scholarly journals BASES GENÉTICAS Y BIOLÓGICAS DEL SÍNDROME DE X FRÁGIL

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ruth Maribel Forero Castro ◽  
Edwin Javier Vergara Estupiñán ◽  
Jefer Iván Moreno Granados
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Messenger Rna ◽  
Fragile Site ◽  
Fragile X ◽  
Normal Population ◽  
Incomplete Penetrance ◽  
Racial Groups ◽  
Full Mutation ◽  
Mendelian Segregation

Después del síndrome de Down, el síndrome de X frágil es la causa más frecuente de retardo mental. Su distribución geográfica es universal y afecta a diferentes grupos raciales. Esta anomalía genética presenta un patrón de herencia ligado a X, dominante, con penetrancia incompleta y anticipación, por lo que revela una segregación no-mendeliana. En 1969, Lubs fue el primero en relacionar el retardo mental con la existencia de un sitio frágil, actualmente reconocido en el brazo largo del cromosoma X en la banda Xq27.3 denominada FRAXA. El gen involucrado en el síndrome de X frágil es el FMR 1, el cual fue identificado en 1991 y su defecto fue atribuido a una expansión del trinucleótido repetitivo CGG, localizado en el primer exón del gen. En la población normal, las repeticiones CGG varían<br />entre un rango de 6 a 54, en individuos portadores entre 43 a 200<br />repeticiones (premutación), mientras que en afectados la expansión de la secuencia CGG tiene más de 200 repeticiones (mutación  completa) y está asociada con la metilación e inactivación del gen. El clonaje del gen FMR 1 condujo a la caracterización de su producto de expresión: la proteína FMRP, involucrada en el metabolismo del RNA y en la función ribosomal. Cuando la región promotora está hipermetilada, se frena la producción del ARN mensajero (ARNm) del gen FMR 1 y, por ende, la producción de la proteína, causando retardo mental, macroorquidismo y otros rasgos físicos y comportamentales característicos del síndrome de X frágil. El diagnóstico del síndrome de X frágil se puede hacer a nivel clínico, citogenético, molecular e inmunohistoquímico, implicando el hallazgo de la fragilidad, la determinación de individuos normales, portadores y afectados, el<br />grado de metilación del gen FMR 1 y la expresión de la proteína FMRP. Aunque este síndrome no tiene cura, el tratamiento en la última década ha sido un foco de interés no solo para los genetistas y médicos generales sino también para otros profesionales, tales como pediatras, psicólogos, trabajadores sociales, logopedas y educadores. El presente artículo tiene como objetivo informar sobre las bases genéticas y biológicas del síndrome de X frágil, y la ruta diagnóstica que debe tenerse en cuenta en el seguimiento de los pacientes y familias afectadas.<br /><br /><strong>Palabras clave:</strong> Síndrome de X frágil, FMR 1, FMRP, retardo mental, premutación, mutación completa.<br /><br /><strong>Abstract</strong><br />Following the Down syndrome, Fragile X Syndrome is the most common cause of mental retardation. Its geographical distribution is universal and affects different racial groups. This genetic anomaly shows a pattern of inheritance linked to X, dominant, with incomplete penetrance and anticipation, so it reveals a non-Mendelian segregation. In 1969, Lubs was the first to link mental retardation with the existence of a fragile site, currently recognised by the long arm of the X chromosome in band Xq27.3 called FRAXA. The gene involved in Fragile X Syndrome is the FMR 1, which was identified in 1991 and its defect was attributed to an expansion of repetitive trinucleotide CGG, located in the first exon of the gene. In the normal population, the CGG repetitions vary from a range of 6 to 54, in carriers between 43 to 200 repetitions (Premutation) while in affected individuals the expansion of the sequence CGG has more than 200 repetitions (Full Mutation) and associated with methylation and gene inactivation. The cloning of the FMR 1 gene led to the characterization of its expression product: FMRP protein, involved in RNA metabolism and<br />ribosomal function. When the promoter region is hypermethylated, it<br />reduces the production of messenger RNA (mRNA) of FMR-1 gene<br />and, thus, the production of the protein, causing mental retardation,<br />macroorquidism and other physical and behavioral traits which are characteristic of Fragile X Syndrome. The diagnosis of Fragile X Syndrome can be made at clinical, cytogenetic, molecular and immunohistochemical level, involving the discovery of the fragility, the determination of normal individuals, carriers and affected persons, <br />the degree of methylation of the FMR-1 gene and expression of<br />FMRP protein. Although this syndrome has no cure, treatment in the<br />last decade has been a source of interest not only for geneticists<br />and general practitioners, but also for other professionals, such as<br />paediatricians, psychologists, social workers, speech therapists and<br />educators. This article aims to report on the biological and genetic<br />bases of the Fragile X Syndrome, and the diagnostic route to be<br />taken into account in the follow-up of patients and families affected.<br /><strong>Keywords:</strong> Fragile X Syndrome, FMR 1, FMRP, mental retardation,<br />premutation, full mutation.

Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽  
1996 ◽  
Vol 97 (1) ◽  
pp. 122-126
Author(s):  
Randi J. Hagerman ◽  
Louise W. Staley ◽  
Rebecca O'Conner ◽  
Kellie Lugenbeel ◽  
David Nelson ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Size Range ◽  
Cpg Island ◽  
Fragile X ◽  
Learning Disabled ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Responsible Gene ◽  
Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

scholarly journals Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

1996 ◽  
Vol 43 (2) ◽  
pp. 383-388
Author(s):  
M Milewski ◽  
M Zygulska ◽  
J Bal ◽  
W H Deelen ◽  
E Obersztyn ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Dna Sequence ◽  
Clinical Features ◽  
Fragile Site ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Repeat Number ◽  
Full Mutation ◽  
Cgg Repeats ◽  
Large Expansion

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

Fragile X: A Family of Disorders

2010 ◽  
Author(s):  
Ann M. Mastergeorge ◽  
Jacky Au
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
X Chromosome ◽  
Culture Media ◽  
Fragile Site ◽  
Fragile X ◽  
Single Gene ◽  
Repeat Sequence ◽  
Full Mutation ◽  
Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

scholarly journals Macroorchidism in FMR1 Knockout Mice Is Caused by Increased Sertoli Cell Proliferation during Testicular Development*

Endocrinology ◽  
1998 ◽  
Vol 139 (1) ◽  
pp. 156-162 ◽  
Author(s):  
Karin E. Slegtenhorst-Eegdeman ◽  
Dirk G. de Rooij ◽  
Miriam Verhoef-Post ◽  
Henk J. G. van de Kant ◽  
Cathy E. Bakker ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Sertoli Cell ◽  
Knockout Mice ◽  
Messenger Rna ◽  
Fragile X ◽  
Fsh Receptor ◽  
Cgg Repeat

Abstract The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5′-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.

Health Supervision for Children With Fragile X Syndrome

PEDIATRICS ◽  
1996 ◽  
Vol 98 (2) ◽  
pp. 297-300
Author(s):  
Keyword(s):  
Mental Retardation ◽  
Developmental Delay ◽  
Fragile X Syndrome ◽  
X Chromosome ◽  
Dna Analysis ◽  
Fragile Site ◽  
Fragile X ◽  
Physical Features ◽  
Relationship Of ◽  
The Relationship

This set of guidelines is designed to assist pediatricians in caring for children with fragile X syndrome confirmed by DNA analysis (Table). Occasionally pediatricians are called on to advise a pregnant woman who has been informed of a prenatal diagnosis of fragile X syndrome. Therefore, guidelines are also offered for this situation. Fragile X syndrome is usually diagnosed during childhood and is characterized by developmental delay or mental retardation, characteristic physical features, and abnormal behavioral patterns.1,2 The distinctive fragile site on the X chromosome was first described in 1969 as a discontinuous site on the long arm of the X chromosome present after cell culture under folate-deficient conditions. In 1977 the relationship of this site to X-linked mental retardation was noted, and fragile X syndrome began to be defined. Since that time, the cytogenetic, molecular, and clinical features of the condition have been more clearly defined,3 and it is now recognized as the most common hereditary cause of mental retardation. Its frequency has been estimated to be approximately per 2500 to 1 per 1250 males and 1 per 5000 to 1 per 1600 females. The phenotype of fragile X syndrome in males often has a number of distinctive, recognizable features, including developmental delay or mental retardation, a prominent forehead, a long, thin face and a prominent jaw that appear late in childhood or early adolescence, large protuberant and slightly dysmorphic ears, and the presence of or ultimate development of macro-orchidism. This phenotype can be very subtle, is not always apparent, and becomes more identifiable with age.2

Mosaicism in Fragile X syndrome: A family case series

2021 ◽  
pp. 174462952199534
Author(s):  
Wilmar Saldarriaga ◽  
Laura Yuriko González-Teshima ◽  
Jose Vicente Forero-Forero ◽  
Hiu-Tung Tang ◽  
Flora Tassone
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Molecular Testing ◽  
Full Mutation ◽  
Mild Phenotype ◽  
Variable Expression ◽  
Fragile X Mental Retardation ◽  
Classic Phenotype

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 ( FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

scholarly journals Experience with molecular and cytogenetic diagnosis of fragile X syndrome in Brazilian families

1997 ◽  
Vol 20 (4) ◽  
pp. 731-739 ◽  
Author(s):  
Regina C. Mingroni-Netto ◽  
Rita C.M. Pavanello ◽  
Paulo A. Otto ◽  
Angela M. Vianna-Morgante
Keyword(s):  
Mental Retardation ◽  
Dna Analysis ◽  
Fragile Site ◽  
Fragile X ◽  
False Negative ◽  
Full Mutation ◽  
Negative Results ◽  
Cgg Repeats ◽  
False Negative Results ◽  
Normal Males

We report on the cytogenetic and DNA analysis of 55 families with the fragile X (FMR-1 locus) mutation (318 individuals and 15 chorionic villi samples). A total of 129 males were investigated, 54 mentally normal and 75 presenting mental retardation. Among the 54 normal males, 11 had the premutation, and none expressed the fragile site. The full mutation was detected in 73 retarded males, and 14 (18%) presented a premutation along with the full mutation (mosaics). All of them manifested the fragile site. The frequencies of fragile site expression correlated positively with the sizes of the expansion of the CGG repeats (<FONT FACE="Symbol">D</FONT>). Among 153 normal females, 85 were found to be heterozygous for the premutation and 15 had the full mutation. In the premutated females the fragile site was not observed or it occurred at frequencies that did not differ from those observed in 53 noncarriers. Cytogenetic analysis was thus ineffective for the diagnosis of premutated males or females. Among the 51 heterozygotes for the full mutation, 36 (70%) had some degree of mental impairment. As in males, a positive correlation was detected between the frequencies of fragile site manifestation and the size of the expansion. However, the cytogenetic test was less effective for the detection of fully mutated females, than in the case of males, since 14% false negative results were found among females. Segregation analysis confirmed that the risk of mental retardation in the offspring of heterozygotes increases with the length of <FONT FACE="Symbol">D</FONT>. The average observed frequency of mental retardation in the offspring of all heterozygotes was 30%. There was no indication of meiotic drive occurring in female carriers, since the number of individuals who inherited the mutation did not differ from the number of those inheriting the normal allele. No new mutations were detected in the 55 genealogies studied here.

Fragile X Syndrome in Humans and Mice

1996 ◽  
Vol 45 (1-2) ◽  
pp. 93-108 ◽  
Author(s):  
B. A. Oostra
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Fragile Site ◽  
Fragile X ◽  
Methylation Status ◽  
Physical Symptoms ◽  
Post Mortem Brain ◽  
Iq Scores

Fragile X syndrome is the most common cause of interited mental retardation in humans, with a frequency of approximately 1 in 1200 males and 1 in 2500 females [1]. It is second only to Down syndrome as a genetic cause of mental retardation, which has an overall frequency of 1 in 600. These frequency estimates suggest that fragile X syndrome accounts for approximately 3% of mental retardation in males, and perhaps as much as 20% in males with IQs between 30 and 55 [2]. The disease derives its name from the observation of a fragile site at Xq27.3 in cultured lymphocytes, fibroblasts and amniocytes [3].The phenotype of the fragile X syndrome is mental retardation, usually with an IQ in the 4-70 range [4] and a number of dysmorphic features: long face, everted ears and large testicles [for review see ref. 5] (Fig. 1). Not every patient shows all the physical symptoms, which are generally more apparent after childhood. Macroorchidism is a common feature of fragile X syndrome in more than 90% of postpuberal males. Some patients show hyperactivity and attention deficits as well as avoidance behaviour similar to autism. Affected females generally have a less severe clinical presentation, and their IQ scores are generally higher, with typically borderline IQs or mild mental retardation.No gross pathological abnormalities have been described in the brains of fragile X patients. Only a few post-mortem brain studies of fragile X males have been described and the information is very limited, presenting only non-specific findings such as brain atrophy, ventricular dilatation and pyramidal neurons with abnormal dendritic spines. It has been shown that the volume of the hippocampus was enlarged compared to controls [6], while a significantly decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle was found [7]. Using magnetic resonance imaging it was shown that fragile X patients have an increased volume of the caudate nucleus [8]. The caudate volume is correlated with IQ and methylation status of the FMR1 gene.

Fragile X Syndrome

1999 ◽  
Vol 18 (6) ◽  
pp. 15-22 ◽  
Author(s):  
Judy Welch ◽  
Janet Williams
Keyword(s):  
Health Care ◽  
Mental Retardation ◽  
Family Planning ◽  
Fragile X Syndrome ◽  
Newborn Infant ◽  
Care Management ◽  
Fragile X ◽  
Health Care Management ◽  
Full Mutation ◽  
Neonatal Nurses

Fragile X syndrome is the most common inherited condition causing mental retardation in males. Females with the full mutation expansion can have milder signs of the disorder. Families with members who have been diagnosed with fragile X syndrome face concerns about the health of their newborn infant, decisions regarding family planning, and questions about the possibility that other family members could have this disorder. Neonatal nurses participate in assessment, health care management, counseling, and referral of the families regarding this syndrome.

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