TAFAZZIN – Barth Syndrome

TAFAZZIN (TAZ) encodes a mitochondrial phospholipid transacylase essential for cardiolipin remodeling in the inner mitochondrial membrane. Barth syndrome is an X-linked recessive multisystem disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, growth delay, and 3-methylglutaconic aciduria (MONDO:0010543). Mutations in TAZ disrupt cardiolipin maturation, leading to mitochondrial dysfunction and the characteristic clinical phenotype.

Genetic evidence supports a definitive association between TAZ and Barth syndrome. Over 22 unrelated probands with pathogenic TAZ variants have been reported nationwide (PMID:23656970), including six cases across four families demonstrating co-segregation (PMID:8042670). The inheritance follows an X-linked recessive pattern with male‐specific hemizygosity; female carriers are generally asymptomatic unless mosaicism or structural X anomalies occur. A recurrent missense variant, c.280C>A (p.Arg94Ser), has been described in a Japanese patient presenting with cardiomyopathy and 3-methylglutaconic aciduria (PMID:12032589).

The variant spectrum in Barth syndrome encompasses missense substitutions (e.g., p.Arg94Ser), nonsense mutations introducing premature stop codons, splice‐site alterations, small insertions/deletions causing frameshifts, and large intragenic deletions. Loss-of-function alleles predominate, consistent with a mechanism of defective cardiolipin remodeling. No common founder effects have been established, reflecting considerable allelic heterogeneity across diverse populations.

Functional studies corroborate the pathomechanism of TAZ deficiency. Patient‐derived cells exhibit reduced cardiolipin content and elevated monolysocardiolipin levels, impairing mitochondrial respiratory chain assembly and membrane potential. A Drosophila TAZ knockout recapitulates Barth-related mitochondrial and motor deficits, confirming conserved in vivo function (PMID:16855048). AAV9-mediated TAZ gene replacement in a mouse model restores cardiolipin remodeling, improves cardiac output, and rescues skeletal muscle function, demonstrating proof-of-concept for gene therapy (PMID:30070157).

No significant conflicting evidence has been reported; individuals with normal TAZ sequencing but BTHS-like biochemistry have been shown to have wild-type TAZ, reinforcing gene specificity. Alternative disease genes have not been implicated in classic Barth presentations.

In summary, genetic and experimental data establish a definitive TAFAZZIN–Barth syndrome relationship. Comprehensive TAZ sequencing and cardiolipin profiling enable accurate diagnosis. Emerging gene therapy approaches targeting TAZ hold promise for clinical translation by correcting the underlying cardiolipin defect.

Key Take-home: TAFAZZIN loss-of-function variants cause Barth syndrome via impaired cardiolipin remodeling; molecular diagnosis informs management, and gene replacement restores mitochondrial function.

References

• Orphanet Journal of Rare Diseases • 2013 • Natural history of Barth syndrome: a national cohort study of 22 patients PMID:23656970
• American Journal of Medical Genetics • 1994 • Barth syndrome: clinical observations and genetic linkage studies PMID:8042670
• Journal of Human Genetics • 2002 • Novel missense mutation (R94S) in the TAZ (G4.5) gene in a Japanese patient with Barth syndrome PMID:12032589
• Proceedings of the National Academy of Sciences USA • 2006 • A Drosophila model of Barth syndrome PMID:16855048
• Human Gene Therapy • 2019 • AAV-Mediated TAZ Gene Replacement Restores Mitochondrial and Cardioskeletal Function in Barth Syndrome PMID:30070157

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