Implicações clínicas dos factores genéticos envolvidos em doenças neurodegenerativas caracterizadas por alterações do movimento ou cognitivas

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Fragile X mental retardation 1 (FMR1) premutations: instability and associated phenotypes

Publication . Loureiro, Joana; Jorge, Paula; Marques, Isabel; Santos, Rosário; Seixas, Ana; Martins, Márcia; Vale, José; Sequeiros, Jorge; Silveira, Isabel

Fragile X syndrome (FXS) is the most common hereditary form of intellectual disability with an estimated frequency of 1/4000 males and 1/8000 females. FXS is caused by a (CGG)n expansion of over 200 repeats, in the 5’UTR of the FMR1 gene, which as a result is usually methylated and the gene silenced. Based on CGG repeat length, four classes of alleles can be distinguished: normal (5-44), intermediate (45-54), premutation (55-200; PM) and full mutation (>200; PM) alleles. Premutations expand to full mutation alleles only via maternal transmission and larger premutations have an increased risk of expansion to full mutation. Paternal premutations and full mutations are inherited in the premutation range. The aim of this study is to gain insights into instability of FMR1 CGG repeat alleles and associated phenotypes in 128 Portuguese FXS families.

2012-05-10Conference object

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FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypes

Publication . Seixas, Ana; Vale, José; Jorge, Paula; Marques, Isabel; Santos, Rosário; Alonso, Isabel; Fortuna, Ana; Pinto-Basto, Jorge; Coutinho, Paula; Margolis, Russell; Sequeiros, Jorge; Silveira, Isabel

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5'UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members.

2011-06Journal article

Open access

FMR1 premutations may be associated with a wider spectrum of phenotypes

Publication . Seixas, Ana; Vale, José; Martins, Márcia; Loureiro, Joana; Jorge, Paula; Maques, Isabel; Santos, Rosário; Coutinho, Paula; Margolis, Russell; Sequeiros, Jorge; Silveira, Isabel

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5’UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline.

2011-09Other

Open access

Fragile X mental retardation 1 (FMR1) premutations: instability and associated phenotypes

Publication . Loureiro, Joana; Jorge, Paula; Marques, Isabel; Santos, Rosário; Seixas, Ana; Martins, Márcia; Vale, José; Sequeiros, Jorge; Silveira, Isabel

Fragile X syndrome (FXS) is the most common hereditary form of intellectual disability with an estimated frequency of 1/4000 males and 1/8000 females. FXS is caused by a (CGG)n expansion of over 200 repeats, in the 5’UTR of the FMR1 gene, which as a result is usually methylated and the gene silenced. Based on CGG repeat length, four classes of alleles can be distinguished: normal (5-44), intermediate (45-54), premutation (55-200; PM) and full mutation (>200; PM) alleles. Premutations expand to full mutation alleles only via maternal transmission and larger premutations have an increased risk of expansion to full mutation. Paternal premutations and full mutations are inherited in the premutation range. The aim of this study is to gain insights into instability of FMR1 CGG repeat alleles and associated phenotypes in 128 Portuguese FXS families.

2012-05-23Conference object

Restricted access

Fragile X syndrome: intergenerational allele instability and associated phenotypes in families

Publication . Joana, Loureiro; Marques, Isabel; Santos, Rosário; Seixas, Ana; Martins, Márcia; Vale, José; Sequeiros, Jorge; Silveira, Isabel

Fragile X syndrome (FXS) is the most common hereditary form of intellectual disability with an estimated frequency of 1/4000 males and 1/8000 females. This disease is caused by a (CGG)n expansion in the 5’UTR of the FMR1 gene, which as a result is methylated and gene silenced. Four classes of alleles can be found based on CGG repeat length: normal (5-44), intermediate (45-54), premutation (55-200) and full mutation (>200). In premutation carriers, both FMR1-related primary ovarian insufficiency (FXPOI) and fragile-X associated tremor/ataxia syndrome (FXTAS) have been described. To gain insights into instability of FMR1 CGG repeats and associated phenotypes, we studied 541 individuals from 128 FXS Portuguese families. DNA samples were genotyped by PCR and Southern blot analysis. Additional clinical evaluation was performed in premutation carriers. Among FXS families, 5.3% intermediate, 29.9% premutation and 26.6% full mutation alleles were found. Normal and intermediate alleles were stable upon transmission. For 115 maternal premutation transmissions, 26 (23%) with alleles ranging 60-98 CGGs remained in premutation size with an average expansion of 17 repeat units, whereas 89 (77%) with alleles ranging from 66-199 CGGs expanded to full mutation. In 44 transmissions of maternal full mutation, the offspring inherited alleles in the full mutation range. For 10 paternal transmissions of premutations, ranging 56-120 CGGs, all daughters inherited a premutation allele, with an average expansion of 7 repeat units. After clinical evaluation of 7 premutation carriers, 1 male with FXTAS and 2 females with FXPOI were identified; however the remaining premutation individuals were not yet examined. In Portuguese FXS families, allele instability upon transmission is in agreement with previous reports. The risk of premutation to full mutation expansion increases with maternal premutation size.

2012-11-22Conference object

Open access