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The Old Order Amish communities (Plain people) of North America have altered health risks that stem from unbalanced population sampling of European founders followed by genetic drift in derivative generations. These population effects have resulted in a high prevalence of specific genetic disorders that vary from the general population and from each other. Several characteristics of these communities facilitate genetic analysis. Most isolates keep excellent historical and genealogical records. Due to their sociologic and/or geographic isolation, there is usually little or no migration into the group, and the members of the group exhibit relatively homogeneous lifestyles. Large nuclear families are frequent, which provides adequate numbers of affected and unaffected siblings within a sibship for blood samples. The primary genetic advantage, however, results from the interaction of two overlapping phenomena: the founder effect and inbreeding.
Mitochondrial DNA mutations have not previously been reported in any Old Order Amish community. We have recently described an Amish family with the MTTL1 mitochondrial gene mutation m.3243A>G. A second patient with an m.13513G>A (D393N) mutation has also been diagnosed. These mutations classically cause mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). We identified the first mutation in a young woman from the Mercer County Amish community at age 15 years. She had a history of developmental delay, short stature, hearing loss, fatigability, and poor appetite. She presented acutely with vomiting, altered mental status, status epilepticus, and lactic acidosis. Magnetic resonance imaging (MRI) of the brain showed a small, focal, left occipital lobe infarct. She subsequently developed other stroke-like episodes in the left occipital and temporal areas. Molecular testing revealed 74 percent heteroplasmy in saliva for the MELAS 3243A>G mutation. Several members of the extended maternal pedigree exhibit variable clinical problems including developmental delay, mild hypotonia, hearing loss, renal failure, migraine headaches, adult-onset diabetes mellitus, and recurrent miscarriages, but have never had genetic evaluations.
A patient from a second Amish family was diagnosed with MELAS/Leigh overlap syndrome resulting from the mitochondrial mutation m.13513G>A(D393N) in the ND5 subunit of respiratory chain complex I, with blood heteroplasmy level of 2 percent and urine heteroplasmy level of 43 percent. The proband was diagnosed at 12 years of age with an acute stroke after a history of developmental delay. His lactate was mildly increased. He has subsequently had recurrent strokes and developed Leigh-like basal ganglia and brainstem lesions with progressive spasticity, dysphagia, and weakness. No siblings were affected, and the mother tested negative for the mutation in blood and urine.
A third patient in this Amish community has been diagnosed with an autosomal recessive respiratory chain disorder due to a homozygous deletion in the NDUFAF2 gene, which was in one of the nine areas of homozygosity detected on SNP microarray. He had a history of developmental delay, nystagmus, and hypotonia, and was subsequently admitted to the hospital with a viral illness with progressive respiratory failure. He required intubation, and his MRI revealed Leigh-like lesions. He could not be weaned from the ventilator and three weeks later, his repeat MRI showed worsening of lesions with infarction of cerebellar white matter. He remained unresponsive and fulfilled brain death criteria, ultimately dying after discontinuation of life support.
Amish populations are unique in that they represent genetic bottlenecks dating back to the 18th century, distinguishing them from the European population as a whole, as well genetic drift, which has given rise to variable distributions of pathogenic alleles among North American settlements. Our mitochondrial studies and other clinical encounters lead us to the hypothesis that many unrecognized genetic disorders are present in the Mercer County Amish. This is in keeping with studies conducted by the Clinic for Special Children in Strasburg, Pa., founded and led by Holmes Morton. The clinic is a comprehensive care facility for the Plain people in and around Lancaster County. Morton has extensively characterized this population genetically, including variant analysis through whole-genome and exome sequencing. Not surprisingly, the Old Order Amish demonstrate significant population divergence from the general European population. More surprisingly, genetic variants in the Old Order Amish isolate in Lancaster also differ from those in Big Valley, Pa., and those in Cuyahoga County, Ohio.
The Mercer County Amish are among the least genetically characterized Amish communities in the United States, with no catalogue of either genetic disorders or variants seen in the community. We have developed a new program to characterize the genetic variability between Amish Mercer County population and other Amish counties by doing whole-exome and mitochondrial DNA sequencing. This will be crucial to determining the phenotype and frequency of other known and unknown genetic disorders in this population. This project will allow us to characterize load of genetic disease in Old Order Amish of Mercer County and identify disorders that can benefit from early treatment.
Gerard Vockley, MD, PhD
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