Multiple acyl-CoA dehydrogenase deficiency due to a novel homozygous and compound heterozygous mutation in the ETFDH gene in three South African patients 

Presented By:

Francois H van der Westhuizen (PhD)^a, Izelle Smuts (MBChB, MMed (Pead), PhD)^b, Engela M Honey (MBChB.; MMed (Pead)^c, Michael M Lippert (MBChB, MMed (Pead)^d, Marleen Engelbrecht

(MBChB, MMed (Pead)^d, Maryke Schoonen (MSc)^a, Lindi-Maryn Jonck (MSc)^a, Roan Louw (PhD)^a, Marli Dercksen (PhD)^a

^a Human Metabolomics, North-West University, Potchefstroom, South Africa

^b Department of Paediatrics and Child Health, Steve Biko Academic Hospital,
University of Pretoria, South Africa

^c Engela M Honey, Department Genetics, University of Pretoria, South Africa

^d Private Practice, Pretoria, South Africa

Corresponding Author: Marli Dercksen. Marli.dercksen@nwu.ac.za , Tel: 0027 018 299 2302

Introduction and objectives: Multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM: 231680) is an autosomal recessive metabolic disorder due to mutations in the ETFA, ETFB and ETFDH genes resulting in the deficient function of alpha or beta subunits of the electron transfer protein (ETF) or electron transferring flavoprotein dehydrogenase (ETFDH), respectively. Dysfunction in either of these two flavoproteins leads to compromised fatty acid and amino acid oxidation as well as choline metabolism. We report on clinical, biochemical and genetic findings of three South African patients with ETFDH deficiency.

Patients and results: These patients were found to be homozygous (patient 1) for a novel c.1067G>A (p.Gly356Glu) or compound heterozygous (patient 2 and 3) for the described novel and known c.1448C>T (p.Pro483Leu) mutations in the ETFDH gene, respectively. Functional studies in muscle and fibroblasts confirmed the deleterious effects of compromised ETFDH expression on the respiratory chain function and fatty acid oxidation. The clinical-biochemical presentation for patient 1 included severe neonatal onset with congenital abnormalities, hypoglycaemia, metabolic acidosis, hyperammonemia as well as a characteristic metabolite profile of accumulating mono- and dicarboxylic acids, N-acylglycines and acylcarnitines commonly associated with MADD. Delayed onset was noted for patients 2 and 3 which also presented with the characteristic MADD metabolite profile as well as episodic metabolic acidosis, non-ketotic hypoglycaemia, mild hyperammonemia, progressive myopathy and hepatosplenomegaly. Early death in patient 1 occurred whereas the compound heterozygotes responded to L-carnitine and riboflavin treatment. Progressive muscle weakness and severe migraine-like episodes occurred in patient 2 and 3. Patient 3 died at the age of 23 years after a stroke.  Conclusion: A clear genotype-phenotype correlation was confirmed for the novel mutation present in homozygous and/or compound heterozygous state. These findings may potentially predict the prognosis of MADD due to ETFDH deficiency in the affected South African population.