Abstract Details

Title Infantile Mitochondrial Encephalomyopathy Due to a Novel Mutation in ACAD9

Topic Child Neurology/Developmental Neurobiology

Presentation(s) P03 - (-)

Poster/Presentation
Number 017

Objective

Background BACKGROUND: Complex I deficiency is the most common respiratory chain defect with early-onset fatal encephalomyopathy. Although many molecular defects have been described both in structural subunits and in assembly factors, the genetic diagnosis remains unknown in a large cohort of patients.

Design/Methods DESIGN/METHODS: We carried out biochemical and molecular studies in muscle and cultured fibroblasts from a patient with infantile mitochondrial encephalomyopathy. Next generation exome sequencing with a mitochondrial gene library (MitoExome) was applied to identify the molecular defect.

Results RESULTS: A 9-year-old Italian boy had severe infantile-onset myopathy with exercise intolerance, weakness, muscle wasting. He also had mental retardation and severe complex I deficiency. Metabolic workup showed increased levels of plasma lactic acid, acylcarnitine C0, and alanine, and thyroid dysfunction. EMG was compatible with a myopathic process and muscle biopsy revealed mitochondrial proliferation. Cardiac function was normal and there were no abnormalities of brain MRI. Biochemical studies showed severe complex I and moderate complex III deficiencies both in muscle and in fibroblasts. Western blot analysis of mtDNA-encoded respiratory chain components showed reduced protein level of complex I. MitoExome sequencing revealed a new homozygous mutation in ACAD9 gene (p.R414C) that was confirmed by Sanger sequence and found in heterozygosity in both parents. Improvement of muscle strength was reported after treatment with high-dose riboflavin.

Conclusions CONCLUSIONS: ACAD9 is a complex I assembly factor whose defects have been associated with a protean clinical spectrum spanning from pure myopathy with exercise intolerance and lactic acidosis to rapidly progressive encephalomyopathy and hypertrophic cardiomyopathy. Our case contributes adds to the clinical heterogeneity of ACAD9 deficiency and confirms the importance of assembly factors in causing complex I deficiency.

Authors/Disclosures
Caterina Garone PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Beatriz Garcia-Diaz	No disclosure on file
	No disclosure on file
	No disclosure on file
Krzysztof W. Selmaj (University of Warmia and Mazury)	Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astra. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astra. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.

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