Amish lethal microcephaly

Synonyms

2

Overview

Amish lethal microcephaly is a disorder in which infants are born with a very small head and underdeveloped brain.

Infants with Amish lethal microcephaly have a sloping forehead and an extremely small head size. They may also have an unusually small lower jaw and chin (micrognathia) and an enlarged liver (hepatomegaly).

Affected infants may have seizures and difficulty maintaining their body temperature. Often they become very irritable starting in the second or third month of life. A compound called alpha-ketoglutaric acid can be detected in their urine (alpha-ketoglutaric aciduria), and during episodes of viral illness they tend to develop elevated levels of acid in the blood and tissues (metabolic acidosis). Infants with this disorder typically feed adequately but do not develop skills such as purposeful movement or the ability to track faces and sounds. Affected infants live only about six months.

Symptoms

  • Very small head
  • Death
  • Severe 2-ketoglutaric aciduria
  • Metabolic acidosis
  • Smooth brain structure
  • Aplasia/Hypoplasia of the cerebellum
  • Behavioral abnormality
  • Cognitive impairment
  • Microcephaly
  • Optic atrophy
  • Sloping forehead

Causes

Mutations in the SLC25A19 gene cause Amish lethal microcephaly.

All known individuals with Amish lethal microcephaly have a mutation in which the protein building block (amino acid) alanine is substituted for the amino acid glycine at position 177 of the SLC25A19 protein, written as Gly177Ala or G177A. Researchers believe that this mutation interferes with the transport of thiamine pyrophosphate into the mitochondria and the activity of the alpha-ketoglutarate dehydrogenase complex, resulting in the abnormal brain development and alpha-ketoglutaric aciduria seen in Amish lethal microcephaly.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Diagnosis

Amish lethal microcephaly is diagnosed by presence of microcephaly and a tenfold increase in the levels of the urinary organic acid 2-ketoglutarate. SLC25A19 (also known as DNC or MUP1) is the only gene known to be associated with Amish lethal microcephaly. All affected individuals within the Old Order Amish population are homozygous for the same single-base pair substitution. Molecular genetic testing of the SLC25A19 gene is available on a research basis only.

Resources

  • Genetics Home Reference
  • NIH