Case 9: Petter Khant - Fragile X Syndrome

Developmental Delay: Description

Milestones in expected order at delayed age (≤ 5 years)

Isolated: 1 domain affected

Global: ≥ 2 domains affected

Neurodevelopmental Disorders

Childhood conditions affecting brain + NS development

• Global developmental delay

Fragile X Syndrome: Description

X-linked genetic disorder causing intellectual disability (ID) + neurodevelopment disorders

Fragile X Syndrome: Epidemiology

2nd most common genetic cause of ID (after trisomy 21)

Most common inherited cause of ID

Affects more males

Fragile X Syndrome: Etiology

X-linked dominant genetic mutation

• FMR1 gene mutation

• X inactivation (lyonization)

Fragile X Syndrome Etiology: FMR1 Gene Mutation

Inactivation = Hypermethylation = Expansion: CGG trinucleotide repeats

• DNA replication error = Increase 3 nucleotide sequence

  • More repeats = Increase chance of symptoms + worse phenotype

    • Premutation: < 200 repeats

    • Full Mutation: > 200 repeats

• Anticipation: In offspring vs parents

  • Earlier disease onset

  • More severe disease

Fragile X Syndrome Etiology: X Inactivation (Lyonization)

In females

1 X chromosome randomly inactivated during embryogenesis

• Normal process

Phenotypic variation depending on inactivation pattern

• Preferentially active X = Normal, mutated, or 50/50

Fragile X Syndrome: Pathophysiology

1. FMR1 mutation = Loss of function = Impair fragile X messenger ribonucleoprotein (FMRP) production

• Normal FMRP:

  • Bind ribosomes = Normal synapse development, neuroplasticity, RNA stability

  • Regulate collagen + elastin production

2. Abnormal neural + synaptic development = ID

Fragile X Syndrome: Clinical Presentation

Premutation:

• Ataxia: Lack of coordination in voluntary movements

• POI

• Tremor

Full Mutation:

• ID

• Delayed language development

• Seizures

• Behaviour changes

  • Autistic behaviour

  • Hyperactivity

  • Anxiety

• Facial anomalies

  • Long + narrow face

  • Prominent forehead + jaw

  • Large everted ears

• Large head circumference

• Large testes

• Hypermobile joints

• Mitral valve prolapse

Fragile X Syndrome: Investigations

Clinical + family history diagnosis

Molecular genetic testing

ECG

Fragile X Syndrome Investigations: Molecular Genetic Testing

FMR1 mutations

• PCR: CGG repeats

• Southern Blot: Abnormal methylation

Fragile X Syndrome Investigations: ECG

Mitral valve prolapse

Fragile X Syndrome: Management

Speech + language therapy

Genetic counselling

Pharmacological

Fragile X Syndrome Management: Pharmacological

Stimulants

• Hyperactivity

• Inattention

• Impulsivity

Antidepressants

• Anxiety

Antipsychotics

• Aggression

Fragile X Syndrome: Complications

Recurrent otitis media → Hearing loss

Connective tissue dysplasia

• Mitral valve prolapse

• Joint laxity + hypermobility

• Hip dysplasia

• Scoliosis

Impaired mobility

Fragile X Syndrome: Prognosis

Normal life expectancy