Scad. Muscle biopsy showed diminished cytochrome oxidase; spectrophotometric dosage of respiratory chain complexes on the sample confirmed deficiency of mitochondrial complex IV. Gene sequencing for Scad and ethylmalonic encephalopathy

ethylmalonic encephalopathy (ee) is an autosomally recessive inherited disorder with a relentlessly progressive decline in neurological function, usually fatal by the age of ten. it is characterised by generalised hypotonia, psychomotor regression, spastic tetraparesis, dystonia, seizures and, eventually, global neurological failure. approximately 50 reports have been published worldwide describing this devastating disease, most involving patients of Mediterranean or arab origin. The fundamental defect in ee likely involves the impairment of a mitochondrial sulphur dioxygenase coded by the eTHe1 gene responsible for the catabolism of sulphide, which subsequently accumulates to toxic levels. a diagnosis of ee should initiate careful genetic evaluation and counselling, particularly if the parents intend to have additional offspring. The present report describes the diagnosis of ee in a reproductive endocrinology context, where both members of a non-consanguineous couple were confirmed to be carriers of an identical A→G mutation. This previously unknown mutation at nucleotide position c.494 resulted in an amino acid substitution, p.asp165Gly. although consideration was given to in vitro fertilisation, embryo biopsy and single gene pre-implantation genetic diagnosis, the couple decided to first utilise a less aggressive therapeutic approach with donor sperm insemination. Pregnancy with a low risk of ee was indeed achieved; however, the infant was affected with a different anomaly (hypoplastic left heart). as this case demonstrates, prior to the initiation of fertility therapy, genetic analysis may be used to provide a confirmatory diagnosis when ee is suspected. Case report Clinical presentation. The patient, aged 361⁄2 years, sought reproductive endocrinology consultation with her husband. She suffered from mild hypothyroidism and pernicious anaemia, which were medically managed and stable before presentation. Her blood type was o+. neither partner smoked and both were in good general health. The ethnicity of both partners was caucasian, and there was no family history of any genetic condition. consanguinity was absent. The couple had achieved a total of four pregnancies together, none of which had required medical assistance. The first two pregnancies yielded term male deliveries, both via caesarean. The second two pregnancies ended in miscarriage, one each in the first and second trimester. The second delivery resulted in the birth of a son who evidenced developmental delay at the age of approximately six months. Paediatric neurology assessment of this infant included EEG and brain MR, which revealed non-specific abnormalities. initial investigations for spastic diplegia and global developmental delay included the measurement of blood lactate, which was elevated, and of urine organic acids, which revealed high ethylmalonic acid and methylsuccinate. a defect in fatty acid oxidation was thus suspected, with short chain acyl-coA dehydrogenase deficiency (SCAD) and ethylmalonic aciduria considered as provisional diagnoses. a study of fatty acid β-oxidation in fibroblasts excluded mediumand long-chain fatty acid defects. The serum acylcarnitine profile revealed elevated butyrylcarnitine, which did not exclude Scad. Muscle biopsy showed diminished cytochrome oxidase; spectrophotometric dosage of respiratory chain complexes on the sample confirmed deficiency of mitochondrial complex IV. Gene sequencing for Scad and ethylmalonic encephalopathy identified no mutations in the ACADS gene (SCAD), but did identify a novel mutation in eTHe1. This mutation was determined to be homozygous by confirmation of carrier status via blood samples from both parents of the proband. a treatment regimen was started for the proband, and the parents were advised that any future pregnancies would have a 25% risk of being affected with ee. The parents understood that the metabolic derangements associated with the mitochondrial Novel ETHE1 mutation in a carrier couple having prior offspring affected with ethylmalonic encephalopathy: Genetic analysis, clinical management and reproductive outcome DAVID J. WAlSh1, eric ScoTT SillS1, deboraH M. laMberT2, nilS GreGerSen4, FerGal d. Malone3 and AnThony P.h. WAlSh1 1The Sims institute/Sims international Fertility clinic; 2department of Genetics, children's university Hospital; 3department of obstetrics and Gynaecology, School of Medicine, royal college of Surgeons in ireland, dublin, ireland; 4research unit for Molecular Medicine, aarhus university Hospital, Skejby, denmark received october 21, 2009; accepted november 27, 2009 doi: 10.3892/mmr_00000243 Correspondence to: dr eric Scott Sills, The Sims institute/Sims international Fertility clinic, rosemount Hall, dundrum road, dundrum, dublin 14, ireland e-mail: [email protected]