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

Richard I. Kelley, Donna Robinson, Erik G. Puffenberger, Kevin A. Strauss, D. Holmes Morton

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)318-326
Number of pages9
JournalAmerican Journal of Medical Genetics
Issue number4
Publication statusPublished - Nov 1 2002



  • 17q25
  • 2-ketoglutaric acid
  • Amish
  • Microcephaly
  • Mitochondrial disease

ASJC Scopus subject areas

  • Genetics(clinical)

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