What is the chromosomal abnormality in Down syndrome and its consequences?

Chromosomal Abnormality in Down Syndrome and Its Consequences

Down syndrome is caused by the presence of an extra copy of chromosome 21 (trisomy 21), which results in widespread developmental effects including intellectual disability, characteristic physical features, and increased risk for multiple health conditions throughout life. 1

Genetic Basis of Down Syndrome

• Primary chromosomal abnormality: Trisomy 21, which can occur in three forms:

  • Free trisomy 21 (95% of cases) - An extra complete chromosome 21
  • Robertsonian translocation involving chromosome 21
  • Reciprocal translocation involving chromosome 21 1

• Origin of nondisjunction:

  • 95% of cases result from sporadic nondisjunction during parental meiosis
  • 95% of these nondisjunctions are maternal in origin
  • 77% of maternal nondisjunctions occur during Meiosis I 1
  • Risk increases with advancing maternal age 1

• Genetic mechanism: The extra chromosome leads to overexpression of genes located on chromosome 21, including the amyloid precursor protein (APP) gene, which plays a significant role in later-life complications 2

Clinical Consequences

Physical Features

• Hypotonia (virtually all individuals)
• Characteristic facial features:
  • Upslanting palpebral fissures
  • Epicanthal folds
  • Flat nasal bridge
  • Brushfield spots of the iris
• Shortened, incurving fifth finger
• Transverse palmar crease 1

Major Health Consequences

1. Cardiovascular System:

   • Congenital heart disease in 40% of cases 1
   • Requires specialized cardiac care throughout life 1

2. Gastrointestinal System:

   • 5% have anomalies such as duodenal atresia or Hirschsprung disease 1

3. Hematologic System:

   • 20-fold increased risk of childhood leukemia compared to general population 1
   • Higher risk of developing leukemia in childhood (both AML and ALL) 1

4. Neurological System:

   • Moderate to severe intellectual disability 1
   • Neuronal degeneration identical to Alzheimer's disease in adulthood 1
   • 100% of adults with Down syndrome show Alzheimer's disease neuropathology by age 40 2
   • At least 50% of adults with Down syndrome aged 60+ develop clinical dementia 2

5. Endocrine System:

   • Increased risk of hypothyroidism 1

Molecular Mechanisms

The phenotypic features of Down syndrome result from gene dosage effects:

• Not all genes on chromosome 21 contribute equally to the syndrome
• The APP gene on chromosome 21 leads to excessive production of amyloid precursor protein, contributing to early Alzheimer's disease pathology 2
• The region from distal 21q22.1 to 21qter appears particularly important for facial features, heart defects, and mental retardation 3

Life Expectancy and Quality of Life

• Individuals with Down syndrome without congenital heart disease can live beyond 60 years of age 1
• Life expectancy has significantly improved with better medical care and social support
• Quality of life is affected by multiple comorbidities requiring ongoing medical management
• Early-onset Alzheimer's disease is a major factor affecting quality of life in older adults with Down syndrome 2

Management Implications

• Regular screening for common comorbidities is essential throughout life
• Early intervention for developmental issues
• Cardiac monitoring and management
• Screening for Alzheimer's disease after age 40 2
• Comprehensive care addressing both physical and cognitive needs

Down syndrome represents a complex genetic disorder where the extra chromosome 21 affects multiple body systems through gene dosage effects, resulting in lifelong health challenges that require specialized medical care.