What is the cause of the patient's intellectual disability?

Causes of Intellectual Disability: A Diagnostic Approach

The most common causes of intellectual disability are genetic abnormalities, which account for the majority of cases, particularly in severe intellectual disability, while environmental factors, metabolic disorders, and brain malformations constitute other significant etiological categories.

Etiological Classification

Genetic Causes

• Single-gene disorders:

  • Fragile X syndrome (most common inherited cause) - resulting from a repeat variant in the FMR1 gene on the X chromosome 1
  • X-linked intellectual disability genes - multiple genes can present as either intellectual disability or autism spectrum disorder 1
  • MECP2 duplications in males (with features like drooling, recurrent respiratory infections) 1
  • PTEN mutations - particularly in patients with macrocephaly 1

• Chromosomal disorders:

  • Down syndrome (trisomy 21) - most common genetic cause of intellectual disability 1
  • Other autosomal trisomies (13,18) 1
  • Copy number variants - extra or missing copies of chromosomal segments 1

Metabolic Disorders

• Inborn errors of metabolism affecting:
  • Carbohydrate metabolism
  • Amino acid metabolism
  • Nucleic acid metabolism
  • Mitochondrial function 1
• Specific metabolic conditions associated with intellectual disability:
  • Smith-Lemli-Opitz syndrome
  • Adenylosuccinate lyase deficiency
  • Cerebral folate deficiency
  • Disorders of creatine transport or metabolism
  • Disorders of γ-aminobutyric acid metabolism 1

Brain Malformations

• Lissencephaly (absence of cortical folds)
• Abnormal cortical layering 1
• Neurocutaneous syndromes:
  • Tuberous sclerosis
  • Neurofibromatosis 1

Perinatal Causes

• Birth asphyxia and birth trauma - leading causes in developing countries 2
• Caution: Many cases initially attributed to birth injury are later found to have prenatal causes upon detailed investigation 3

Environmental/Acquired Causes

• Infections:
  • Meningitis (tuberculous and pyogenic)
  • Encephalopathies associated with measles and whooping cough 2
• Severe malnutrition in infancy
• Hyperbilirubinaemia in newborns
• Iodine deficiency
• Iron deficiency anemia in infancy 2
• Severe environmental deprivation, child abuse, and neglect 1
• Medical conditions:
  • Brain tumors
  • Intractable epilepsy
  • Central nervous system insults (e.g., hypoxemia) 1

Diagnostic Approach

Step 1: Clinical Assessment

• Determine severity of intellectual disability based on adaptive functioning across:
  • Conceptual domain (academic skills, abstract thinking)
  • Social domain (interpersonal skills, social responsibility)
  • Practical domain (self-management, occupational skills) 1
• Note: DSM-5 focuses on adaptive functioning rather than IQ scores to define severity levels 1

Step 2: Medical Evaluation

• Look for clinical symptoms that might suggest specific syndromes:
  • Distinctive physical features
  • Growth abnormalities
  • Neurological signs
  • Behavioral phenotypes 4
• Check for metabolic disorder indicators:
  • Acid/base or electrolyte disturbances
  • Cyclic vomiting
  • Dermatologic changes
  • Developmental regression associated with illness
  • Gastrointestinal dysfunction
  • Hypotonia/dystonia
  • Lactic acidosis
  • Lethargy
  • Multisystem involvement
  • Poor growth or microcephaly
  • Seizures 1

Step 3: Genetic Testing

• Chromosomal microarray - first-line test to detect copy number variants
• Specific gene testing for suspected conditions (e.g., Fragile X)
• X-linked intellectual disability gene panels when family history suggests X-linked inheritance 1
• Consider whole exome or genome sequencing for undiagnosed cases

Step 4: Metabolic Testing

• Based on clinical suspicion from history and physical examination
• Target testing to specific metabolic disorders when indicated by clinical features 1

Important Considerations

• An etiology can be identified for the majority of individuals with severe intellectual disability and for a substantial subset with mild intellectual disability 1
• Genetic testing has significantly improved diagnostic yield, particularly for previously undiagnosed cases 5
• The prevalence of intellectual disability is estimated at 1-3% of the general population 4
• Approximately 75% of persons with intellectual disability have mild intellectual disability, where a specific etiology is less likely to be identified 4
• In severe to profound intellectual disability, an underlying specific biological cause is highly likely to be identified 4

Preventive Strategies

• Primary health care measures can prevent many conditions causing intellectual disability in developing countries 2
• Early intervention for high-risk infants
• Appropriate management of maternal conditions during pregnancy
• Prevention of infections through vaccination
• Adequate nutrition during pregnancy and early childhood 2

Remember that accurate diagnosis of the underlying cause is crucial for genetic counseling, prognosis determination, and in some cases, specific treatment approaches.