Interpretation of Test Results

The majority of mutations identified in ACADM are missense mutations located away from the active center of the enzyme, and are thought to affect the overall stability of the protein by affecting proper protein folding (Figure 8-2).24 Most patients exhibit the classic MCAD phenotype; however, a small subset of patients has been identified that is compound heterozygous for the A304E mutation or for two other mutations, where at least one mutation is present that does not eliminate MCAD activity. These patients are much less likely to experience metabolic decompensation; however, even mildly symptomatic patients should avoid circumstances that could precipitate a metabolic crisis,

Figure 8-2. Schematic representation of a human MCAD monomer based on the crystal structure with cofactor flavin adenine dinucleotide (FAD) (black) and bound C8-CoA substrate (darker gray).The side chains for residues in which missense mutations have been published are shown in ball-and-stick representation. Only one of these mutations (T168A) is located in close proximity to the active site, forming a hydrogen bond to the flavin N(5) of FAD. (Reprinted from Gregersen N, Andresen BS, Corydon MJ, et al. Mutation analysis in mitochondrial fatty acid oxidation defects: exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Human Mutation 18(3):169-189, by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.,© 2001.)

1350T M30IT

K304E Y327C









since there is variability in age of onset even with classic MCAD deficiency.


Genetic disorders of peroxisomal biogenesis and function have severe phenotypic consequences that often result in death in early childhood. A number of important metabolic processes, including P-oxidation of long- and very-long-chain fatty acids and the degradation of H2O2, take place in the unique microenvironment of the single-membrane-bound matrix of the peroxisome. Whereas the symptoms of most metabolic diseases manifest after birth, disorders of peroxisome biogenesis, such as Zellweger syndrome, are associated with multiple congenital anomalies (for review, see Reference 25). In this section, X-linked adrenoleukody-strophy (X-ALD) is highlighted, as it is the most common of the peroxisomal disorders and one of the few for which clinical molecular genetic testing is available.

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