Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

Abstract

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 neuromuscular phenotype. ( J. Clin. Invest. 1998. 102:1193-1199.)

Isolated Mitochondrial Long-Chain Ketoacyl-CoA Thiolase Deficiency Resulting from Mutations in the HADHB Gene

“…Many patients belong to the group with isolated LCHAD deficiency, with homozygosity for the 1528GϾC mutation in the HADHA gene (11 ). Generalized MTP deficiency as a result of mutations in the HADHA gene has been reported in 15 individuals (3,8,(12)(13)(14)(15)(16)(17)(18)(19), whereas generalized MTP deficiency as a result of a mutation in the HADHB gene has been reported in 19 patients. Until 2003, only 4 patients with this kind of MTP deficiency had been reported (15,20 ).…”

Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to ?-subunit mutations

“…Overall, the heterogeneous phenotypes in patients with TFP deficiency due to either a-or b-subunit mutations are similar [Hintz et al, 2002;Ibdah et al, 1998;Schaefer et al, 1996]. Because both subunits and their association are essential for stabilizing the trifunctional protein complex [Ushikubo et al, 1996], this observation may not be surprising.…”

“…Because six of 13 unrelated patients shared missense mutations at positions 176 or 181-182 on exon 4, we speculate that this region of exon 4 might be a mutational hot spot for b-subunit mutations. a-subunit mutations resulting in TFP deficiency are also molecularly heterogeneous and are not confined to a certain domain of the protein [Brackett et al, 1995;Ibdah et al, 1998;Ibdah et al, 1999;Matern et al, 1999;Hintz et al, 2002].…”

“…To date, 15 patients from 12 families with TFP deficiency due to a-subunit mutations are known [Ushikubo et al, 1996;Schaefer et al, 1996;Isaacs et al, 1996;Ibdah et al, 1998;Ibdah et al, 1999;Matern et al, 1999;Hintz et al, 2002;three patients unpublished]. In contrast, only four patients with TFP deficiency due to b-subunit mutations have been reported [Ushikubo et al, 1996;Orii et al, 1997].…”

Long-Chain L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency: A Molecular and Biochemical Review

“…The HADHA gene defects include the following: a 71-bp deletion at position 110 -180 (Ushikubo et al, 1996); a T845A mutation that substitutes aspartic acid for valine at residue 246, a T914A mutation that substitutes asparagine for isoleucine at residue 269, and a C871T mutation that creates a premature termination at residue 255 (Ibdah et al, 1998); mutations in the 5' donor splice site following exon 3-a G to A substitution at the invariant position ϩ1 and an A to G substitution at position ϩ3, both apparently causing exon 3 skipping (Brackett et al, 1995); and a C to T mutation (C1678T) in exon 16 that creates a premature termination codon (R524Stop) in the LCHAD domain (Isaacs et al, 1996).…”