Mendelian forms of complex I deficiency are usually associated with fatal infantile encephalomyopathy. Application of “MitoExome” sequencing (deep sequencing of the entire mitochondrial genome and the coding exons of >1000 nuclear genes encoding the mitochondrial proteome) allowed us to reveal an unusual clinical variant of complex I deficiency due to a novel homozygous mutation in ACAD9. The patient had an infantile-onset but slowly progressive encephalomyopathy and responded favorably to riboflavin therapy.
A 13-year-old boy had exercise intolerance, weakness, and mild psychomotor delay. Muscle histochemistry showed mitochondrial proliferation, and biochemical analysis revealed severe complex I deficiency (15% of normal). The level of complex I holoprotein was reduced as determined by use of Western blot both in muscle (54%) and in fibroblasts (57%).
Conclusions and Relevance
The clinical presentation of complex I deficiency due ACAD9 mutations spans from fatal infantile encephalocardiomyopathy to mild encephalomyopathy. Our data support the notion that ACAD9 functions as a complex I assembly protein. ACAD9 is a flavin adenine dinucleotide–containing flavoprotein, and treatment with riboflavin is advisable.
The patient at 13 years of age shows scoliosis and truncal obesity (A); Gomori trichrome (B [original magnification ×20]) and cytochrome c oxidase (C [original magnification ×20]) histochemical stains show mitochondrial proliferation. Images of Western blot analysis of oxidative phosphorylation proteins (D) in the fibroblasts (left) and muscle (right) of the patient (P) and controls (C) are shown. I indicates complex; II, complex II; III, complex III; IV, complex IV; and V, complex V. The electropherogram of the patient’s DNA shows the variant (c.1240C>T) and evolutionary conservation of the mutated amino acid (E).
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