Prader-Willi Syndrome and Angleman Syndrome


BACKGROUND:

Prader-Willi Syndrome (PWS) is a congenital disorder characterized by hypotonia, weak cry and poor feeding in neonates, followed later in childhood with global developmental delay, hypogonadism, short stature, small hands and feet and hyperphagia leading to obesity. Angelman Syndrome (AS) is a non progressive congenital disorder characterized by profound mental retardation/developmental delay, ataxia, jerky arm movements, macrostomia, tongue thrusting, brachycephaly, seizures unprovoked laughter and absence of speech.

Both disorders arise from lack of expression of distinct (but closely spaced) genes at chromosome location 15q11-q13. In normal circumstances, only the paternally inherited PWS gene is expressed (the maternal copy is silent due to imprinting). Therefore, either a deletion of 15q11-q13 inherited from the father (75% of cases) or maternal chromosome 15 disomy (two chromosome 15s from the mother and none from the father; 25% of cases) results in PWS due to the absence of a paternally derived PWS gene. Conversely, the maternally inherited AS gene is expressed in normal circumstances (the paternal copy is imprinted). A deletion of 15q11-q13 inherited from the mother (80% of cases) or paternal chromosome 15 disomy (two chromosome 15s from the father and none from the mother; 5% of cases) results in AS due to lack of a maternal copy of the AS gene. 15% of AS cases are caused by subtle mutations and are undetectible with current technology.

Laboratory assessment of patients suspected of having PWS or AS includes one or more of the following tests:

  • Routine chromosomal analysis detects other chromosomal abnormalities.

  • Fluorescent in situ hybridization (FISH) detects large and small 15q11-q13 deletions found in both PWS and AS.

  • Analysis of polymorphic markers in the 15q11-q13 area by PCR determines parent of origin of each chromosome 15.

  • Analysis by methylation sensitive PCR reveals deletions as well as chromosome 15 parent of origin.

INDICATIONS FOR TESTING:

  • Confirmation of diagnosis in patients suspected of having PWS or AS based on clinical assessment or previous laboratory analysis.

SAMPLE REQUIREMENTS:

Blood: Two 5 ml purple top (EDTA) vacutainers of whole blood inverted several times to mix. Forward within 48 hours at room temperature.

INTERPRETATION:

Paternal deletions of 15q11-q13 or maternal chromosome 15 disomy is found in virtually all cases of PWS. Maternal deletion of 15q11-q13 or paternal chromosome 15 disomy is found in 85% of AS cases. Report includes background information and an explanation of test results.

COUNSELING ISSUES:

  1. Each of the three tests used has limitations:

    1. FISH analysis requires minimal patient material and no culturing of cells. However, this method does not detect uniparental disomy which is particularly important in PWS.

    2. Linkage analysis by PCR using polymorphic markers has the same advantages of FISH and does detect uniparental disomy. Parental blood samples are necessary, however, for an accurate conclusion to be reached.

    3. Southern blot analysis identifies both the origins of 15q11-q13 deletions and uniparental disomy by detecting methylation differences within the PWS/AS critical region. The limitations are that a significant amount of patient material is needed (two full vacutainers of blood) and the analysis requires several weeks to complete.

  2. The accuracy of the clinical assessment contributes to the likelihood of identifying a deletion or uniparental disomy.

  3. A negative molecular test result, especially in the case of suspicion of AS, does not rule out the clinical diagnosis because point mutations are not detected by these methods.

SPECIAL NOTE:

Analysis for Prader-Willi/Angelman Syndrome can be accomplished by both cytogenetic and molecular methods (see cytogenetic section). The use of those different technologies is complementary. The decision as to which tests are appropriate for any sample is made on a case by case basis. The usual procedure is to perform cytogenetic and FISH studies first and molecular studies if these are negative. Therefore both green and purple top tubes should be submitted for any diagnosis.

 

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