title: Mitochondrial respiratory chain disorders in the Old Order Amish population.
abstract: The Old Order Amish populations in the US are one of the Plain People groups and are descendants of the Swiss Anabaptist immigrants who came to North America in the early eighteenth century. They live in numerous small endogamous demes that have resulted in reduced genetic diversity along with a high prevalence of specific genetic disorders, many of them autosomal recessive. Mitochondrial respiratory chain deficiencies arising from mitochondrial or nuclear DNA mutations have not previously been reported in the Plain populations. Here we present four different Amish families with mitochondrial respiratory chain disorders. Mutations in two mitochondrial encoded genes leading to mitochondrial respiratory chain disorder were identified in two patients. In the first case, MELAS syndrome caused by a mitochondrial DNA (mtDNA) mutation (m.3243A>G) was identified in an extended Amish pedigree following a presentation of metabolic strokes in the proband. Characterization of the extended family of the proband by a high resolution melting assay identified the same mutation in many previously undiagnosed family members with a wide range of clinical symptoms. A MELAS/Leigh syndrome phenotype caused by a mtDNA mutation [m.13513G>A; p.Asp393Asn] in the ND5 gene encoding the ND5 subunit of respiratory chain complex I was identified in a patient in a second family. Mutations in two nuclear encoded genes leading to mitochondrial respiratory chain disorder were also identified in two patients. One patient presented with Leigh syndrome and had a homozygous deletion in the NDUFAF2 gene, while the second patient had a homozygous mutation in the POLG gene, [c.1399G>A; p.Ala467Thr]. Our findings identify mitochondrial respiratory chain deficiency as a cause of disease in the Old Order Amish that must be considered in the context of otherwise unexplained systemic disease, especially if neuromuscular symptoms are present.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Electronic address: lina.gonzalez@chp.edu.
authors.forename: Lina
authors.initials: L
authors.lastname: Ghaloul-Gonzalez
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Goldstein
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Walsh Vockley
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dobrowolski
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Biery
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Afifa
authors.initials: A
authors.lastname: Irani
authors.affiliation: University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Ibarra
authors.affiliation: Central Pennsylvania Clinic, A Medical Home for Special Children and Adults, Belleville, PA, USA.
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: Al-Walid
authors.initials: AW
authors.lastname: Mohsen
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
mesh_terms: D000293:Adolescent; D061365:Amish / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D017241:MELAS Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008928:Mitochondria / Q000235:genetics; D028361:Mitochondrial Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009656:North America; D010375:Pedigree; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C501824:NDUFAF2 protein, human; C481838:MT-ND5 protein, human; D000074002:DNA Polymerase gamma; C413027:POLG protein, human; D042967:Electron Transport Complex I
keywords: Amish; MELAS; Mitochondrial disease; ND5 gene; NDUFAF2 gene; POLG gene