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.
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.
Biochemistry and Molecular Genetics Service, Hospital Clínic, C/Villarroel, 170, 08036, Barcelona, Spain.|CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Laia
L
Rodriguez-Revenga
Neurology Service, Hospital Sant Pau, Barcelona, Spain.|CIBER de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
Javier
J
Pagonabarraga
Neuroradiology Unit, Radiology Department, Hospital Sant Pau, Barcelona, Spain.|Institut d'Investigacions Biomèdiques Sant Pau (IIB), Barcelona, Spain.|PIC, IFAE, Universitat Autònoma Barcelona, Barcelona, Spain.|Universitat Autònoma Barcelona (UAB), Barcelona, Spain.
Beatriz
B
Gómez-Anson
PIC, IFAE, Universitat Autònoma Barcelona, Barcelona, Spain.
Olga
O
López-Mourelo
Sección de Genética Clínica y Reproducción Asistida, Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain.
Silvia
S
Izquierdo
Biochemistry and Molecular Genetics Service, Hospital Clínic, C/Villarroel, 170, 08036, Barcelona, Spain.|CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Maria Isabel
MI
Alvarez-Mora
Neuroradiology Unit, Radiology Department, Hospital Sant Pau, Barcelona, Spain.|Institut d'Investigacions Biomèdiques Sant Pau (IIB), Barcelona, Spain.|PIC, IFAE, Universitat Autònoma Barcelona, Barcelona, Spain.
Esther
E
Granell
Biochemistry and Molecular Genetics Service, Hospital Clínic, C/Villarroel, 170, 08036, Barcelona, Spain.|CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Irene
I
Madrigal
Biochemistry and Molecular Genetics Service, Hospital Clínic, C/Villarroel, 170, 08036, Barcelona, Spain. mmila@clinic.ub.es.|CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain. mmila@clinic.ub.es.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. mmila@clinic.ub.es.
Montserrat
M
Milà
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001259:Ataxia / Q000000981:diagnostic imaging / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging; D005190:Family; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*; D018628:Gene Dosage; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D014202:Tremor / Q000000981:diagnostic imaging / Q000235:genetics*
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
FMR1 gene; FMR1 premutation carrier; FXTAS