Medium chain acyl CoA dehydrogenase deficiencyMCADD June 28, 2011 APHL-CDC Carlos A. Saavedra-Matiz, MD Newborn Screening Program Wadsworth Center New.

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Presentation transcript:

Medium chain acyl CoA dehydrogenase deficiencyMCADD June 28, 2011 APHL-CDC Carlos A. Saavedra-Matiz, MD Newborn Screening Program Wadsworth Center New York State Department of Health

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Fatty Acid Oxidation Disorders Genetically determined inborn errors of metabolism Myopathy/cardiomyopathy/SIDS Initial presentacion: Hypoketotic hypoglycemia Abnormal response to fasting and/or infectious disease stress Fasting >12 exhaust glycogen and mobilizes FAO Overlapping specificities for chain length dehydrogenases

Medium chain acyl CoA dehydrogenase deficiency 1/6,000-10,000 caucasian births Most common/Classic FAO disorder Present as hypoketotic/hypoglycemic (Reye Sx) and/or myo/cardiomyophaty, hypotonia, CHF, arrhythmia, SIDS Episodic illness 6m–2y after 12 h fasting or intercurrent infectious disease (vomiting / lethargy / seizures / coma) Most patients normal between episodes / some hypotonic or poor muscle strength

Acyl CoA Dehydrogenases / Substrate specificities EnzymeSubstrate Chain length Deficiency Disease Short Chain (SCAD)C4-6Rare Medium-chain (MCAD)C6-12Common (1:10,000) Very long-chain (VLCAD)C12-16Rare MCAD is one of three mitochondrial Acyl CoA dehydrogenases The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway MCAD substrates are fatty acyl CoAs with acid chain length of C6-C12 The examination of DBS by MS/MS to establish an Acylcarnitine Profile is the method used by the NYS-NBSP Elevation of octanoylcarnitine (C8) is the main marker C6 and ratio C8:C2 help as discriminators

C8 C8-IS C6 Courtesy Dr. M. Morrissey NBSP-NYSDOH NYSDOH-NBSP MCADD MS/MS Detection

p.Y67H ’ UTR region 3’ UTR region p.K329E c T>C c G>C c.-985 C>G c.-725 C>G c.-257 G>Ap.M1R p.G310R p.T121I p.R206H p.W82Lfsx23 p.R243Q p.G402D p.Y145H p.T193A p.R29X Autosomal recessive Gene (ACADM) on chromosome 1p exons, 421 amino acids c.985A>G (p.Lys329Glu = p.K304E) most common mutation C8>0.8 μmole/L are referred for DNA analysis NYS-NBSP uses FRET/RT-PCR to detect p.K329E Complete gene sequencing Genetics

Wtc.985A>G MCADD c.985A>G = p.K329E (K304E) NYSDOH-NBSP FRET analysis most common ACADM Mutation

c.DNAProteinHomoHetCarrier FreqAllele Freq c.985A>Gp.K329E c.199T>Cp.Y67H c.843A>Tp.R281S c.449_452del4p.T150RfsX c.1257C>Ap.Y394X101.9 c.443G>Ap.R148K101.9 c.331G>Ap.E111K101.9 C.320T>Cp.L107S101.9 c.617G>Ap.R206H c.567delGp.M190CfsX c.526G>Ap.A176T c.166G>Ap.A56P Modified from: Arnold GL, Saavedra-Matiz CA et al. Mol Genet & Met 99(2010)263-8