesting case, among a few other (6 IAs in all cases identified in our laboratory), supports the recent consensus that a subtle phenotype with behavioral disturbances, including energy and metabolic impairments, can be due to subclinical HTT toxicity IAs-associated.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
