title: Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome.
abstract: Phelan-McDermid Syndrome (PMS), which is defined by a deletion within 22q13, demonstrates significant phenotypic variation. Given that six mitochondrial genes are located within 22q13, including complex I and IV genes, we hypothesize that mitochondrial complex activity abnormalities may explain phenotypic variation in PMS symptoms. Complex I, II, II + III and IV activity was measured in 51 PMS participants. Caretakers completed questionnaires and provided genetic information through the PMS foundation registry. Complex activity was abnormal in 59% of PMS participants. Abnormalities were found in complex I and IV but not complex II + III and II activity, consistent with disruption of genes within the 22q13 region. However, complex activity abnormalities were not related to specific gene deletions suggesting a "neighboring effect" of regional deletions on adjacent gene expression. A specific combination of symptoms (autism spectrum disorder, developmental regression, failure-to-thrive, exercise intolerance/fatigue) was associated with complex activity abnormalities. 64% of 106 individuals in the PMS foundation registry who did not have complex activity measured also endorsed this pattern of symptoms. These data suggest that mitochondrial abnormalities, specifically abnormalities in complex I and IV activity, may explain some phenotypic variation in PMS individuals. These results point to novel pathophysiology mechanisms and treatment targets for PMS patients.
authors.affiliation: University of Arkansas for Medical Sciences, Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, AR 72202, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Frye
authors.affiliation: Kansas University Medical Center, Kansas City, Kansas, KS, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Cox
authors.affiliation: University of Arkansas for Medical Sciences, Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, AR 72202, USA.
authors.forename: John
authors.initials: J
authors.lastname: Slattery
authors.affiliation: University of Arkansas for Medical Sciences, Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, AR 72202, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Tippett
authors.affiliation: University of Arkansas for Medical Sciences, Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, AR 72202, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kahler
authors.affiliation: Center for Autism and Related Disorders, Inc., Woodland Hills, California, CA, USA.
authors.forename: Doreen
authors.initials: D
authors.lastname: Granpeesheh
authors.affiliation: Drexel University College of Medicine, Department of Pediatrics, Neurology Section, St. Christopher's Hospital for Children, Philadelphia, PA 19134, USA.
authors.forename: Shirish
authors.initials: S
authors.lastname: Damle
authors.affiliation: Drexel University College of Medicine, Department of Pediatrics, Neurology Section, St. Christopher's Hospital for Children, Philadelphia, PA 19134, USA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Legido
authors.affiliation: Drexel University College of Medicine, Department of Pediatrics, Neurology Section, St. Christopher's Hospital for Children, Philadelphia, PA 19134, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goldenthal
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002892:Chromosomes, Human, Pair 22 / Q000201:enzymology / Q000235:genetics; D002950:Citrate (si)-Synthase / Q000235:genetics; D004579:Electron Transport / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D050259:Genes, Mitochondrial; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000473:pathology*; D012042:Registries; D055815:Young Adult
chemical_list: D002950:Citrate (si)-Synthase
references.citation: Am J Med Genet A. 2014 Jul;164A(7):1666-76
references.pmid: 24700646
references.citation: Mol Genet Metab. 2008 Mar;93(3):314-22
references.pmid: 18023382
references.citation: Biochem Biophys Res Commun. 1997 Dec 18;241(2):589-94
references.pmid: 9425316
references.citation: Biochim Biophys Acta. 1996 Jun 7;1307(2):157-61
references.pmid: 8679700
references.citation: PLoS Genet. 2011 Jul;7(7):e1002173
references.pmid: 21779178
references.citation: Nat Genet. 1999 Nov;23(3):333-7
references.pmid: 10545952
references.citation: Nat Genet. 2009 Apr;41(4):430-7
references.pmid: 19270704
references.citation: Science. 2007 Feb 9;315(5813):848-53
references.pmid: 17289997
references.citation: Nat Genet. 2009 Apr;41(4):424-9
references.pmid: 19270705
references.citation: PLoS One. 2013 Nov 12;8(11):e79973
references.pmid: 24265791
references.citation: PLoS Biol. 2010 Nov 23;8(11):e1000543
references.pmid: 21124890
references.citation: Am J Hum Genet. 2009 Sep;85(3):401-7
references.pmid: 19732863
references.citation: Neuromuscul Disord. 2009 Feb;19(2):151-4
references.pmid: 19056268
references.citation: Transl Psychiatry. 2013 Jun 18;3:e273
references.pmid: 23778583
references.citation: J Child Neurol. 2000 Jun;15(6):357-61
references.pmid: 10868777
references.citation: Pediatrics. 2004 Jul;114(1):129-40
references.pmid: 15231919
references.citation: Eur J Hum Genet. 2014 Mar;22(3):431-4
references.pmid: 23838601
references.citation: Hum Genet. 2014 Jul;133(7):847-59
references.pmid: 24481935
references.citation: Biochim Biophys Acta. 2004 Jan 20;1676(2):119-26
references.pmid: 14746906
references.citation: Mol Psychiatry. 2010 Jan;15(1):38-52
references.pmid: 18607376
references.citation: Methods Cell Biol. 2007;80:93-119
references.pmid: 17445690
references.citation: Am J Med Genet A. 2008 Nov 1;146A(21):2822-7
references.pmid: 18924171
references.citation: PLoS One. 2014 Jan 08;9(1):e85436
references.pmid: 24416410
references.citation: Sleep. 2000 Dec 15;23(8):1043-51
references.pmid: 11145319
references.citation: Nature. 2011 Apr 28;472(7344):437-42
references.pmid: 21423165
references.citation: Am J Hum Genet. 2006 Aug;79(2):332-41
references.pmid: 16826523
references.citation: Mol Genet Metab. 2012 Mar;105(3):457-62
references.pmid: 22189081
references.citation: Mol Syndromol. 2012 Apr;2(3-5):186-201
references.pmid: 22670140
references.citation: Exp Neurol. 2014 Nov;261:553-62
references.pmid: 25109669
references.citation: Transl Psychiatry. 2013 Mar 05;3:e237
references.pmid: 23462988
references.citation: J Child Neurol. 2010 Oct;25(10):1232-5
references.pmid: 20179003
references.citation: J Child Neurol. 2012 Jul;27(7):942-9
references.pmid: 22378673
references.citation: Hum Mol Genet. 2000 Mar 22;9(5):795-801
references.pmid: 10749987
references.citation: Genome Res. 2010 May;20(5):554-64
references.pmid: 20212020
references.citation: Nat Genet. 1993 Jul;4(3):289-94
references.pmid: 7689389
references.citation: Hum Mol Genet. 2009 Feb 15;18(4):714-22
references.pmid: 19028666
references.citation: Transl Psychiatry. 2013 Jan 22;3:e220
references.pmid: 23340503
references.citation: Pediatrics. 2008 Dec;122(6):1343-50
references.pmid: 19047255
references.citation: Arch Neurol. 2004 Jun;61(6):950-2
references.pmid: 15210538
references.citation: J Child Neurol. 2012 Mar;27(3):398-401
references.pmid: 22114216
references.citation: Hum Mol Genet. 2009 Nov 1;18(21):4118-29
references.pmid: 19648292