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 �- and four �-subunits that catalyzes three steps in the �-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 polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patient mutations in exon 9 of the �-subunit. One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at residue 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 codon. This study suggests a novel genotype–phenotype correlation in TFP deficiency; that is, mutations in exon 9 of the �-subunit, which encodes a linker domain between the NH 2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neuromuscula