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M edium c hain a cyl C oA d ehydrogenase d eficiency MCADD

M edium c hain a cyl C oA d ehydrogenase d eficiency MCADD. Carlos A. Saavedra- Matiz , MD Newborn Screening Program Wadsworth Center New York State Department of Health. June 28, 2011 APHL-CDC. Humpath.com. http://web.virginia.edu/Heidi/chapter24/chp24.htm.

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M edium c hain a cyl C oA d ehydrogenase d eficiency MCADD

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  1. Medium chain acylCoAdehydrogenasedeficiency MCADD Carlos A. Saavedra-Matiz, MD Newborn Screening Program Wadsworth Center New York State Department of Health June 28, 2011 APHL-CDC

  2. Humpath.com

  3. http://web.virginia.edu/Heidi/chapter24/chp24.htm

  4. http://www.ncbi.nlm.nih.gov/books/NBK28177/figure/A2964 http://www.newbornscreening.info/Parents/fattyaciddisorders/MCADD.html

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

  6. Medium chain acylCoAdehydrogenasedeficiency • 1/6,000-10,000 caucasianbirths • 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

  7. AcylCoADehydrogenases / Substrate specificities • MCAD is one of three mitochondrial AcylCoAdehydrogenases • The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway • MCAD substrates are fatty acylCoAs 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

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

  9. 5’ UTR region 1 2 c.-1375 G>C c.-1028 T>C c.-985 C>G p.Y67H 3 c.-725 C>G c.-257 G>A p.M1R 4 p.R29X 5 6 p.W82Lfsx23 7 p.T121I 8 p.Y145H 9 p.T193A 10 p.R206H p.K329E 11 p.R243Q 12 p.G310R 3’ UTR region p.G402D Genetics • Autosomalrecessive • Gene (ACADM) on chromosome 1p31.1 • 12 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

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

  11. Modified from: Arnold GL, Saavedra-Matiz CA et al. Mol Genet & Met 99(2010)263-8

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