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Down's syndrome

Epidemiology: 1) 1 in 600 live births 2) frequency increases with maternal age > 36 years Pathology: 1) congenital heart disease a) atrioventricular septal defect b) atrial septal defect c) ventricular septal defect d) tetralogy of Fallot 2) predisposition to early Alzheimer's disease (AD) a) diffuse amyloid deposits in limbic & association cortex observed in teenage years b) cerebral amyloid angiopathy [20] c) neuritic plaques & neurofibrillary tangles observed in patients in their 30s & 40s d) neuroinflammation, & brain atrophy [20] e) AD pathology observed ONLY when 3 copies of APP gene are present f) ref [13] suggests APP not overexpressed in brain of patients with Down syndrome Genetics: - trisomy 21 - defects or deficiency of SNX27 [8] - apoE4 allele linked to clinical expression & biomarkers* of Alzheimer's disease [20] * CSF amyloid-beta, amyloid PET, plasma phosphorylated tau181, cerebral glucose hypometabolism & hippocampal atrophy (carriers vs non-carriers of apoE4 allele) [20] Clinical manifestations: 1) hypotonia 2) hyperextensible joints 3) mongoloid facies 4) mental retardation 5) protruding tongue 6) dementia at an early but variable age (50-70 years) [20] a) earlier frontal lobe manifestations - slowing of speech & motor activities b) social withdrawal c) insomnia d) balance disorder e) emotional lability [5] f) dementia only in 25% of patients by age 60 7) premature age-related changes - early onset menopause - diabetes mellitus Laboratory: - amniocentesis with genetic karyotyping - trisomy 21 - maternal screen for fetal abnormalities panel in serum/plasma - multiplexed maternal plasma DNA sequencing - serum hCG, serum estriol, serum alpha-fetoprotein (triple screen) Complications: - obesity, hypognathia & hypotonia may result in obstructive sleep apnea [5] - diabetes mellitus type 2 - congenital heart disease,in 1.2-5.2% - pulmonary-artery hypertension associate with - obstructive sleep apnea, gastroesophageal reflux,obesity,[16] - respiratory disease common - risk of malignancy: acute myeloid leukemia, testicular cancer [16] - autoimmune disorders - Hashimoto's thyroiditis*, type 1 diabetes, alopecia, celiac disease, juvenile idiopathic arthritis, vitiligo [16] - early mortality - life expectancy < 60 years [11]; 60 years [18] - ref [5] implies it is longer - dementia, functional decline, seizures, visual impairment & institutionalization predict mortality [10] - ~5-fold risk for COVID-19 hospitalization & ~10-fold risk for COVID-19 mortality [19] * incidence of thyroid disease 50% by age 45 years [16] Management: 1) cholinesterase inhibitors not effective for treatment of dementia [5,12] - may be of some benefit in adolescents [6] - treat as Alzheimer's disease (low-dose donepezil) [5] 2) memantine not effective for treatment of dementia [5,7,12] 3) pulsatile GnRH therapy improves cognition & brain connectivity in adults with Down's syndrome [21] 4) prognosis - life expectancy < 60 years [11]; 60 years [18] - marked racial & temporal differences in prognosis [3] - caucasian: 50 years (1997); 2 years (1968) - black: - 25 years (1997); < 5 years (1985); < 1 year (1967) c) other races: 11 years (1997); < 1 year (1967)

Related

Alzheimer's disease (AD) APP gene human chromosome-21

General

developmental disorder syndrome (multisystem disorder) genetic syndrome (multisystem disorder)

Properties

ASSOCIATED-NEOPLASM[S]: acute lymphoblastic leukemia (ALL) acute myeloid leukemia (AML) AML-M7; acute megakaryoblastic leukemia

Database Correlations

OMIM 190685

References

  1. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 380
  2. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
  3. Journal Watch 21(14):116, 2001 MMWR Morb Mortal Wkly Rep 50:463, 2001
  4. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  5. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004 - Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  6. Heller JH et al, Safety and efficacy of rivastigmine in adolescents with Down's syndrome: A preliminary 20-week, open label study. J Child Adolesc Psychopharmacol 2006, 16:755 PMID: 17201619
  7. Hanney M et al. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): A randomised, double-blind, placebo-controlled trial. Lancet 2012 Feb 11; 379:528. PMID: 22236802
  8. Jones MW. Sorting receptors at Down's syndrome synapses. Nat Med. 2013 Apr;19(4):404-6 PMID: 23558625
  9. Adorno M, Sikandar S, Mitra SS et al Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature. 2013 Sep 19;501(7467):380-4 PMID: 24025767
  10. Coppus AM1, Evenhuis HM, Verberne GJ et al Survival in elderly persons with Down syndrome. J Am Geriatr Soc. 2008 Dec;56(12):2311-6 PMID: 19093931
  11. Esbensen AJ Health conditions associated with aging and end of life of adults with Down syndrome. Int Rev Res Ment Retard. 2010;39(C):107-126. PMID: 21197120
  12. Livingston G, Strydom A. Improving Alzheimer's disease outcomes in Down's syndrome. Lancet. 2012 Feb 11;379(9815):498-500 PMID: 22236803
  13. Argellati F, Massone S, d'Abramo C et al Evidence against the overexpression of APP in Down syndrome. IUBMB Life. 2006 Feb;58(2):103-6. PMID: 16608822
  14. Esbensen AJ. Health conditions associated with aging and end of life of adults with Down syndrome. Int Rev Res Ment Retard. 2010;39(C):107-126. PMID: 21197120
  15. Esbensen AJ, Mailick MR, Silverman W. Long-term impact of parental well-being on adult outcomes and dementia status in individuals with Down syndrome. Am J Intellect Dev Disabil. 2013 Jul;118(4):294-309. PMID: 23937371 Free PMC Article
  16. Rothaus C Down Syndrome NEJM Resident 360. June 10, 2020 https://resident360.nejm.org/clinical-pearls/down-syndrome
  17. Fortea J et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: A cross-sectional study. Lancet 2020 Jun 27; 395:1988. PMID: 32593336 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30689-9/fulltext - Head E, Ances B. Biomarkers in Down syndrome can help us understand Alzheimer's disease. Lancet 2020 Jun 27; 395:1951 PMID: 32593327 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30916-8/fulltext
  18. Tsou AY, Bulova P, Capone G et al Medical Care of Adults With Down Syndrome. A Clinical Guideline. JAMA. 2020;324(15):1543-1556. Oct 20, PMID: 33079159 https://jamanetwork.com/journals/jama/fullarticle/2771907 - Woodward JF, Jan S, Ciccarelli MR. Guidelines for Care of Adults With Down Syndrome. JAMA. 2020;324(15):1509-1511. Oct 20 PMID: 33079137 https://jamanetwork.com/journals/jama/fullarticle/2771878
  19. Clift AK et al COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study Of 8 Million Adults. Ann Intern Med 2020. Oct 21 PMID: 33085509 https://www.acpjournals.org/doi/10.7326/M20-4986
  20. George J APOE Gene Influences Alzheimer's Symptoms, Biomarkers in Down Syndrome. Earlier Alzheimer's changes seen in APOE4 carriers. MedPage Today July 6, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/93442 - Bejanin A, Iulita MF, Vilaplana E et al Association of Apolipoprotein E epsilon4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome. JAMA Neurol. Published online July 6, 2021. PMID: 34228042 https://jamanetwork.com/journals/jamaneurology/fullarticle/2781524 - Lemere CA, Head E, Holtzman DM APOE epsilon4 Association With Cognition and Alzheimer Disease Biomarkers in Down Syndrome - Implications for Clinical Trials and Treatments for All. JAMA Neurol. Published online July 6, 2021 PMID: 34228117 https://jamanetwork.com/journals/jamaneurology/article-abstract/27815277
  21. Manfredi-Lozano M et al. GnRH replacement rescues cognition in Down syndrome. Science 2022 Sep 2; 377:1064. PMID: 36048943 https://www.science.org/doi/10.1126/science.abq4515