Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria

Am J Med Genet. 2002 Nov 1;112(4):318-26. doi: 10.1002/ajmg.10529.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Comment

MeSH terms

  • Ethnicity / genetics*
  • Family Health
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Ketoglutaric Acids / urine
  • Magnetic Resonance Imaging
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / urine
  • Microcephaly / genetics*
  • Microcephaly / metabolism
  • Microcephaly / mortality
  • Microcephaly / pathology
  • Pedigree
  • Pennsylvania
  • Survival Rate


  • Ketoglutaric Acids