Pathophysiology examines how a biological condition interferes with the body’s standard operations. Down syndrome is the most prevalent chromosomal disorder in humans, characterized by a wide spectrum of physical and intellectual challenges. The disorder arises from a fundamental error in genetic material, which cascades into various developmental and functional changes throughout an individual’s life.
The Genetic Origin
Down syndrome originates from a chromosomal anomaly involving chromosome 21. In about 95% of cases, the condition is caused by Trisomy 21, meaning every cell in the body contains three copies of chromosome 21 instead of two. This is the result of an error during cell division called nondisjunction. During the formation of reproductive cells, a pair of chromosome 21s fails to separate, leading to an egg or sperm cell with an extra chromosome. While this error can occur in either parent, the extra chromosome most often originates from the mother’s egg, and the chances of this increase with maternal age.
Less common mechanisms can also result in Down syndrome. Translocation Down syndrome accounts for about 3-4% of cases and occurs when a portion of chromosome 21 breaks off and attaches to another chromosome, often chromosome 14. Even though the total chromosome count remains 46, the presence of the extra piece of chromosome 21 leads to the characteristics of the syndrome. Another form, Mosaic Down syndrome, is found in about 2% of cases, where the error in cell division happens after fertilization, resulting in a mixture of two cell lines.
The Gene Dosage Effect
The presence of an extra full or partial chromosome 21 is the foundational cause of Down syndrome’s characteristics. This additional genetic material leads to a “gene dosage effect.” With three copies of the genes on chromosome 21 instead of the usual two, the cells produce an excess of the proteins encoded by these genes. This overexpression disrupts the biochemical environment required for typical development and cellular function.
Chromosome 21 is the smallest human chromosome, but it contains hundreds of genes involved in early development. The overproduction of these proteins interferes with complex cellular pathways. Scientists have identified specific sections of the chromosome, known as “Down Syndrome Critical Regions” (DSCRs), which house genes that are major contributors to the syndrome’s features. This concept helps researchers narrow their focus to understand which overexpressed genes are linked to specific traits.
One such gene that has been studied extensively is DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A). This gene is located on chromosome 21 and plays a part in brain development. The overexpression of the DYRK1A protein is thought to be a significant factor in the cognitive and intellectual disabilities associated with Down syndrome.
Neurological System Impact
The gene dosage effect has significant implications for the neurological system’s development and function. The overexpression of genes on chromosome 21 contributes to differences in brain structure. Individuals with Down syndrome often have a smaller brain, with specific reductions in the volume of the cerebellum and hippocampus. These areas are involved in motor coordination and memory.
These structural alterations are accompanied by changes at the cellular level. The intricate network of connections between neurons, known as synapses, can be affected. The processes governing synaptic plasticity, the ability of these connections to strengthen or weaken over time, are altered, which impacts learning and memory formation.
A significant neurological consequence seen later in life is an increased risk for developing early-onset Alzheimer’s disease. This connection is directly tied to the gene dosage effect. The gene that codes for amyloid precursor protein (APP) is located on chromosome 21. The lifelong overexpression of APP leads to a higher accumulation of amyloid-beta plaques in the brain, a hallmark pathological feature of Alzheimer’s.
Systemic Health Consequences
The impact of having an extra copy of chromosome 21 extends beyond the nervous system, affecting multiple organs and bodily functions. One of the most significant health concerns is the high incidence of congenital heart defects, present in about half of all infants born with Down syndrome. These structural heart issues, such as septal defects, are a direct result of genetic overexpression disrupting heart formation in the embryo.
The immune system is also commonly affected. Individuals with Down syndrome often experience immune dysregulation, which makes them more susceptible to infections. This altered immune response also increases the prevalence of autoimmune disorders, where the immune system mistakenly attacks the body’s own tissues, such as hypothyroidism and celiac disease.
Other systems can also be involved. Gastrointestinal issues, such as duodenal atresia (a blockage in the first part of the small intestine), occur with greater frequency. There is also an elevated risk for certain types of blood cancers, specifically leukemia, in childhood.