A number sign (#) is used with this entry because of evidence that Amish-type microcephaly, also known as thiamine metabolism dysfunction syndrome-3 (THMD3), is caused by homozygous mutation in the SLC25A19 gene (606521) on chromosome 17q25.

Thiamine metabolism dysfunction syndrome-4 (THMD4; 613710) is an allelic disorder with a milder phenotype.

Amish-type microcephaly (MCPHA) is a severe autosomal recessive metabolic disorder characterized by severe microcephaly apparent at birth, profoundly delayed psychomotor development, brain malformations, and episodic encephalopathy associated with lactic acidosis and alpha-ketoglutaric aciduria (summary by Kelley et al., 2002).

For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).

Kelley et al. (2002) described a metabolic disorder among the Old Order Amish of Lancaster County, Pennsylvania, characterized by severe congenital microcephaly, death within the first year, and severe 2-ketoglutaric aciduria. The disorder segregated as an autosomal recessive and had the unusually high incidence of at least 1 in 500 births. When the infants were well, urine organic acid profiles showed isolated, extreme elevations of 2-ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often developed metabolic acidosis, which sometimes followed a lethal course. Cranial MRI of 1 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 (613022) in cultured lymphoblasts of 1 patient showed normal activity.

Rosenberg et al. (2002) stated that at least 61 affected infants had been born in the previous 40 years in 23 nuclear families. Affected individuals had head circumferences that were 6 to 12 SD less than the population mean.

Siu et al. (2010) reported a male infant with Amish microcephaly. He was born of distantly related parents in Ontario, Canada, who had Amish ancestors. Microcephaly was first noted at 21 weeks' gestation. At birth, he showed severe microcephaly, a sloping forehead, and extremely small anterior fontanel. He had truncal hypotonia with hypertonia of the extremities, spontaneous myoclonic jerks, and optic nerve atrophy with foveal hypoplasia. He exhibited extreme irritability and developed failure to thrive. Brain MRI showed partial agenesis of the corpus callosum, large cisterna magna communicating with the fourth ventricle, enlarged lateral ventricles, hypoplastic cerebellar vermis, and lissencephaly. He also had spinal dysraphism and osteopenia. The patient was alive at 7 years, with a static microcephaly, profound developmental delay, and metabolic lactic acidosis controlled by a high fat diet.

The transmission pattern of MCPHA in the family reported by Siu et al. (2010) was consistent with autosomal recessive inheritance.

In the patient with MCPHA reported by Siu et al. (2010), lactic acidosis was present from birth, but urinary alpha-ketoglutarate did not appear until age 8 months, even during metabolic crisis. After institution of a high-fat diet, lactate decreased and urinary alpha-ketoglutarate increased. These findings indicated that increased urine alpha-ketoglutaric acid is not a constant feature of MCPHA. Siu et al. (2010) noted that, since mutations in the SLC25A19 gene result in a thiamine deficiency, these biochemical characteristics could be explained by deficient activities of 2 of the 3 mitochondrial thiamine-requiring enzymes, pyruvate dehydrogenase (PDC) and alpha-ketoglutaric acid dehydrogenase. During metabolic crisis, there is reduced PDC activity, resulting in lactic acidosis and less acetyl-CoA entering the citric acid cycle, with decreased production of alpha-ketoglutarate. Later accumulation of alpha-ketoglutarate may occur because thiamine deficiency reduces alpha-ketoglutaric acid dehydrogenase activity.

Siu et al. (2010) reported that their patient with MCPHA was treated successfully with a high-fat diet, which likely provided energy in mitochondria primarily through fatty acid beta-oxidation, bypassing pyruvate dehydrogenase to directly enter the tricarboxylic acid cycle. Importantly, the metabolic similarity of MCPHA to pyruvate dehydrogenase deficiency (see, e.g., 312070) indicates that glucose should be administered with caution to patients with MCPHA to avoid a risk of exacerbating the lactic acidemia.

Through a whole-genome scan, fine mapping, and haplotype analysis, Rosenberg et al. (2002) mapped a locus for Amish microcephaly to a region of 2 Mb on chromosome 17q25.

Rosenberg et al. (2002) identified a list of positional candidate genes, comprising 7 full-length cDNAs, 3 EST clusters, and 11 predicted genes. The authors reasoned that because alpha-ketoglutarate is a component of the Krebs cycle, the alpha-ketoglutarate abnormality in MCPHA could be an indication of mitochondrial dysfunction. Two of the genes on the list of candidates, SLC25A19 and ATP5H (ATP5PD; 618121), encode proteins with known mitochondrial functions and therefore were particularly attractive candidates. The coding region of the ATP5H gene was normal, but Rosenberg et al. (2002) identified a homozygous nucleotide change in the coding region of SLC25A19 gene in an affected child (G177A; 606521.0001).

In a male child with Amish microcephaly, Siu et al. (2010) found the same homozygous G177A mutation (606521.0001) observed in other Amish patients with the disorder.