Objective:

To describe a rare presentation of Mitochondrial Trifunctional Protein Deficiency (MTPD).

Background:

Biallelic pathogenic variants in the HADHA and HADHB genes cause MTPD, a rare metabolic disorder affecting mitochondrial β-oxidation. Although MTPD usually presents in infancy with cardiomyopathy and hepatic failure, it can manifest with isolated neuromuscular features, such as myopathy and/or neuropathy.

Design/Methods:

Two unrelated patients with progressive distal weakness and foot deformities were evaluated clinically, electrophysiologically, and genetically.

Results:

Case 1: A 19-year-old woman with progressive gait difficulty since early childhood presented with distal muscle weakness, pes cavus, areflexia, and decreased vibration sense. Her parents were consanguineous. Nerve conduction studies revealed sensory and motor axonal polyneuropathy. Whole-exome sequencing identified a homozygous HADHA (NM_000182.5) variant, c.955G>A (p.Gly319Ser), classified as likely pathogenic. Case 2: A 39-year-old man, born to consanguineous parents, presented with gait difficulty from childhood. He exhibited similar distal weakness with mild proximal involvement and calf pseudohypertrophy. Electrophysiology showed sensory and motor axonal polyneuropathy with a median motor conduction velocity of 50 m/s. Whole-exome sequencing revealed a homozygous HADHB (NM_000183.3) variant, c.740G>A (p.Arg247His), classified as pathogenic.

Conclusions:

MTPD can present with isolated peripheral neuropathy resembling CMT, occasionally with subclinical myopathy. As HADHA and HADHB genes are not routinely included in standard CMT panels, clinicians should consider these genes in patients with unexplained hereditary axonal neuropathy.