Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (439 page)

   Early-onset familial Alzheimer disease (EOFAD) is associated with multiple affected family members having onset before 65 years (often before 55 years) and/or a mutation in the APP (AD1; 21q21.3), PSEN1(AD3), or PSEN2(AD4) genes that is are known to be associated with EOFAD.

   EOFAD is inherited in an autosomal dominant manner. Children of an affected parent have a 50% chance of inheriting a mutation causing EOFAD and genetic counseling can be helpful to at-risk individuals.

   Additional disease causing mutations remain to be identified.

   Relevant Tests and Diagnostic Value

   Sequence analysis for the A673T mutation in the APP gene that protects against Alzheimer disease and cognitive decline in the elderly without Alzheimer disease.

   Sequence analysis of the PSEN1 gene entire coding and associated intronic regions to detect missense and splice site mutations. Deletion/duplication analysis screening of the entire gene to detect deletions, including the 4,555 bp Finnish population mutation.

   Sequence analysis of the PSEN2 gene entire coding region to detect mutations causing EOFAD.

   Sequence analysis of APP gene exons 16 and 17 identifies most pathologic missense, nonsense, or indel mutations. FISH and other deletion/duplication analysis is useful to detect the <1% pathogenic duplication mutations in APP.

Suggested Readings

American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer’s disease. Statement on use of apolipoprotein E testing for Alzheimer’s disease.
JAMA.
1995;274(20):1627–1629.

Bird TD. Early-onset familial Alzheimer disease. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews
^™
[Internet]
. Seattle, WA: University of Washington, Seattle; 1999:1993–2013 [Updated 2012 Oct 18]. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1236

Cao G, Bales KR, DeMattos RB, et al. Liver X receptor-mediated gene regulation and cholesterol homeostasis in brain: relevance to Alzheimer’s disease therapeutics.
Curr Alzheimer Res.
2007;4(2):179–184.

Jonsson T, et al. A mutation in
APP
protects against Alzheimer’s disease and age-related cognitive decline.
Nature.
2012;488:96–99.

ANGELMAN SYNDROME (AS)

MIM #105830

   Definition

Angelman syndrome is a neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, excessive laughter, jerky movements, and walking and balance disorders. Most cases are caused by absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Approximately 70% of AS cases result from de novo maternal deletions involving chromosome 15q11.2-q13; approximately 2–3% result from paternal uniparental disomy of 15q11.2-q13; 3–5% result from imprinting defects; 5–10% of cases are caused by mutations or deletions in the gene encoding the ubiquitin-protein ligase E3A gene (UBE3A); 1–2% by other chromosomal rearrangements; and 10–15% by unknown causes.

   Relevant Tests and Diagnostic Value

Laboratory diagnostic testing for AS can be complex. The evaluation of an individual suspected of AS may be initiated with DNA methylation analysis of the AS/ PWS imprinting center region.

If the methylation test is positive, additional studies are needed to define which of these genetic mechanisms is present and causes the disease:

   The large common deletion can be tested by FISH (fluorescent in situ hybridization) or array-based comparative genomic hybridization [CGH]).