MILD TRIFUNCTIONAL PROTEIN-DEFICIENCY IS ASSOCIATED WITH PROGRESSIVE NEUROPATHY AND MYOPATHY AND SUGGESTS A NOVEL GENOTYPE-PHENOTYPE CORRELATION

Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the b eta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropath y and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patien t mutations in exon 9 of the alpha-subunit, One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at re sidue 246. The second patient is a compound heterozygote for the T914A that substitutes asparagine for isoleucine at residue 269 and a C871T that creates a premature termination at residue 255. Allele-specific oligonucleotide hybridization studies revealed undetectable levels of the mRNA corresponding to the mutant allele carrying the termination c odon. This study suggests a novel genotype-phenotype correlation in TF P deficiency; that is, mutations in exon 9 of the alpha-subunit, which encodes a linker domain between the NH2-terminal hydratase and the CO OH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neurom uscular phenotype.