Screening for the presence of FMR1 premutation alleles in women with parkinsonism.
BACKGROUND
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disease that affects older carriers of premutation (CGG) repeat expansions of the fragile X mental retardation 1 (FMR1) gene. Clinical features include intention tremor, gait ataxia, memory loss, peripheral neuropathy, autonomic dysfunction, and parkinsonism. The presence of parkinsonism in FXTAS raises the possibility that some individuals who have Parkinson disease are actually carriers of a premutation FMR1 allele.


OBJECTIVE
To screen DNA samples from a large cohort of females with Parkinson disease for an excess of expanded alleles of the FMR1 gene.


METHODS
We screened a cohort of 595 women with parkinsonism, the largest screening of a parkinsonism-associated group to date, for the presence of an FMR1 premutation allele (55-200 CGG repeats). The screening protocol uses an enhanced polymerase chain reaction method capable of flagging any FMR1 expanded CGG repeat in women as well as in men.


METHODS
Diagnostic assessments were performed at an outpatient tertiary clinic (Parkinson Institute, Milan). Genotyping was conducted at the University of California, Davis.


METHODS
CGG repeat number and clinical/neuroimaging assessments of patients with Parkinson disease were conducted. Two premutation carriers were identified.


RESULTS
Two individuals possessed an FMR1 allele in the premutation range (CGG repeats: 30 and 75; 30 and 115). This carrier frequency (2 of 595 [0.34%]) is not significantly different from estimates of the allele frequency among women in the general population (0.4%-0.8%). Clinical and radiologic features of these 2 patients were similar to those of the general Parkinson disease population; however, 1 patient (115 CGG repeats) had a family history of 2 sons with the fragile X syndrome.


CONCLUSIONS
Screening of women within the parkinsonism clinical spectrum is unlikely to be productive in the absence of additional medical or family history suggestive of involvement of the FMR1 gene.
Cilia
Roberto
R
Parkinson Institute-Clinici di Perfezionamento, Milan, Italy.
Kraff
Jeremy
J
Canesi
Margherita
M
Pezzoli
Gianni
G
Goldwurm
Stefano
S
Amiri
Khalid
K
Tang
Hiu-Tung
HT
Pan
Ruiqin
R
Hagerman
Paul J
PJ
Tassone
Flora
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
D051860:Fragile X Messenger Ribonucleoprotein 1; D005819:Genetic Markers; C497683:FMR1 protein, human