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Amish lethal microcephaly: A new metabolic disorder with severe congenital microcephaly and 2‐ketoglutaric aciduria
Author(s) -
Kelley Richard I.,
Robinson Donna,
Puffenberger Erik G.,
Strauss Kevin A.,
Morton D. Holmes
Publication year - 2002
Publication title -
american journal of medical genetics
Language(s) - English
Resource type - Journals
eISSN - 1096-8628
pISSN - 0148-7299
DOI - 10.1002/ajmg.10529
Subject(s) - microcephaly , metabolic disorder , medicine , metabolic acidosis , endocrinology , pediatrics
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. © 2002 Wiley‐Liss, Inc.

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