Amish lethal microcephaly

Alternate names

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

Epidemiology

Amish lethal microcephaly occurs in approximately 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population.

Cause

• Mutations in the SLC25A19 gene cause Amish lethal microcephaly.
• The SLC25A19 gene provides instructions for producing a protein that is a member of the solute carrier (SLC) family of proteins.
• Proteins in the SLC family transport various compounds across the membranes surrounding the cell and its component parts.
• The protein produced from the SLC25A19 gene transports a molecule called thiamine pyrophosphate into the mitochondria, the energy-producing centers of cells.
• This compound is involved in the activity of a group of mitochondrial enzymes called the dehydrogenase complexes, one of which is the alpha-ketoglutarate dehydrogenase complex.
• The transport of thiamine pyrophosphate into the mitochondria is believed to be important in brain development.

Gene mutations

• 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

• 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Cerebellar vermis hypoplasia
• Death in infancy(Infantile death)
• Feeding difficulties(Feeding problems)
• Irritability(Irritable)
• Metabolic acidosis
• Microcephaly(Abnormally small skull)
• Micrognathia(Little lower jaw)
• Optic atrophy
• Organic aciduria
• Severe global developmental delay
• Sloping forehead(Inclined forehead)

30%-79% of people have these symptoms

• Agenesis of corpus callosum
• Limb hypertonia(Increased muscle tone of arm or leg)
• Lissencephaly(Fewer or absent grooves in brain)
• Muscular hypotonia(Low or weak muscle tone)
• Osteoporosis
• Spina bifida
• Temperature instability
• Ventriculomegaly

5%-29% of people have these symptoms

• Bilateral tonic-clonic seizure(Grand mal seizures)
• Cleft soft palate
• Decreased fetal movement(Less than 10 fetal movements in 12 hours)
• Decreased skull ossification(Decreased bone formation of skull)
• Hepatomegaly(Enlarged liver)
• Limitation of joint mobility(Decreased joint mobility)

Diagnosis

• The diagnosis of Amish lethal microcephaly is established with clinical findings , identification of biallelic pathogenic variants in SLC25A19 by molecular genetic testing.
• All affected individuals within the Old Order Amish population are homozygous for the same single-base pair substitution.

Treatment

• Treatment is supportive care based on signs and symptoms.
• Phenobarbital has been used to treat a few children with seizures.
• Physical therapy may alleviate contractures or other secondary neurologic manifestations.
• Infectious illnesses are managed to minimize acidosis.[1].

NIH genetic and rare disease info

• NIH info on Amish lethal microcephaly

Amish lethal microcephaly is a rare disease.

Amish lethal microcephaly Resources
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