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Guideline Summary
Guideline Title
EFNS guidelines on the molecular diagnosis of mitochondrial disorders.
Bibliographic Source(s)
Finsterer J, Harbo HF, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schols L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Gasser T, European Federation of Neurological Sciences. EFNS guidelines on the molecular diagnosis of mitochondrial disorders. Eur J Neurol. 2009 Dec;16(12):1255-64. [33 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Angelini C, Federico A, Reichmann H, Lombes A, Chinnery P, Turnbull D. Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol 2006 Sep;13(9):923-9.

Scope

Disease/Condition(s)

Mitochondrial disorders:

  • Mitochondrial DNA (mtDNA) mutations
  • Nuclear DNA mutations
  • Defects of intergenomic signaling
Guideline Category
Diagnosis
Evaluation
Clinical Specialty
Medical Genetics
Neurology
Pediatrics
Intended Users
Physicians
Guideline Objective(s)
  • To provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs)
  • To summarise the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding in which case a molecular diagnostic work-up is indicated
Target Population

Patients with suspected mitochondrial disorders

Interventions and Practices Considered
  1. Comprehensive individual and family history and clinical investigations
    • Chemical investigation of serum, cerebrospinal fluid and urine
    • Electrophysiological investigations
    • Functional and imaging studies of cerebrum
    • Muscle biopsy
  2. Determining if phenotype conforms to distinct syndromic mitochondrial disorder (MID) or non-syndromic MID and if phenotype occurred sporadically or was autosomally or maternally inherited
  3. Genetic testing
    • Nuclear gene sequencing
    • Mitochondrial DNA sequencing
    • Southern blot
Major Outcomes Considered

Accuracy of diagnostic tests

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

To collect data about planning, conditions and performance of molecular diagnosis of mitochondrial disorders (MIDs), a literature search in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, was carried out and original papers, meta-analyses, review papers and guideline recommendations were reviewed.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus (Consensus Development Conference)
Description of Methods Used to Formulate the Recommendations

Consensus about the recommendations was reached by a step-wise approach. First, task force members met at the European Federation of Neurological Societies (EFNS) congresses in 2007 and 2008 to discuss the preparations of the guidelines. In a second step, experts in the field of genetics of mitochondrial disorders (MIDs) wrote a guideline proposal. In a third step, these recommendations were discussed in detail amongst all task force members until a final consensus had been reached.

Recommendations follow the criteria established by the EFNS, with some modifications to account for the specific nature of genetic tests. Since genetic testing is by definition the gold standard to diagnose a genetic disease, its diagnostic accuracy cannot be tested against another diagnostic method. Therefore, the level of recommendations will be based on the quality of available studies, which investigate the proportion of cases of a clinically defined group of patients that are explained by a specific molecular diagnostic test. As nearly all of these studies have a retrospective design and look for a specific mutation in a previously ascertained and clinically diagnosed cohort of patients, the highest achievable recommendation level will be B (see "Rating Scheme for the Strength of the Recommendations" below). If only small case-series studying genotype-phenotype correlations are available, the level of recommendation will be C. If only case reports are available but experts still provided recommendations, the recommendation level is assessed as 'good practice point'.

Rating Scheme for the Strength of the Recommendations

Rating of Recommendations

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

The guidelines were validated according to the European Federation of Neurological Societies (EFNS) criteria (see "Availability of Companion Documents" field in this summary).

Recommendations

Major Recommendations

Summary of Recommendations for the Genetic Diagnosis of Mitochondrial Disorders

Diagnostic work-up for suspected mitochondrial disorder (MID) is a stepwise procedure. The first step comprises a comprehensive individual and family history and clinical investigations by specialists in neurology, ophthalmology, otology, endocrinology, cardiology, gastroenterology, nephrology, haematology or dermatology. Important instrumental procedures include chemical investigations of the serum, cerebrospinal fluid (CSF) and urine, electrophysiological investigations, functional and imaging studies of the cerebrum, and muscle biopsy. Based on their results the probability for the presence of a MID can be assessed according to the Nijmegen, Bernier or Walker diagnostic criteria.

In a second step, clinicians need to decide whether an individual phenotype conforms to any of the syndromic MIDs or represents a non-syndromic MID and need to determine if the phenotype occurred sporadically or followed a Mendelian or maternal trait of inheritance.

Genetic testing is the third step and depends on step 1 and 2. If the phenotype suggests syndromic MID due to mitochondrial DNA (mtDNA) point mutations (MELAS, MERRF, NARP, LHON) DNA-microarrays using allele-specific oligo-nucleotide hybridisation, real-time-polymerase chain reaction (PCR) or single-gene-sequencing are indicated. If the phenotype suggests syndromic MID due to mtDNA deletion (mtPEO, KSS, Pearson's syndrome) mtDNA analysis starts with restriction fragment length polymorphism (RFLP) or Southern-blot from appropriate tissues (see Fig. 2 in the original guideline document). mtDNA deletions with low heteroplasmy rate may be detected only by long-range PCR. If neither a single deletion nor multiple deletions are found, mtDNA sequencing is recommended (Level B).

If RFLP or Southern-blot of muscle mtDNA detects multiple mtDNA deletions (breakage syndromes), sequencing of POLG1 (adPEO, arPEO, SANDO, SCAE, AHS), POLG2, PEO1 (adPEO), ANT1 (adPEO), TYMP (MNGIE) or OPA1 (ADOAD) genes should follow (Level B). Sequencing should start with the POLG1 gene, since it is the most likely to carry a mutation. Sequencing of TYMP should be performed only if serum thymidine is elevated. If the phenotype suggests LS appropriate nuclear DNA (nDNA) genes encoding for respiratory chain complex (RCC) subunits or assembly factors (SURF1, ATP12, SCO1, SCO2, COX10, COX15, NDUFS, NDUFV, SDH) need to be sequenced. Sequencing of appropriate nDNA genes is also required if the phenotype suggests GRACILE (TMEM70), IOSCA (PEO1), MLASA (PUS1), Barth syndrome (TAZ/G4.5), DDS/Mohr-Tranebjaerg syndrome (DDP1), MIRAS (POLG1) or CMT2A (mitofusin-2) (Level B).

If an individual presents with a non-syndromic phenotype, biochemical investigations of the most affected tissues (muscle, liver, brain, skin) should clarify if a single or multiple RCCs are defective (Level B). If a single autosomally inherited defect is present, sequencing of appropriate structural subunits or assembly-factors of RCCI, III, IV or V is necessary (Level B). If biochemical investigations in muscle tissue suggest coenzyme-Q (CoQ)-deficiency, sequencing of genes involved in the Co-Q biosynthesis (most frequently ETFDH) should be carried out (Level B). If the single RCC defect is maternally inherited, one should proceed with mtDNA sequencing of appropriate mtDNA genes (Level B).

If multiple autosomally inherited biochemical defects are found, a Southern-blot or quantitative PCR should clarify if there is mtDNA depletion or not. If these investigations detect mtDNA depletion, sequencing of the TK2 or RRM2B genes is indicated if the skeletal muscle is the predominantly affected organ. Elevated creatine-kinase may help to prioritise testing for TK2 or RRM2B. If muscle and cerebrum are the most affected organs, sequencing of the SUCLG1, SUCLA2 genes or if the liver is the predominantly affected organ sequencing of the POLG1, PEO1, DGUOK or MPV17 genes is recommended (Level B, see Fig. 2 in the original guideline document).

If Southern-blot fails to detect mtDNA depletion, sequencing of genes involved in the mitochondrial protein synthesis machinery (PUS1, ETF, EFG1, ETFs, MRPS16, MRPS22, RARS2, DARS2) is recommended (Level B, see Fig. 2 in the original guideline). Corresponding proteins of the MRPS22, ETF and ETFs genes are involved in the initiation and elongation of peptides during protein synthesis and are responsible for the group of elongation-factor-disorders. In case of pontocerebellar hypoplasia (PCH) and severe psychomotor impairment, the RARS2 gene should be sequenced for splice-site mutations. Sequencing of the FASTKD2 gene is required in cases with developmental delay, asymmetric cerebral atrophy, epilepsy, hemiplegia and myopathy with COX-deficiency after exclusion of other causes of COX-deficiency.

Tissues most frequently chosen are blood (MELAS, MERRF, NARP, LHON, Pearson's syndrome) or muscle (KSS). Availability of muscle tissue for mtDNA-analysis is mandatory in patients with phenotypes associated with large-scale mtDNA rearrangements, which can be easily missed in leukocytes except for Pearson syndrome. Alternative tissues for DNA analysis are cells from the urine sediment, buccal mucosa, or hair follicles. mtDNA point mutations can be also detected in blood samples. However, in maternally inherited phenotypes associated with heteroplasmic point mutations, the percentage of mutant mtDNA is often significantly higher in muscle than other tissues.

Definitions:

Genetic Acronyms

  • ADOAD = autosomal dominant optic atrophy
  • adPEO = autosomal dominant progressive external ophthalmoplegia
  • AHS = Alpers-Huttenlocher syndrome
  • ANT = adenine nucleotide translocase
  • arPEO = autosomal recessive progressive external ophthalmoplegia
  • ATP = adenosine-5'-triphosphate
  • COX = cytochrome c oxidase
  • CMT = Charcot-Marie-Tooth disease type 2A
  • DARS2 = aspartyl-tRNA synthetase 2
  • DDP = deafness dystonia peptide 1
  • DDS = deafness-dystonia syndrome
  • DGUOK = deoxyguanosine kinase
  • DNA = deoxyribonucleic acid
  • EFG = elongation factor G
  • ETF = electron transfer flavoprotein
  • ETFDH = electron-transferring flavoprotein dehydrogenase
  • FASTKD2 = Fas-activated serine/threonine kinase (FAST) kinase domains 2
  • GRACILE = growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death
  • IOSCA = infantile-onset spinocerebellar ataxia
  • KSS = Kearns-Sayre syndrome
  • LHON = Leber's hereditary optic neuropathy
  • LS = Leigh syndrome
  • MELAS = mitochondrial encephalopathy, lactic acidosis and stroke-like-episodes syndrome
  • MERRF = myoclonus epilepsy with ragged-red fibres
  • MIRAS = mitochondrial recessive ataxia syndrome
  • MLASA = mitochondrial myopathy and sideroblastic anaemia
  • MNGIE = Myo-neuro-gastro-intestinal encephalomyopathy
  • MPV17 = mitochondrial inner membrane protein
  • MRPs = mitochondrial ribosomal proteins
  • mtPEO = chronic progressive external ophthalmoplegia
  • NADH = nicotinamide adenine dinucleotide (reduced form)
  • NARP = neurogenic weakness, ataxia and retinitis pigmentosa
  • NDUFS = NADH dehydrogenase (ubiquinone) Fe-S protein
  • NDUFV = NADH dehydrogenase (ubiquinone) flavoprotein
  • OPA1 = optic atrophy type 1
  • PEO1 = progressive external ophthalmoplegia 1
  • POLG1 = polymerase (DNA directed), gamma
  • PUS1 = pseudouridylate synthase 1
  • RARS2 = arginyl-transfer (t)RNA synthetase 2
  • RRM2B = ribonucleotide reductase M2 B (TP53 inducible)
  • SANDO = sensory ataxic neuropathy, dysarthria and ophthalmoparesis
  • SCAE = spino-cerebellar ataxia and epilepsy with or without ophthalmoplegia
  • SCO1 and SCO2 = human cytochrome c oxidase assembly factors 1 and 2
  • SDH = succinate dehydrogenase
  • SUCLA2 = succinate-CoA ligase, beta subunit
  • SUCLG1 = succinate-CoA ligase, alpha subunit
  • SURF1 = surfeit locus protein 1
  • TAZ/G4.5= tafazzin/G4.5 gene
  • TK2 = thymidine kinase 2
  • TMEM70 = transmembrane protein 70
  • TYMP = thymidine phosphorylase

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).

Rating of Recommendations

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Clinical Algorithm(s)

An algorithm for the genetic analysis of mitochondrial disorders (MIDs) is provided in the original guideline document.

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for selected recommendations (see "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate use of molecular genetics for diagnosis of mitochondrial disorders

Potential Harms

Not stated

Qualifying Statements

Qualifying Statements

This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.

Implementation of the Guideline

Description of Implementation Strategy

The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies, national ministries of health, World Health Organisation, European Union, and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels, provided there is no advertising attached.

Implementation Tools
Clinical Algorithm
Staff Training/Competency Material
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Finsterer J, Harbo HF, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schols L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Gasser T, European Federation of Neurological Sciences. EFNS guidelines on the molecular diagnosis of mitochondrial disorders. Eur J Neurol. 2009 Dec;16(12):1255-64. [33 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2006 Sep (revised 2009 Dec)
Guideline Developer(s)
European Academy of Neurology - Medical Specialty Society
Source(s) of Funding

European Federation of Neurological Societies

Guideline Committee

European Federation of Neurological Societies Task Force on Diagnosis and Management of Fatty Acid Mitochondrial Disorders

Composition of Group That Authored the Guideline

Task Force Members: J. Finsterer, Krankenanstalt Rudolfstiftung, Vienna, Danube University Krems, Krems, Austria; H. F. Harbo, Department of Neurology, Ulleval, Oslo University Hospital, and Faculty Division Ulleval, University of Oslo, Oslo, Norway; J. Baets, Department of Neurology, University Hospital Antwerp, Antwerpen; Department of Molecular Genetics, VIB, Antwerpen; Laboratory of Neurogenetics, Institute Born-Bunge; University of Antwerp, Antwerpen, Belgium; C. Van Broeckhoven, Department of Molecular Genetics, VIB, Antwerpen; Laboratory of Neurogenetics, Institute Born-Bunge; University of Antwerp, Antwerpen, Belgium; S. Di Donato, Fondazione-IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy; B. Fontaine, Assistance Publique-Hopitaux de Paris, Centre de Reference des Canalopathies Musculaires, Groupe Hospitalier Pitie-Salpetriere, Paris, France; P. De Jonghe, Department of Neurology, University Hospital Antwerp, Antwerpen; Department of Molecular Genetics, VIB, Antwerpen; Laboratory of Neurogenetics, Institute Born-Bunge; University of Antwerp, Antwerpen, Belgium; A. Lossos, Department of Neurology, Hadassah University Hospital, Jerusalem, Israel; T. Lynch, The Dublin Neurological Institute, Mater Misericordiae University, Beaumont & Mater Private Hospitals, Dublin, Ireland; C. Mariotti, Unit of Biochemistry and Genetic of Neurogenetic and Metabolic Diseases, IRCCS Foundation, Neurological Institute Carlo Besta, Milan, Italy; L. Schols, Clinical Neurogenetics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; A. Spinazzola, Division of Molecular Neurogenetics, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy; Z. Szolnoki, Department of Neurology and Cerebrovascular Diseases, Pandy County Hospital, Gyula, Hungary; S. J. Tabrizi, Department of Neurodegenerative Disease, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; C. M. E. Tallaksen, Faculty Division Ulleval University Hospital, University of Oslo, Oslo, Norway; M. Zeviani, Division of Molecular Neurogenetics, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy; J.-M. Burgunder, Department of Neurology, University of Bern, Bern, Switzerland and T. Gasser, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Angelini C, Federico A, Reichmann H, Lombes A, Chinnery P, Turnbull D. Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol 2006 Sep;13(9):923-9.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies (EFNS) Web site External Web Site Policy.

Print copies: Available from Dr Corrado Angelini, Department of Neurology, University of Padova, Padova, Italy; Phone: +39 049 821 3625; Fax: +39 049 875 1770; E-mail: corrado.angelini@unipd.it

Availability of Companion Documents

The following are available:

  • Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K, Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies (EFNS) Web site External Web Site Policy.
  • Continuing Medical Education (CME) questions are available from the EFNS Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI on April 10, 2007. The information was verified by the guideline developer on May 18, 2007. This NGC summary was updated by ECRI Institute on February 8, 2011. The updated information was verified by the guideline developer on April 13, 2011.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the Blackwell-Synergy copyright restrictions.

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The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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