Phenotypic spectrum of SLC25A4 mutations

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• The phenotypic variability in patients with SLC25A4 mutations is not well-documented.
• SLC25A4 gene mutations are linked to mitochondrial disorders.

Purpose of the Study:

• To review and discuss the clinical presentation and phenotypic heterogeneity of SLC25A4 mutations.
• To provide a comprehensive overview of SLC25A4 mutation phenotypes.

Main Methods:

• Systematic literature review.
• Search terms included 'mitochondrial', 'myopathy', 'nuclear DNA', 'mitochondrial DNA', 'SLC25A4', and 'AAC1'.

Main Results:

• Phenotypic heterogeneity of SLC25A4 mutations is broader than anticipated.
• Manifestations include encephalo-myo-cardiomyopathy, scoliosis, cataract, depression, headache, hydrocephalus, and arterial hypertension.
• SLC25A4 mutations can cause mitochondrial DNA (mtDNA) depletion or multiple mtDNA deletions, with depletion resulting in a more severe phenotype and worse prognosis.

Conclusions:

• SLC25A4 mutations are associated with multiorgan abnormalities beyond encephalo-myo-cardiomyopathy.
• mtDNA depletion due to SLC25A4 mutations presents with severe phenotypes, including respiratory insufficiency and cerebral disease.
• Congenital respiratory insufficiency requiring mechanical ventilation is a poor prognostic indicator in SLC25A4-associated mtDNA depletion syndrome.