APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: SLC25A19

Amish lethal microcephaly
MCPHA

Microcephaly
2-ketoglutaric aciduria

Microcephaly, Amish Type

Clinical Characteristics

General description (for patients):   

Infants with this disorder are born with very small heads.  So far, it has only been observed among the Old Order Amish of Lancaster County, Pennsylvania where it is estimated to have an incidence of approximately 1 in 500 births. Decreased fetal movement is often noted during pregnancy and the condition can be diagnosed in the uterus by ultrasound. The affected children within the community are simply referred to as ‘small-headed’.  The brain does not become fully developed.   It is associated with or a result of metabolic abnormalities. Children often become highly irritable after several months of age.  Early neonatal death is common.

Medical description:  

This form of severe microcephaly is associated with 2-ketoglutaric aciduria.   No abnormalities are generally detected in affected pregnancies, apart from decreased fetal movement or the observation of microcephaly on sonographic evaluation.  Affected individuals have head circumferences that are 6-12 standard deviations less than the population mean but there is substantial variation.  Profound microcephaly can lead to craniofacial distortions due to frontal sloping and a nearly absent cranial vault which creates a facial appearance similar to anencephaly, e.g., protruding eyes.  Micrognathia and cleft palate may also be present.  Stretch reflexes are variable and can be normal or of a brisk nature.  Mild diffuse dystonia may be present although muscle tone is usually normal. Hepatomegaly is often present.  Affected children do not display any gross or fine motor development.  MRI evaluation shows no gyral development, a hypoplastic pons and an underdeveloped cerebellar vermis.  The smooth cerebrum is similar to the fetal brain at 20 weeks gestation and head growth slows after that.  Children become ‘irritable’ after 2-3 months old age which is characterized by persistent crying and difficulty maintaining normal body temperature.  Following the onset of irritability, the next viral illness (usually of a respiratory nature) leads to signs of metabolic acidosis, weakness, progressive lethargy, and death over a period of 24-48 hrs. Diagnosis is based on the clinical features and increased levels of the urinary organic acid 2-ketoglutarate in the absence of increased levels of other citric acid cycle intermediates or lactate.

Genetics:

All affected children were found to have a 530G>C change in the gene SLC25A19 that results in substitution of alanine for glycine in the protein product.  The locus is on chromosome 17 (17q25).  SLC 25A19 is a nuclear gene but is called a mitochondrial carrier gene since it's product shuttles metabolites across the mitochondrial membrane.
TREATMENT:  No effective treatment of the malformation is known. Children who experience seizures respond well to phenobarbital.   Physical therapy may be useful if contractures or secondary neurological manifestations develop.   B vitamins can moderately lower the amount of urinary 2-ketoglutarate.

Prognosis:

Poor, with the average age of death being 24 weeks.  One child lived for 14 months.  

Ancillary treatments and support:

Support and respite for the family may be needed during the stressful terminal irritability phase of the disease, which can last for several weeks.  Common childhood illnesses which can be fatal to these infants require prompt attention.

Specialists and specialty centers:

Neurologist, Pediatrician.

References:

Kelley, R.I., Robinson, D., Puffenberger, E.G., Strauss, K.A., and Morton, D.H.:  Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria.   Am. J. Hum. Genet . 112: 318-326, 2002. PubMed ID: 12376931

Rosenberg, M.J., Agarwala, R., Bouffard, G., Davis, J., Fiermonte, G., Hilliard, M.S., Koch, T., Kalikin, L.M., Makalowska, I., Morton, D.H., Petty, E.M., Weber, J.L., Palmieri, F., Kelley, R.I., Shaffer, A.A., and Biesecker, L.G.:  Mutant deoxynucleotide carrier is associated with congenital microcephaly.  Nat. Genet. 32: 175-179, 2002.  PubMed ID: 12185364

Korf, B.R.: What’s new in neurogenetics? Amish microcephaly.  Eur. J. Paediatr. Neurol. 7: 393-394, 2003. PubMed ID: 14623217

Resources:

Associated Graphics