• Fragile X syndrome is also known as marker X syndrome or Martin-Bell syndrome.
• It is one of the genetic disorders that is also considered as second most common cause for inherited mental disfunction after trisomy 21.
• It is manifested by various changes in the behavior and cognitive recognition that differs widely in severity among the patients.
• Both males and females are affected by it, but males are more likely to be severely affected in comparison to females.
• It has been estimated to affect 1 in 4000 boys whereas 1 in 8000 girls.
• Approximately 1 in 259 women of all races carry the fragile X gene and may transmit it to their children, whereas about 1 in 800 men of all races and ethnicities are carriers. Carrier females have 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.
• Despite being an X chromosome recessive trait with changeable expression and partial penetrance, 30% of all carrier females are affected.
• Penetrance is the proportion of individuals carrying a particular variant of a gene which also express an associated trait or phenotype.
• It is lifelong condition and only few people with FXS can live independently.

Causes:

• A “fragile” site at the end of the long arm of the X chromosome results in Fragile X syndrome.
• Loss-of-function mutations in the fragile X mental retardation 1 (FMR1) gene causes Fragile X syndrome.
• FMR1 encodes the FMRP protein present in many tissues and at relatively high levels in the brain and testes.
• In the brain, it functions in the development of neuronal synapses and cell communication.
• The synapses can change and adjust over time in response to event, a feature called synaptic plasticity.
• The FMRP protein may aid in regulating synaptic plasticity and thus direct learning and memory.
• Fragile X syndrome fit in to an emerging class of neurodegenerative disorders known as trinucleotide repeat disorders. Out of these disorders, 14 affect humans and obtain neurological dysfunction.
• The inactivation of the FMR1 gene by trinucleotide CGG repeat expansions (200 to more than 1,000 repeats) are the most common mutations observed at this locus.
• The repeat expansion mutation results in high methylation in the FMR1 promoter region that halts transcription of FMR1.
• This expansion mutation is a null mutation (i.e., does not alter the function of the protein it codes for).
• Few typical alterations occur at this locus of FMR1.
• Array-based sequence analyses manifested that missense mutation (a single nucleotide change resulting in a codon that encodes a different amino acid) in FMR1 is not a common cause of the fragile X syndrome phenotype in patients who have normal-length CGG repeat tracts.
•  Thus, screening for small deletions of FMR1 may be of clinical advantage.
• In most people who lack fragile X syndrome, the number of CGG repeats ranges from about 1 to 40. This CGG repeat segment is typically disrupted several times by a different trinucleotide, AGG.
• Having AGG scattered among the CGG trinucleotides aids to sustain the length of the long repeated segment.
•  In patients with fragile X syndrome, the CGG trinucleotide is abnormally repeated from 200 to more than 1,000 times, resulting in instability of this region of gene.
•  An unstable mutation is a mutation that has a high chances of reverting to its native form.
• The insertion of a controlling element (e.g., repeat expansion) can also result in unstable mutation whose subsequent deletion can result in a reversion to the original form of the gene.
• The inserted repeat expansion of the FMR1 gene turns it off, and it thus makes very little or no FMRP protein. A loss or reduction in the level of FMRP expression interrupts normal neuronal functions, causing severe learning problems, intellectual disability, and the other characters of fragile X syndrome.
•  About 1 in 3 of males with an FMR1 gene mutation and the characteristic symptoms of fragile X syndrome also have characters of autism spectrum disorders that affect communication and social interaction. Other changes in FMR1 account for less than 1% of cases of fragile X syndrome.

Symptoms:

• Individuals with FXS show a combination of symptoms as children and throughout lifetime as follows:
• Developmental retardation:
  -not being able to sit, walk, or talk at the same time as other children of the same age
• Learning difficulties:
  • trouble learning new skills
• Social and behaviour problems:
  • not making eye contact
  • anxiety
  • delay in paying attention
  • hand flapping
  • acting and speaking without thinking
  • Hyperactivity in case of children
  • Highly sensitive to loud noises and bright light
• Other health problems:
  • Seizures (Epilepsy)
  • Hearing problems
  • Vision problems
  • Heart problems
• Physical symptoms:
  • large ears
  • flat feet
  • long face
  • Scoliosis
  • testes enlarged in males after puberty

Diagnosis:

• The pregnant women undergo following tests to detect FXS in their babies:
  1) Amniocentesis: a sample of amniotic fluid is tested for FMR1 gene.
  2) Chorionic villus sampling (CVS): cells from placenta are checked for the FMR1 gene.
• The person’s DNA from blood test confirms the FXS.
• Both karyotyping and DNA test are advised for the diagnosis.
• Southern blot and PCR are techniques for genetic analysis in present condition.

Treatment:

• No any medications or cure is available for FXS, thus the management and cure is a must for the individuals.
• Medications as such methylphenidate, guanfacine, clonidine, etc are prescribed for the attention deficit disorder or anxiety.
• Treatments include managing the symptoms that includes:
• Speech therapy
• Behaviour therapy
• Special education to help them learn
• Neurologist consultations for seizures
• Occupational and physical therapist
• People with FXS, parents, teachers and therapists should work closely with one another for the best treatment plans.

References:

• https://ghr.nlm.nih.gov/condition/fragile-x-syndrome#diagnosis
• https://www.cdc.gov/ncbddd/fxs/facts.html
• https://www.webmd.com/children/what-is-fragile-x-syndrome#1
• https://emedicine.medscape.com/article/943776-overview
• https://www.healthline.com/health/fragile-x-syndrome#treatment
• https://www.aafp.org/afp/2005/0701/p111.html
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Fragile X syndrome: Causes, Symptoms, Diagnosis and Treatment

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