Glutaric Acidemia Types I
and II
Glutaric acidemias are recessively inherited human
disorders characterized by the accumulation and excretion
of glutaric acid. Glutaric acidemia type I (GAI) is
due to deficiency of glutaryl-CoA dehydrogenase (GCDH),
an FAD-containing enzyme of the mitochondrial matrix
involved in the oxidation of lysine, hydroxylysine
and tryptophan, and is characterized clinically by
a progressive movement disorder with neuronal loss
and gliosis in the basal ganglia. Glutaric acidemia
type II (GAII) is due to an abnormality in electron
transfer from the FAD of GCDH (and other flavoprotein
dehydrogenases) to ubiquinone in the respiratory chain;
in some patients this is due to deficiency of electron
transfer flavoprotein (ETF) in the matrix, and in
others it is due to deficiency of ETF: ubiquinone
oxidoreductase (ETF:QO) in the inner mitochondrial
membrane. Patients with the most severe forms of GAII,
defining how these (and other) mutations cause enzyme
deficiency, and determining how enzyme deficiency
causes the disease manifestations.
We have cloned and expressed
cDNAs that encode human GCDH and ETF:QO, and cDNAs
that encode the human alpha and beta subunits of ETF
have been cloned by others. We have identified several
mutations in GAI and GAII patients, in some cases
by examining GCDH, ETF and ETF:QO mRNA, and in others
by examining the genes themselves. The method used
to search for mutations is to amplify appropriate
segments of mRNA or DNA by PCR (polymerase chain reaction),
and to examine the products by methods sensitive enough
to recognize even single base changes. We have expressed
some of these mutations in bacteria and/or yeast,
and are now examining in detail their effect on enzyme
structure and function.
Present directions are
to continue mutation analysis on GAI and GAII patients,
hoping in this way to build comprehensive structure-function
maps of these proteins. We are also making transgenic
models of GAI and GAII in mice, using the general
method of gene knockout by homologous recombination
in embryonic stem (ES) cells, to determine the precise
relationships between genotype and phenotype.
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Selected Publications
Ojwang PJ, Pegoraro RJ, Deppe WM, Sankar R, McKerrow
N, Varughese L, Stoker AF, Goodman SI. Biochemical
and molecular diagnosis of glutaric aciduria type
1 in a black South African male child: case report.
East Afr Med J. 2001 Dec;78(12):682-5.
Wajne M, Vargas CR, Funayama C, Fernandez A, Elias
ML, Goodman SI, Jakobs C, van der Knaap MS. D-2-Hydroxyglutaric
aciduria in a patient with a severe clinical phenotype
and unusual MRI findings. J Inherit Metab Dis. 2002
Feb;25(1):28-34.
Koeller DM, Woontner M, Crnic LS, Kleinschmidt-DeMasters
B, Stephens J, Hunt EL, Goodman SI. Biochemical, pathologic
and behavioral analysis of a mouse model of glutaric
acidemia type I. Hum Mol Genet. 2002 Feb 15;11(4):347-57.
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