HADHB – Mitochondrial Trifunctional Protein Deficiency

Mitochondrial trifunctional protein deficiency is an autosomal recessive disorder caused by loss-of-function mutations in the HADHB gene, which encodes the β-subunit long-chain ketoacyl-CoA thiolase of the mitochondrial trifunctional enzyme complex (HADHB; Mitochondrial Trifunctional Protein Deficiency). Affected individuals present with energy deficiency on long-chain fatty acid oxidation leading to hypoketotic hypoglycemia, cardiomyopathy, neuropathy, and sudden death.

Genetic evidence supports a definitive gene–disease relationship. More than 27 unrelated families have been reported with biallelic HADHB mutations segregating with disease ([PMID:12754706]). Case series include 14 Japanese patients with complete enzyme deficiency and heterogeneous clinical types, correlating mutational location with neonatal, hepatic, or neuromyopathic phenotypes ([PMID:19699128]). A recurrent missense variant, c.1364T>G (p.Val455Gly), has been identified in both lethal and myopathic phenotypes ([PMID:19880769]).

The inheritance is autosomal recessive with compound heterozygous or homozygous LoF alleles. Segregation in sibships confirms pathogenicity, including two siblings with deep intronic and frameshift variants ([PMID:39723123]). More than 50 distinct pathogenic variants have been described across >150 probands, comprising missense, splicing, frameshift, and large deletions ([PMID:12754706]; [PMID:31521624]).

Phenotypic spectrum ranges from infantile cardiomyopathy, Reye-like episodes, and sudden neonatal death to later-onset polyneuropathy with episodic rhabdomyolysis ([PMID:10400133]; [PMID:14694500]). Key clinical features include hypoketotic hypoglycemia (HP:0001985), cardiomyopathy (HP:0001638), and peripheral neuropathy (HP:0009830).

Functional studies demonstrate markedly reduced β-thiolase activity in patient fibroblasts and lymphocytes. Isolated long-chain ketoacyl-CoA thiolase deficiency was confirmed in a newborn with preserved dehydrogenase activity ([PMID:16423905]). Thermo-sensitive mutations (e.g., p.Thr133Ala) show temperature-dependent stability loss in vitro ([PMID:31521624]).

Therapeutic insights include successful dietary management and medium-chain triglyceride supplementation. Bezafibrate treatment improved myopathic attacks in compound heterozygotes for c.1175C>T/c.1364T>G by enhancing residual enzyme expression ([PMID:32509533]).

No studies have refuted the HADHB–TFP deficiency association. Molecular diagnosis via newborn screening and gene panels is recommended for early intervention. Key take-home: HADHB should be included in diagnostic genetic panels for fatty acid oxidation disorders to enable prompt metabolic management and genetic counseling.

References

• Human mutation • 2003 • Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations PMID:12754706
• Molecular genetics and metabolism • 2009 • Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency PMID:19699128
• Annals of clinical and laboratory science • 2009 • Two novel HADHB gene mutations in a Korean patient with mitochondrial trifunctional protein deficiency PMID:19880769
• Journal of inherited metabolic disease • 1999 • Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis PMID:10400133
• Muscle & nerve • 2004 • Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein PMID:14694500
• Clinical chemistry • 2006 • Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene PMID:16423905
• Mitochondrion • 2019 • Identification and functional characterization of mutations within HADHB associated with mitochondrial trifunctional protein deficiency PMID:31521624
• Molecular genetics and metabolism reports • 2020 • Efficacy of bezafibrate in two patients with mitochondrial trifunctional protein deficiency PMID:32509533
• JIMD reports • 2025 • Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing PMID:39723123

Evidence Based Scoring (AI generated)