Mitochondrial DNA Deletion Syndromes Genetic Testing Policy

Transcription

1 Mitchndrial DNA Deletin Syndrmes Genetic Testing Plicy Prcedure(s) addressed by this plicy: Prcedure Cde(s) mtdna Deletin Analysis What are mtdna Deletin Syndrmes? Mitchndrial DNA deletin syndrmes include three verlapping phentypes: Kearns-Sayre syndrme (KSS), Pearsn syndrme, and prgressive external phthalmplegia (PEO). 1,2 These three phentypes may be bserved in different members f the same family r may evlve in a given individual ver time. 1 KSS is a multisystem disrder defined by three key signs and symptms: nset befre age 20 years (typically in childhd), pigmentary retinpathy, and PEO. Affected individuals must als have at least ne f the fllwing: cardiac cnductin blck, cerebrspinal fluid prtein cncentratin >100 mg/dl, r cerebellar ataxia. Other findings may include shrt stature, hearing lss, dementia, limb weakness, diabetes mellitus, hypparathyridism, and grwth hrmne deficiency. 1,2 Pearsn syndrme includes the findings f siderblastic anemia and excrine pancreas dysfunctin. It is usually fatal in infancy. Thse surviving int childhd develp features f KSS. 1,3 PEO is a mitchndrial mypathy characterized by findings including drping f the eyelids (ptsis), paralysis f the extracular muscles (phthalmplegia), and variably severe prximal limb weakness. 1 Rarely Leigh syndrme can manifest due t a mtdna deletin which is characterized by basal ganglia and brain stem lesins. 1 These cnditins are caused by pathgenic variants in mitchndrial DNA (mtdna). Pathgenic variants can be spradic (nt inherited) r maternally inherited. Deletins f mitchndrial DNA (mtdna), ranging in size frm 1.1 t 10 kb, are assciated with Kearns-Sayre syndrme, Pearsn syndrme, prgressive external phthalmplegia, and rarely Leigh syndrme. mtdna deletins are rarely transmitted. A male wh carries the mtdna mutatin cannt pass it n t his children. 1,2,4 The same mtdna deletin can be respnsible fr different syndrmes. The wide variability in clinical presentatin depends n hw much mutant mtdna is present in a tissue (heterplasmy), which rgans and tissues have mutant mtdna, and hw vulnerable thse tissues are t impaired mitchndrial functin (threshld effect). 1 Management is usually symptmatic and supprtive. 1 An epidemilgic study f an adult ppulatin in the Nrth East f England estimated the prevalence f large-scale mtdna deletins at 1.2:100,000. 5

2 Test Infrmatin Diagnsis f mtdna deletin syndrmes is based n a cmbinatin f clinical findings and genetic testing. 1,2 Findings in KSS and PEO may include elevated lactate and pyruvate levels in bld and cerebrspinal fluid while at rest, with excessive increases in bld after mderate activity. MRI can demnstrate leukencephalpathy, ften assciated with cerebral r cerebellar atrphy r basal ganglia lesins. 1 Bichemical studies may als be perfrmed, thugh: "It is imprtant t nte that bichemical abnrmalities may nt be present during perids when the mitchndrial disease is quiescent/drmant." 6 Detectin rate fr cases f KSS and PEO by deletin/duplicatin analysis is 90% and 50%, respectively. 1 In cases f KSS and PEO, the disease-causing rearrangements can be detected n a muscle specimen but typically are undetectable in bld, therefre mutatinal analysis is best btained thrugh muscle bipsy by NGS. 1 The same wuld apply t the rare cases f Leigh syndrme. 1 Fr Pearsn syndrme, the disease-causing rearrangements can be detected in bld by whle mitchndrial genme amplificatin fllwed by massively parallel sequencing, detecting abut 90% f thse affected. 1,2,3 Any mlecular genetic test fr a mtdna mutatin shuld ideally be directed by the clinical phentype and results f ther clinical, labratry, and radilgical investigatins. 2(CMGS) Genetic test results alne cannt predict the exact curse r phentype f the disease. Therefre, testing is nt apprpriate fr asymptmatic at-risk individuals. 1,2 Prenatal Testing fr At-Risk Pregnancies: Prenatal testing fr a knwn mitchndrial mutatin has limited clinical utility. Even in circumstances where a mther is carrier f a mtdna deletin, it is rare t transmit it. 7 And when transmitted, it is typically transmitted as a duplicatin, which des nt prduce symptms. 8,9,10 As a result f the issues described abve, the availability f prenatal testing fr mtdna deletins is presently limited. Published guidelines frm the 74 th Eurpean Neurmuscular Centre Internatinal Cnsensus stated regarding prenatal testing via CVS: Recurrence risks fr Kearns Sayre syndrme (KSS) are cmplex. Fr wmen with KSS due t mtdna rearrangements, particularly thse in whm rearrangements are detectable in bld (>5%), we recmmend CVS. The analysis shuld be dne by Suthern bltting (PCR analysis may be misleading bth because f cntaminatin with maternal mtdna and f prblems with interpretatin). Fr wmen with chrnic prgressive external phthalmplegia (CPEO) in whm nly mtdna deletins are detectable in muscle, we believe that the risk f transmitting the disease is very lw and that n special precautins are essential. Fr healthy wmen with a single affected child with KSS r Pearsn's syndrme and n detectable deletin in bld, the risk f anther affected child is prbably very lw. CVS analysis may be an ptin. 10 Page 2

3 A retrspective chart review f prenatal samples prcessed in Eurpe cncluded that prenatal testing fr mitchndrial diseases was infrmative fr the select mutatins studied. 11 Guidelines and Evidence N specific evidence-based U.S. testing guidelines were identified. The Mitchndrial Medicine Sciety develped cnsensus recmmendatins using the Delphi methd and published them in Recmmendatins fr testing bld, urine, and spinal fluid The initial evaluatin in bld fr mitchndrial disease shuld include cmplete bld cunt, creatine phsphkinase, transaminases, albumin, lactate and pyruvate, amin acids, and acylcarnitines, alng with quantitative r qualitative urinary rganic acids. Cautin must be taken t ensure that specimens are cllected apprpriately, especially fr lactate and pyruvate measurements. Pstprandial lactate levels are mre sensitive than fasting specimens and are preferred when pssible. Cautin must be taken t nt verinterpret small elevatins in pstprandial lactate. The lactate/pyruvate rati in bld r CSF is f value nly when the lactate level is elevated. Quantitative 3-methylglutacnic acid (3MG) measurements in plasma and urine shuld be btained when pssible in additin t urine rganic acids in patients being evaluated fr mitchndrial disease. Creatine phsphkinase and uric acid shuld be assessed in patients with muscle symptms wh are suspected f having mitchndrial diseases. Urine amin acid analysis shuld be btained in the evaluatin f mitchndrial tubulpathy. When CSF is btained, it shuld be sent fr lactate, pyruvate, amin acid, and 5- methyltetrahydrflate measurements. Further research is needed regarding ther bimarkers such as FGF21, glutathine, and CSF nepterin. Recmmendatins fr DNA testing Massively parallel sequencing/ngs f the mtdna genme is the preferred methdlgy when testing mtdna and shuld be perfrmed in cases f suspected mitchndrial disease instead f testing fr a limited number f pathgenic pint mutatins. Patients with a strng likelihd f mitchndrial disease because f a mtdna mutatin and negative testing in bld, shuld have mtdna assessed in anther tissue t avid the pssibility f missing tissue-specific mutatins r lw levels f heterplasmy in bld; tissue-based testing als helps assess the risk f ther rgan invlvement and hetergeneity in family members and t guide genetic cunseling. Heterplasmy analysis in additinal tissues can selectively be mre infrmative and accurate than testing in bld alne. Page 3

4 The mst cmmnly used methds fr detectin f mtdna deletins previusly included Suthern blt and lng range (deletin-specific) PCR analysis. Hwever, Suthern blt analysis lacks sufficient sensitivity t detect lw levels f heterplasmic deletins. In cntrast, array cmparative genme hybridizatin detects deletins and als estimates the deletin breakpints and deletin heterplasmy. All f these methdlgies are being replaced by NGS f the entire mitchndrial genme which prvides sufficiently deep cverage unifrmly acrss the mtdna genme t sensitively detect and characterize either single r multiple deletins. 12 When cnsidering nuclear gene testing in patients with likely primary mitchndrial disease, NGS methdlgies prviding cmplete cverage f knwn mitchndrial disease genes is preferred. Single-gene testing shuld usually be avided because mutatins in different genes can prduce the same phentype. If n mutatin is identified via knwn NGS panels, then whle exme sequencing shuld be cnsidered. Recmmendatins fr pathlgy testing Bipsy shuld nly be cnsidered when the diagnsis cannt be cnfirmed with DNA testing f ther mre accessible tissues. Muscle (and/r liver) bipsies are ften nt necessary and shuld be avided when pssible due t their invasive nature, unless ther types f analyses such as pathlgy, enzymlgy, r mtdna cpy number analyses in these tissues are required fr diagnsis. Quantitative 3-methylglutacnic (3MG) may be useful, if elevatins are bserved in rganic acids. Grwth differentiatin factr 15 (GDF15) has been shwn t be a sensitive and specific bimarker fr mitchndrial dysfunctin. 13 A wrkshp f the Natinal Institute f Neurlgical Disrders and Strke (2008) 6 summarizes: "The diagnsis f mitchndrial diseases is cmplicated by their hetergeneus presentatins and by the lack f screening prcedures r diagnstic bimarkers that are bth sensitive and specific. The wrkshp panelists explained that diagnsis is ften a lengthy prcess beginning with a general clinical evaluatin fllwed by metablic screening and imaging and finally by genetic tests and mre invasive bichemical and histlgical analyses. The identificatin f knwn mitchndrial mutatins in tissue has greatly aided diagnsis. Hwever, even when clinical features and family histry strngly suggest mitchndrial disease, the underlying genetic mutatin can elude detectin, and there is n current screening prcedure that wuld be practical fr all cases f suspected mitchndrial disease." The Eurpean Federatin f Neurlgical Sciences (2009) 3 prvided mlecular diagnstic cnsensus-based guidelines fr these cnditins: "If the phentype suggests syndrmic MID [mitchndrial disrders] due t mtdna deletin (mtpeo, KSS, Pearsn's syndrme), mtdna analysis starts with RFLP r Suthern-blt frm apprpriate tissues. mtdna deletins with lw heterplasmy rate Page 4

5 Criteria may be detected nly by lng-range PCR. If neither a single deletin nr multiple deletins are fund, mtdna sequencing is recmmended." mtdna Deletin Knwn Familial Mutatin Genetic cunseling: Pre and pst-test cunseling by an apprpriate prvider (as deemed by the Health Plan plicy), AND Previus Genetic Testing: N previus genetic testing in the individual fr mtdna deletin syndrmes*, and A mtdna deletin identified in the mther, AND Diagnstic Testing fr Symptmatic Individual: Clinical exam and/r bichemical testing suggestive, but nt cnfirmatry, f a diagnsis f a mtdna deletin syndrme, OR Prenatal Testing fr At-Risk Pregnancies: mtdna deletin syndrme-causing mutatin identified in a previus child r in the mther. mtdna Deletin Analysis Genetic cunseling: Pre and pst-test cunseling by an apprpriate prvider (as deemed by the Health Plan plicy), AND Previus Testing: N previus genetic testing in the individual fr mtdna deletins*, and N knwn mitchndrial pathgenic variants r deletins in the family, AND Diagnstic Testing fr Symptmatic Individuals: Clinical examinatin and/r bichemical testing suggestive, but nt cnfirmatry, f ne f the mtdna deletin syndrmes described abve, and Genetic testing is needed fr ne f the fllwing purpses: T cnfirm the diagnsis, r T ffer testing t family members, r Fr prenatal diagnstic purpses, AND N evidence f paternal transmissin. *Genetic testing has rapidly advanced ver the last 20 years. Exceptins may be cnsidered if an individual has previusly had negative genetic testing, but technical advances in testing demnstrate significant advantages that wuld supprt a medical need t re-test. Exclusins and Other Cnsideratins: Testing addressed in this guideline is nt applicable in the fllwing cases: Mitchndrial DNA depletin syndrmes, and Cnditins in which secndary mtdna deletins are due t variants in nuclear genes. Page 5

6 References 1. DiMaur S, Hiran M. (Updated May 3, 2011). Mitchndrial DNA deletin syndrmes. In: GeneReviews at GeneTests: Medical Genetics Infrmatin Resurce (database nline). Cpyright, University f Washingtn, Seattle Available at: 2. Clinical Mlecular Genetics Sciety Guidelines (CMGS), UK. Practice guidelines fr the mlecular diagnsis f mitchndrial diseases. July Available at 3. Finsterer J, Harb HF, Baets J, et al. EFNS guidelines n the mlecular diagnsis f mitchndrial disrders. Eur J Neurl. 2009;16(12): Ma C, Hlt I. Clinical and Mlecular Aspects f Diseases f Mitchndrial DNA Instability. Chang Gung Med J. 2009;32: Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylr RW, Chinnery PF, Turnbull DM. Prevalence f mitchndrial DNA disease in adults. Ann Neurl. 2008;63:35 9. Available at 6. Natinal Institute f Neurlgical Disrders and Strke wrkshp prceedings. Mitchndrial encephalpathies: ptential relatinships t autism? Available at: 7. Chinnery PF. Inheritance f mitchndrial disrders. Mitchndrin Nv;2(1-2): PMID: Marchingtn DR, Macaulay V, Hartshrne GM, Barlw D, Pultn J. Evidence frm Human Ocytes fr a Genetic Bttleneck in an mtdna Disease. Am J Hum Genet. 1998;63: Manfredi G, Vu T, Bnilla E, Schn EA, DiMaur S, Arnaud E, Zhang L, Rwland LP, Hiran M. Assciatin f mypathy with large-scale mitchndrial DNA duplicatins and deletins: which is pathgenic? Ann Neurl Aug;42(2): PubMed PMID: Pultn J, Finsterer J, Yu-Wai-Man P. Genetic Cunselling fr Maternally Inherited Mitchndrial Disrders. Ml Diagn Ther Aug;21(4): di: /s Review. Erratum in: Ml Diagn Ther Jul 4 PMID: Nesbitt V, Alstn CL, Blakely EL, Fratter C, Feeney CL, Pultn J, Brwn GK, Turnbull DM, Taylr RW, McFarland R. A natinal perspective n prenatal testing fr mitchndrial disease. 2014; 22(11). 12. Parikh S, Gldstein A, Kenig MK, Scaglia F, Enns G, Sanet R, Anselm I, Chen B, Falk M, Greene C, Grpman A, Haas R, Hiran M, Mrgan P, Sims K, Tanplsky M, Van Hve JLK, Wlfe L, DiMaur S. Diagnsis and management f mitchndrial disease: a cnsensus statement frm the Mitchndrial Medicine Sciety. Gen in Med. 2015; (17): Mnter et al. GDF-15 Is Elevated in Children with Mitchndrial Diseases and Is Induced by Mitchndrial Dysfunctin. PLOS One. 2016;Feb 11;11(2). This plicy was develped by the PLUGS Insurance Advcacy Mitchndrial Plicy Subcmmittee and was supprted by a grant frm the Seattle Children s Hspital Mitchndrial Research Guild. Last update June 2018 Page 6