Mitochondrial Trifunctional Protein Deficiency due to HADHA Variants Masquerading as Charcot-Marie-Tooth Disease

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Mitochondrial trifunctional protein deficiency (MTPD) is an inherited metabolic disorder affecting fatty acid beta-oxidation.
• Caused by mutations in HADHA or HADHB genes, MTPD typically manifests in childhood with cardiomyopathy or liver failure.
• Adult-onset neuromyopathic forms of MTPD are rare.

Observation:

• A 40-year-old man presented with isolated axonal neuropathy, diagnosed as Charcot-Marie-Tooth disease (CMT) in childhood.
• Symptoms included pes cavus, distal limb weakness, sensory loss, and fatigability.
• Neurological decompensation occurred during a chest infection, without rhabdomyolysis.

Findings:

• Neurophysiological studies revealed a non-length-dependent axonal sensorimotor neuropathy.
• Genetic testing identified compound heterozygous HADHA variants, including a novel pathogenic variant (c.1003G>A, p.(Glu335Lys)).
• Enzymatic analysis confirmed MTPD.

Implications:

• This case highlights a rare isolated neuropathic phenotype of MTPD.
• MTPD should be considered in the differential diagnosis of CMT, necessitating inclusion in neuropathy gene panels.
• Early MTPD diagnosis is vital for implementing dietary management and preventing severe complications.