Long chain acyl-CoA dehydrogenase (LCHAD) deficiency / Mitochondrial trifunctional protein (MTF) deficiency

Contact details Introduction Regional Genetics Service Long chain acyl-CoA dehydrogenase (LCHAD) deficiency / mitochondrial trifunctional Levels 4-6, Barclay House protein (MTF) deficiency is an autosomal recessive disorder of mitochondrial beta- 37 Queen Square oxidation of fatty acids. The mitochondrial trifunctional protein is composed of 4 alpha London, WC1N 3BH and 4 beta subunits, which are encoded by the HADHA and HADHB genes, respectively. It is characterized by early-onset cardiomyopathy, hypoglycemia, T +44 (0) 20 7762 6888 neuropathy, and pigmentary retinopathy, and sudden death. There is also an infantile F +44 (0) 20 7813 8578 onset form with a hepatic Reye-like syndrome, and a late-adolescent onset form with primarily a skeletal myopathy. Tandem mass spectrometry of organic acids in urine, Samples required and carnitines in blood spots, allows the diagnosis to be unequivocally determined. An  5ml venous blood in plastic EDTA additional clinical complication can occur in the pregnant mothers of affected fetuses; bottles (>1ml from neonates) they may experience maternal acute fatty liver of pregnancy (AFLP) syndrome or  Prenatal testing must be arranged hypertension/haemolysis, elevated liver enzymes and low platelets (HELLP) in advance, through a Clinical syndrome. Genetics department if possible. The genes encoding the HADHA and HADHB subunits are located on chromosome  Amniotic fluid or CV samples 2p23.3. The pathogenic variant c.1528G>C, p.(Glu510Gln) on the HADHA gene should be sent to Cytogenetics for accounts for approximately 87% of LCHAD alleles in affected patients. dissecting and culturing, with instructions to forward the sample Referrals to the Regional Molecular Genetics  Clinically affected patients should have their diagnosis confirmed by laboratory for analysis biochemical analysis; this should be arranged either locally or with Chemical  A completed DNA request card Pathology, Great Ormond Street Hospital (tel: 0207 4059200 ext 5009). should accompany all samples Affected patients can then be referred for genetic testing. If the necessary patient samples are unavailable, genetic testing can be undertaken in the Patient details parents of an affected child. To facilitate accurate testing and  Pregnant patients who have AFLP or HELLP can be referred for carrier testing reporting please provide patient for the c.1528G>C pathogenic variant, along with their partners. demographic details (full name, date of  Carrier testing can be offered to the adult relatives of affected patients once a birth, address and ethnic origin), details pathogenic variant has been identified. of any relevant family history and full contact details for the referring clinician Prenatal testing Prenatal testing is available, if required, for families where pathogenic variants have been identified - please contact the laboratory to discuss. Service offered  Level 1 analysis: testing for the c.1528G>C pathogenic variant in the HADHA gene by Sanger sequencing analysis.  Level 2 analysis: Analysis of the HADHA and HADHB genes by next generation sequencing (Agilent SureSelect and Illumina NextSeq). A minimum coverage of 30 reads is required to call a variant. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. This assay is not currently validated to detect large deletions / duplications. All clinically relevant variants are confirmed by Sanger sequence analysis. Known benign polymorphisms and sequence variants which are unlikely to be pathogenic are not reported.  Detection of known pathogenic variants in relatives of patients with HADHA and HADHB pathogenic variants by Sanger sequencing. Target reporting time

4 weeks for routine level 1 screen in index case, 8 weeks for level 2 screen. 4 weeks for carrier testing for known pathogenic variants. Please contact the laboratory for urgent cases.

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