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Amish lethal microcephaly is an autosomal recessive neurodevelopmental disorder characterized by severe congenital microcephaly, metabolic crises, and early infantile death. It arises from biallelic loss‐of‐function variants in SLC25A19, which encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. The disease is catalogued as Amish lethal microcephaly.
Genetic evidence supporting this association includes at least 4 unrelated Amish probands homozygous for the founder variant c.530G>C (p.Gly177Ala), with consistent homozygosity in multiple Pennsylvania Amish families ([PMID:20583149]). Segregation of the variant in consanguineous pedigrees and its absence in non‐Amish populations reinforce pathogenicity.
To date, the c.530G>C (p.Gly177Ala) founder allele is the sole recurrent variant reported in Amish lethal microcephaly. No additional variant classes or deep‐intronic alleles have been implicated. Carrier frequency data are restricted to the Pennsylvania Amish community.
Functional studies demonstrate that p.Gly177Ala disrupts mitochondrial TPP import, leading to diminished activity of TPP‐dependent enzymes—including pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched‐chain amino acid dehydrogenase—which underlies the metabolic crises and neurodevelopmental phenotype ([PMID:20583149]).
Clinically, affected infants present with severe microcephaly detectable by mid-gestation ultrasound, profound developmental delay, and radiologic features such as partial agenesis of the corpus callosum (HP:0001338) and spinal dysraphism. Biochemical findings include variable alpha-ketoglutaric aciduria and persistent lactic acidosis responsive to high-fat dietary interventions.
Overall, the gene–disease association is classified as Strong based on multiple unrelated probands, clear segregation of a founder variant, and mechanistic concordance. Genetic testing for c.530G>C (p.Gly177Ala) enables definitive diagnosis and informs carrier screening in at-risk Amish populations.
Gene–Disease AssociationStrong4 probands ([PMID:20583149]), founder homozygous c.530G>C variant segregating in multiple Amish families, concordant mitochondrial transporter deficiency Genetic EvidenceStrong4 independent probands with homozygous c.530G>C (p.Gly177Ala) founder variant in SLC25A19 ([PMID:20583149]) Functional EvidenceModerateBiochemical characterization demonstrates impaired TPP transport and decreased activity of TPP-dependent enzymes ([PMID:20583149]) |