FASTKD2 – Combined Oxidative Phosphorylation Deficiency 44

Combined oxidative phosphorylation deficiency 44 (COXPD44) is an autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in FASTKD2. We report two siblings with episodic acute encephalomyopathy triggered by infection, haematological abnormalities, rhabdomyolysis, acute kidney injury and early death, who harbor compound heterozygous missense FASTKD2 variants detected by whole-exome sequencing and confirmed by segregation in one family ([PMID:39575950]). Both siblings exhibited reduced complex IV activity in muscle and decreased ATP production in fibroblasts, consistent with COXPD44.

Functional studies have demonstrated that FASTKD2 loss-of-function mutations cause multi-OXPHOS complex deficiencies. In patient-derived cells, cell-based complementation assays and enzymatic analyses confirm that FASTKD2 variants impair mitochondrial respiratory chain assembly and ATP synthesis. In vivo knockdown in zebrafish recapitulates mitochondrial dysfunction, supporting a mechanism of loss of function ([PMID:31944455]).

Key Take-home: Biallelic FASTKD2 variants underlie COXPD44 and should be included in diagnostic gene panels for mitochondrial encephalomyopathy.

References

• Annals of human genetics • 2024 • Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review PMID:39575950
• Human Mutation • 2020 • Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency PMID:31944455

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