Genetics
Stephan Strobel, Lewis Spitz, Stephen D. Marks in Great Ormond Street Handbook of Paediatrics, 2019
Fragile X is caused by a triplet repeat expansion within the FMR1 gene. Repeat lengths of >200 are referred to as ‘full mutations’ and cause fragile X syndrome. Alleles with 55–200 repeats are referred to as ‘premutations’ and are associated with an increased risk of expansion to >200 repeats when transmitted.
Common Inherited Genetic Disorders
Attila Lorincz in Nucleic Acid Testing for Human Disease, 2016
Fragile X syndrome is a genetic condition that causes a wide range of mental impairments, from mild learning disabilities to severe mental retardation and is the most common cause of inherited mental retardation (MR). A population prevalence figure of 1 in 4,000 or 2.4 in 10,000 has been reported on the basis of molecular genetic analysis. In addition to mental impairment, fragile X syndrome is associated with a number of physical and behavioral characteristics. A carrier female typically has a 30 to 40% chance of giving birth to a mentally retarded male child and a 15 to 20% chance of having a mentally retarded female child. Further, maternal family history frequently reveals a relative with mental retardation or developmental and learning disabilities. Most studies have dealt with recognition of this syndrome in older children and young adults, but many of the physical features, behavioral characteristics, and family history features are apparent earlier. The classic physical features of fragile X syndrome include a long face with a prominent jaw, large prominent ears, and post-pubertal macro-orchidism. In 1991, the fragile X gene (FMR1) was characterized and found to contain a tandemly repeated trinucleotide sequence (CGG) in the 5′ untranslated region. The number of CGG repeats in the FMR1 genes in normal individuals varies from 5 to approximately 40. Premutations, alleles that are not disease-causing in an individual but increase in size in successive generations when transferred through the female germline, range from approximately 55 to 200 repeats. Full mutations are expansions of more than 200 repeats and are disease-causing. Alleles with approximately 41 to 54 copies of the repeat are intermediate size alleles that can be unstable and expand in successive generations or may be stably inherited. A premutation is susceptible to expansion only after passage through a female meiosis, and larger premutations are more likely to expand to full mutations in successive generations.
Offenders with intellectual disabilities
John C. Gunn, Pamela J. Taylor in Forensic Psychiatry, 2014
The gene underlying fragile X syndrome (FMR-1) is located on the distal arm of the X chromosome, Xq27.3, and is associated with a large expansion of a sequence of CGG (cytosine–guanine–guanine) trinucleotide repeats. This gene exerts its impact on brain development by regulating neuron dendritic arborization. In affected individuals, there is failure of inhibition of dendritic arborization, which results in too many inter-neuronal connections: effectively, a reduction of the pruning effect on cerebral structure, which is part of normal development over adolescence. Consequently, the brain of affected individuals is larger – around 10% heavier – than the normal young adult brain, but many of the connections detract from functional adaptation, rather then add to it. There is a direct correlation between the length of the repeat CGG sequence, and the severity of phenotypic expression, in physical, intellectual and behavioural terms. Phenotypic expression of fragile X syndrome depends on the sex of the affected individual. Intellectual disability in males is typically mild to moderate, while females – having one normal X chromosome – generally show IQ in the low normal to borderline range. Affected boys show a combination of an atypical form of autism spectrum disorder, and an attention deficit hyperactivity disorder (ADHD)-type pattern of overactivity. Repetitive behaviour and social anxiety are prominent, but theory of mind test results are less impaired than in typical autism. As they develop, boys become less overactive, indeed, many are quite underactive and listless by adulthood, but the autistic-type features and social anxiety are more persistent among men (Turk, 1992; Hagerman, 2005). Girls and women generally have few autistic features, but some social anxiety.
Parenting of children with Down syndrome compared to fragile X syndrome
Published in Developmental Neurorehabilitation, 2018
Audra Sterling, Steven F. Warren
Children with Down syndrome (DS) and fragile X syndrome (FXS) struggle with language development. Parenting variables, such as responsiveness to children’s communication attempts (Maternal Responsivity), and techniques used to support and teach appropriate behavior (Behavior Management) are known to have a significant impact on early child development. We examined these two aspects of parenting style via coded, videotaped parent-child interactions in two groups of participants matched on child age (2–5 years) and child expressive language level: mothers of children with DS and mothers of children with FXS. The mothers differed in their use of gestures and redirecting the child’s attention. Overall, mothers in both groups of children appeared to adapt appropriately to their children’s developmental needs.
The quest for targeted therapy in fragile X syndrome
Published in Expert Opinion on Therapeutic Targets, 2015
Shimriet Zeidler, Renate K Hukema, Rob Willemsen
Fragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical trials have been extremely disappointing. Complicating factors, particularly in animal studies, include mouse inbred strains, variability in functional studies between laboratories, publication bias and lack of reliable and objective primary outcome measures in both mice and patients. Possibly most important, however, is one factor that has been little explored: the complexity of the molecular imbalance in FXS and the need to simultaneously target several different disturbed pathways and different cellular compartments. New, well-conceived animal studies should generate more productive approaches in the quest for targeted therapy for FXS.
A Neurodevelopmental Perspective on the Acquisition of Nonverbal Cognitive Skills in Adolescents With Fragile X Syndrome
Published in Developmental Neuropsychology, 2013
Sara Kover, Elizabeth Pierpont, Jee-Seon Kim, W. Brown, Leonard Abbeduto
This longitudinal study was designed to investigate trajectories of nonverbal cognitive ability in adolescents with fragile X syndrome with respect to the relative influence of fragile X mental retardation protein (FMRP), autism symptom severity, and environmental factors on visualization and fluid reasoning abilities. Males and females with fragile X syndrome (N = 53; ages 10–16 years) were evaluated with the Leiter–R at up to four annual assessments. On average, IQ declined with age. FMRP levels predicted change in fluid reasoning, but not in visualization. The role of FMRP in the neural development that underlies the fragile X syndrome cognitive phenotype is discussed.
Related Knowledge Centers
- Intellectual Disability
- Genes
- X-Linked Mental Retardation
- Chromosome
- Fraxa
- Fraxe
- Sex Chromosome Disorders