Down syndrome occurs due to trisomy of chromosome 21, which also encodes the beta-amyloid precursor protein. Alzheimer disease occurs at an earlier age in patients with Down syndrome due to abnormal metabolism and accumulation of beta-amyloid protein in amyloid plaques.
Down syndrome is characterized by cognitive impairment as well as several potential medical conditions or congenital abnormalities due to an extra copy of chromosome 21. Reported complications of the disease are numerous, including cardiovascular abnormalities, hearing loss, hypothyroidism, increased incidence of leukemia, increased risk of seizures, and signs and symptoms of Alzheimer disease. Age at onset of dementia is not thought to be related to baseline cognitive function.
Smith reviews general medical care for adult patients with Down syndrome and discusses the diagnosis of dementia in these patients. He notes the challenges of making the diagnosis in persons who may have cognitive delays or limitations in verbal communication at baseline. He reports that caregivers more often bring problems to attention than patients themselves. Other causes of apparent dementia in patients with Down syndrome include hypothyroidism, depression, delirium, or vascular dementias.
Wilcock and Griffin discuss the pathogenesis of Alzheimer disease in Down syndrome, including the role of amyloid precursor protein. They also note that there are neuroinflammatory changes, including overexpression of the gene encoding the inflammatory cytokine IL-2, in the brains of children with Down syndrome. This suggests a role of neuroinflammation in the propagation of Alzheimer disease.
Illustration A shows beta-amyloid plaques (dense, oval shaped lesions with amyloid at their core) as well as neurofibrillary tangles (helical shaped, with tau protein at their core), both key pathologic features of Alzheimer disease. Illustration B is a graph comparing prevalence of Alzheimer disease with age among patients with Down syndrome.
Answer 1: Huntington disease is characterized by a CAG trinucleotide repeat.
Answer 3: Although common in patients with Down syndrome, this is unlikely given the normal TSH value.
Answer 4: The most common mutation in cystic fibrosis is a 508 phenylalanine deletion which results in the instability and premature degradation of the CFTR protein.
Answer 5: Folate deficiency is a cause of dementia, especially among those who may eat a diet low in folate as well as take antiepileptics such as carbamazepine or phenytoin that impair folate metabolism. However, since he has stopped taking these medications, this is less likely.
Smith DS. Health care management of adults with Down syndrome. Am Fam Physician. 2001 Sep 15;64(6):1031-8. Review.
PMID:11578024 (Link to Abstract)
Wilcock DM, Griffin WS. Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation. 2013 Jul 16;10:84. doi: 10.1186/1742-2094-10-84. Review.
PMID:23866266 (Link to Abstract)
USMLE World Step 1 QBank Question #950. Copyright © USMLEWorld, LLC 2012