Journal
AMERICAN JOURNAL OF MEDICAL GENETICS
Volume 112, Issue 4, Pages 318-326Publisher
WILEY-LISS
DOI: 10.1002/ajmg.10529
Keywords
Amish; microcephaly; 2-ketoglutaric acid; mitochondrial disease; 17q25
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Funding
- NICHD NIH HHS [HD24061] Funding Source: Medline
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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. (C) 2002 Wiley-Liss, Inc.
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