title: Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria.
abstract: A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2-ketoglutaric aciduria has been found among the Old-Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2-ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20-week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2-ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2-ketoglutarate transporter.
authors.affiliation: Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. kelle_ri@jhuvms.hcf.jhu.edu
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: Donna
authors.initials: D
authors.lastname: Robinson
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
mesh_terms: D005006:Ethnicity / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007656:Ketoglutaric Acids / Q000652:urine; D008279:Magnetic Resonance Imaging; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics / Q000652:urine; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010375:Pedigree; D010414:Pennsylvania; D015996:Survival Rate
chemical_list: D007656:Ketoglutaric Acids