Cardiomyopathy and mitochondrial encephalomyopathy in a female child associated with a heterozygous X-linked AIFM1 variant.

backgroundAIFM1 encodes the X-linked oxidoreductase 'apoptosis-inducing factor 1, mitochondrial' that mediates caspase-independent programmed cell death and is involved in redox metabolism. To date, cardiac involvement has been reported in four patients with AIFM1 variants, primarily presenting as ventricular hypertrophy, but its clinical course and prognosis remain not well understood.

methodsWe report the first affected female with a heterozygous AIFM1 variant who developed infantile-onset mitochondrial encephalomyopathy and cardiomyopathy with initial ventricular hypertrophy, that progressed to left ventricular dilation and chronic heart failure. In addition, we review the available literature on AIFM1-associated cardiomyopathy to contextualize clinical findings.

resultsGenetic testing identified a heterozygous AIFM1 variant, c.506C > T (p.Pro169Leu), with extremely skewed X-inactivation (98:2) in a female. The patient presented with infantile-onset mitochondrial encephalomyopathy. Echocardiography at 8 months revealed marked left ventricular hypertrophy with preserved systolic function. During follow-up, the cardiac phenotype progressively evolved into dilated cardiomyopathy with systolic dysfunction by 2.5 years of age, necessitating initiation of heart failure therapy.

conclusionsA heterozygous AIFM1 variant can result in disease manifestation in females. The phenotypic spectrum of AIFM1-related disease includes cardiomyopathy, typically characterized by early-onset cardiac hypertrophy that may progress to ventricular dilatation and heart failure. This case highlights the importance of early recognition and careful cardiac monitoring in affected individuals, including female variant carriers.