Fragile X syndrome: Causes, Symptoms, Diagnosis and Treatment

May 31, 2020 Gaurab Karki Health and Diseases 0




Fragile X syndrome (FXS):

  • 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:

Fragile X syndrome: Causes, Symptoms, Diagnosis and Treatment