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Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF.

Genet Med. 2017 Dec;19(12):10.1038/gim.2017.107. doi: 10.1038/gim.2017.107. Epub 2017 Jul 27. ABSTRACT The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease. PMID:28749475 | PMC:PMC7804217 | DOI:10.1038/gim.2017.107

July 28, 2017

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. 

Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, Jhangiani SN, Gibbs RA, Elsea SH, Porter BE, Graham BH.

Mol Genet Metab. 2017 Aug;121(4):314-319. doi: 10.1016/j.ymgme.2017.06.009. Epub 2017 Jun 24. PMID: 28673551; PMCID: PMC7539367. Abstract Objective: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. Methods: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. Results: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. Significance: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. PMID: 28673551 | PMCID: PMC7539367 | DOI: 10.1016/j.ymgme.2017.06.009

June 24, 2017
Gene Discovery

A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

Marin-Valencia I, Novarino G, Johansen A, Rosti B, Issa MY, Musaev D, Bhat G, Scott E, Silhavy JL, Stanley V, Rosti RO, Gleeson JW, Imam FB, Zaki MS, Gleeson JG.

J Med Genet. 2018 Jan;55(1):48-54. doi: 10.1136/jmedgenet-2017-104627. Epub 2017 Jun 16. ABSTRACT BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. CONCLUSION: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function. PMID:28626029 | PMC:PMC6056005 | DOI:10.1136/jmedgenet-2017-104627

June 20, 2017

Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic

Bick D, Fraser PC, Gutzeit MF, Harris JM, Hambuch TM, Helbling DC, Jacob HJ, Kersten JN, Leuthner SR, May T, North PE, Prisco SZ, Schuler BA, Shimoyama M, Strong KA, Van Why SK, Veith R, Verbsky J, Weborg AM Jr, Wilk BM, Willoughby RE Jr, Worthey EA, Dimmock DP. 

J Pediatr Genet. 2017 Jun;6(2):61-76. doi: 10.1055/s-0036-1593968. Epub 2016 Nov 28. ABSTRACT A pilot program was initiated using whole genome sequencing (WGS) to diagnose suspected genetic disorders in the Genetics Clinic at Children’s Hospital of Wisconsin. Twenty-two patients underwent WGS between 2010 and 2013. Initially, we obtained a 14% (3/22) diagnosis rate over 2 years; with subsequent reanalysis, this increased to 36% (8/22). Disease causing variants were identified in SKIV2L, CECR1, DGKE, PYCR2, RYR1, PDGFRB, EFTUD2, and BCS1L. In 75% (6/8) of diagnosed cases, the diagnosis affected treatment and/or medical surveillance. Additionally, one case demonstrated a homozygous A18V variant in VLDLR that appears to be associated with a previously undescribed phenotype. PMID:28496993 | PMC:PMC5423809 | DOI:10.1055/s-0036-1593968

May 13, 2017

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

Manolio TA, Fowler DM, Starita LM, Haendel MA, MacArthur DG, Biesecker LG, Worthey E, Chisholm RL, Green ED, Jacob HJ, McLeod HL, Roden D, Rodriguez LL, Williams MS, Cooper GM, Cox NJ, Herman GE, Kingsmore S, Lo C, Lutz C, MacRae CA, Nussbaum RL, Ordovas JM, Ramos EM, Robinson PN, Rubinstein WS, Seidman C, Stranger BE, Wang H, Westerfield M, Bult C.

Cell. 2017 Mar 23;169(1):6-12. doi: 10.1016/j.cell.2017.03.005. ABSTRACT Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing. PMID:28340351 | PMC:PMC5511379 | DOI:10.1016/j.cell.2017.03.005

March 25, 2017

AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant

Morton SU, Prabhu SP, Lidov HGW, Shi J, Anselm I, Brownstein CA, Bainbridge MN, Beggs AH, Vargas SO, Agrawal PB.

Cold Spring Harb Mol Case Stud. 2017 Mar;3(2):a001560. doi: 10.1101/mcs.a001560. ABSTRACT Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function. PMID:28299359 | PMC:PMC5334471 | DOI:10.1101/mcs.a001560

March 17, 2017


ADCY5 Dyskinesia

Hisama FM, Friedman J, Raskind WH, Bird TD.

2014 Dec 18 [updated 2020 Jul 30]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. ABSTRACT CLINICAL CHARACTERISTICS: ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency. DIAGNOSIS/TESTING: The diagnosis of ADCY5 dyskinesia is established in a proband with a hyperkinetic movement disorder (in the absence of structural brain abnormalities) and a heterozygous pathogenic variant (or, rarely, biallelic pathogenic variants) in ADCY5 identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Management by multidisciplinary specialists, including a neurologist or neurogeneticist, cardiologist, physical therapist, social worker, speech and language pathologist, and other specialists is recommended as needed. Anecdotally, medications have had variable effect in suppressing debilitating symptoms. Treatment should be determined by the individual’s physician, taking into account potential risk/benefit, other medical conditions, allergies, and potential drug-drug interactions. Response to medication is difficult to evaluate because some individuals have long periods (weeks) of remission of the dyskinesia. Physical and occupational therapy may help maintain mobility and function. Speech and language therapy for dysarthria may include alternative communication methods. Cognitive impairment and psychiatric manifestations are managed per standard practice. Surveillance: Routine follow up of neurologic involvement, dysarthria, oculomotor involvement, musculoskeletal involvement, activities of daily living, cognitive impairment, and psychiatric manifestations. Pregnancy management: Potential teratogenic effects of medications given for treatment of ADCY5 dyskinesia should be discussed with affected women of childbearing age, ideally prior to conception. GENETIC COUNSELING: ADCY5 dyskinesia is typically inherited in an autosomal dominant (AD) manner. Autosomal recessive (AR) inheritance has been reported in two families. AD inheritance: The majority of individuals diagnosed with ADCY5 dyskinesia represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo pathogenic variant. Each child of an individual with ADCY5 dyskinesia has a 50% chance of inheriting the pathogenic variant. Both AD and AR inheritance: Once the ADCY5 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ADCY5 dyskinesia are possible. PMID:25521004 | Bookshelf:NBK263441

January 1, 1993

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