Rare Diseases: Amish Lethal Microcephaly

Rare diseases are those that a regular doctor, in general, would not expect to see more than one case in a year. This is really a problem with rare diseases because, generally speaking, doctors do not know them and are often misdiagnosed.

As with many rare diseases, this is the case with Amish Lethal Microcephaly (ALM), also known as Amish Microcephaly or MCPHA. Amish Lethal Microcephaly is characterized by the small or very small size of the head (microcephaly) and early death. The head circumference (the occipitofrontal circumference is the actual medical term) is usually between 6 to 12 standard deviations bellow the mean (average).

So that you try to understand this, let me explain a little bit. All biological variables from a population (human population) such as height, weight, or the occipitofrontal circumference can be characterized by two parameters: the mean and the standard deviation.

In regular terms the mean is the average. So you may have tall people, short people but if you take enough measurements you can calculate an average (mean). In addition to the average, you can calculate in which range the variable is. One way to do this is calculate the standard deviation. Without going into the mathematical formula if you say that the weight of the human population has a mean of (let say) 100 pounds and a standard deviation of 10 pounds, then you would expect that 95% of all people to fall in a range that goes from mean - 3 times standard deviation (70 pounds) and mean + 3 times standard deviation (130). The rest (5%) is outside this range.

So now you can see why this rare disease is known as microcephaly. Again, the head circumference (the occipitofrontal circumference is the actual medical term) is usually between 6 to 12 standard deviations bellow the mean (average). Also, in AML patients the anterior and posterior fontanels are closed at birth and facial features are distorted. No more than a 6 month life span is expected for babies born with this rare disease.

How is Amish Lethal Microcephaly diagnosed? Although it is a very rare disease the clinical diagnostic hallmark is the presence of microcephaly at birth, that is, occipitofrontal circumference very small. In addition, biochemical confirmation is done by testing levels of the urinary organic acid 2-ketoglutarate, which is 10 times higher in babies with ALM.

Amish Lethal Microcephaly is a genetic disease. The only gene that has been associated with ALM is known as the SLC25A19 gene (also known as DNC or MUP1 gene).

Is this disease treatable? Unfortunately this disease has no cure until today. Treatments available are only of a supportive nature. Early death is inevitable. Affected babies have difficulty in maintaining body temperature. After the first two or three months of life, babies increase in their irritability (unknown causes), after which, infants will likely die within 1 to 2 days (Kelley et al 2002). Use of Phenobarbital to alleviate seizures is common practice and physical therapy is administered to help with contractures.

Sources:

Battaglia A, Carey JC. Microcephaly. Rudolph's Pediatrics, 21st ed. McGraw-Hill, Chapter 10.4.3, p 784-6. 2003

Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet. 2002. 112:318-26

Microcephaly Information Page