Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (422 page)

   BCKAD enzyme activity.

Molecular diagnostic testing:

   Gene sequencing and mutation analysis of the three genes: BCKDHA, BCKDHB, and DBT

   Deletion/duplication analysis of the three genes BCKDHA, BCKDHB, and DBT

Molecular carrier testing: Targeted mutation analysis if the mutation is known.

Molecular prenatal testing: Targeted mutation analysis after familial mutation has been identified.

Suggested Reading

Strauss KA, Puffenberger EG, Morton DH. Maple syrup urine disease. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews
^™
[Internet]
. Seattle, WA: University of Washington, Seattle; 2006:1993–2013 [Updated 2013 May 9]. Available from:
http://www.ncbi.nlm.nih.gov/books/ NBK1319/

PHENYLKETONURIA (FOLLING DISEASE; PKU)

MIM #261600

   Definition

   Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If untreated causes mental retardation, but with early diagnosis, it is treatable with dietary therapy.

   Relevant Tests and Diagnostic Value

PAH deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using a blood spot obtained from a heel prick. Normal blood phenylalanine levels are 58 ± 15 μmol/L in adults, 60 ± 13 μmol/L in teenagers, and 62 ± 18 μmol/L (mean ± SD) in childhood. In the newborn, the upper limit of normal is 120 μmol/L (2 mg/dL). In untreated classical PKU, blood levels as high as 2.4 mM/L can be found.

Molecular genetic testing of PAH is used primarily for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.

Suggested Readings

Blau N, van Spronsen FJ, Levy HL. Phenylketonuria.
Lancet.
2010;376:1417–1427.

Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift.
Hum Mutat.
2007;28: 831–845.

   
LYSOSOMAL STORAGE DISORDERS

CANAVAN DISEASE

MIM #271900

   Definition

Canavan disease is an autosomal recessive disorder caused by mutations in the gene encoding aspartoacylase (ASPA) that results in progressive damage of nerve cells in the brain. This disease belongs to a group of genetic disorders called leukodystrophies, which are characterized by degeneration of myelin.

   Relevant Tests and Diagnostic Value

The diagnosis of neonatal/infantile Canavan disease is possible by demonstration of very high concentration of
N
-acetyl aspartic acid (NAA) in the urine. In mild/ juvenile Canavan disease, NAA may only be slightly elevated. The aspartoacylase enzyme activity is not a reliable test.
Molecular genetic testing
—the diagnosis relies on molecular genetic testing of ASPA gene.

   Targeted mutation analysis—testing for three mutations in the ASPA gene: Glu285Ala, p.Tyr231X, and p.Ala305Glu detect 98% of disease alleles in the Ashkenazi population and 30–60% of disease alleles in the non-Ashkenazi European population.

   Sequence analysis of the ASPA coding region is recommended for individuals in whom mutations were not identified by targeted mutation analysis.