Carriage of One or Two FMR1 Premutation Alleles Seems to Have No Effect on Illness Severity in a FXTAS Female with an Autozygous FMR1 Premutation Allele

• Published in: Cerebellum (London, England) Vol. 15; no. 5; pp. 570 - 577
• Main Authors: Rodriguez-Revenga, Laia, Pagonabarraga, Javier, Gómez-Anson, Beatriz, López-Mourelo, Olga, Izquierdo, Silvia, Alvarez-Mora, Maria Isabel, Granell, Esther, Madrigal, Irene, Milà, Montserrat
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2016; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Ataxia - diagnostic imaging; Ataxia - genetics; Biomedical and Life Sciences; Biomedicine; Brain - diagnostic imaging; Family; Female; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome - diagnostic imaging; Fragile X Syndrome - genetics; Gene Dosage; Heterozygote; Humans; Male; Middle Aged; Neurobiology; Neurology; Neurosciences; Original Paper; Severity of Illness Index; Tremor - diagnostic imaging; Tremor - genetics; gene; premutation carrier; FXTAS; FMR1 premutation carrier; FMR1 gene
• ISSN: 1473-4222; 1473-4230
• DOI: 10.1007/s12311-016-0783-z

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.