What's new in Neurogenetics? Amish microcephaly

Microcephaly is a relatively common finding in children with developmental impairment, and can result from a wide range of etiologies. The terms ‘primary microcephaly’ and ‘microcephaly vera’ are used to denote microcephaly and slow development in the absence of other physical or neurological problems. Though etiologically heterogeneous, a high proportion of instances are inherited in an autosomal recessive manner. This past year has seen the discovery of three genes that are associated with microcephaly: ASPM, involved in function of the mitotic spindle, microcephalin, of unknown function, and DNC, a deoxynucleotide carrier protein. The recent identification of mutation in DNC as the cause of Amish microcephaly tells an important story at three levels: the value of careful clinical observation in the elucidation of etiology, the power of genomic and bioinformatic tools in gene identification, and the interrelationship of metabolic and developmental disorders. A recessive form of microcephaly has been known in the Amish population for some time. In 2002, Kelley et al. described the phenotype in detail, and reported a metabolic abnormality in affected children. Individuals with ‘Amish microcephaly’ have congenital microcephaly, sometimes identified by prenatal ultrasound, indicating a reduction in the rate of head growth beginning around 20 weeks. The microcephaly tends to be profound, but usually no other congenital anomalies are seen. Affected children have severely impaired development, become irritable after around 2–3 months of age, and die, usually in the first year of life in the setting of a respiratory infection. Some have been noted to have hepatomegaly, particularly at times of stress such as infection, which prompted metabolic studies. Urine organic acid studies revealed consistent and substantial elevations of 2-ketoglutarate, an intermediate of mitochondrial Krebs cycle metabolism. The relatively high incidence of this recessive disorder among the Amish (1:480 births) suggests a founder effect. Kelley et al. have earned the trust of this group, and were able to trace the inheritance of the condition to a couple through seven generations. This permitted a mapping study to be done, which was reported in abstract form in 1999, showing linkage to chromosome 17q25. Identification of the gene required more detailed mapping and scrutiny of candidate genes within the region. A haplotype was identified that cosegregated with the disease gene and then a physical map was assembled, comprising 3.7 Mb of DNA from the region. Analysis of genomic data revealed over 50 potential genes. Two are involved in mitochondrial function, making them plausible candidates for this disorder. These genes are ATP5H, which encodes an ATP synthase, and DNC, which is involved in the transport of dinucleotides into the mitochondrion. Both genes were sequenced in DNA from affected individuals. No sequence variants were found in ATP5H, but all affected individuals were found to be homozygous for a G to C change in DNC that results in substitution of alanine for glycine at codon 177 in the protein. The change was not found in 252 control chromosomes,