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Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria
Richard I Kelley1, Donna Robinson, Erik G Puffenberger
1Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. kelle_ri@jhuvms.hcf.jhu.edu
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.
Insights
A novel Amish lethal microcephaly disorder causes severe brain development issues and early death. This genetic condition is linked to high levels of 2-ketoglutaric acid in affected infants.
Area of Science:
- Genetics
- Metabolic Disorders
- Neurology
Background:
- A unique metabolic disorder, Amish lethal microcephaly, is identified in the Old-Order Amish population of Lancaster County, Pennsylvania.
- This condition is characterized by severe congenital microcephaly, early mortality within the first year of life, and pronounced 2-ketoglutaric aciduria.
Purpose of the Study:
- To investigate the genetic basis and clinical features of Amish lethal microcephaly.
- To identify the underlying molecular defect responsible for this severe metabolic disorder.
Main Methods:
- Segregation analysis to determine inheritance pattern.
- Biochemical assays of organic acids in urine.
- Cranial magnetic resonance imaging (MRI) for neuroimaging.
- Enzyme activity assays in cultured cells.
- Genetic linkage analysis to map the disease locus.
Main Results:
- Amish lethal microcephaly follows autosomal recessive inheritance with a high incidence (at least 1 in 500 births).
- Affected infants exhibit extreme elevations of 2-ketoglutaric acid in urine, particularly during illness, leading to metabolic acidosis.
- MRI revealed smooth, immature brains with cerebellar hypoplasia; 2-ketoglutarate dehydrogenase activity was normal.
- The disorder was mapped to chromosome 17q25.
Conclusions:
- Amish lethal microcephaly is a distinct genetic disorder caused by a defect potentially involving a mitochondrial inner membrane 2-ketoglutarate transporter.
- The findings highlight a novel mechanism contributing to severe microcephaly and early lethality due to impaired mitochondrial metabolism.