Advertisement

Journal of Neurology

, Volume 263, Issue 7, pp 1314–1322 | Cite as

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases

  • Martial Mallaret
  • Mathilde Renaud
  • Claire Redin
  • Nathalie Drouot
  • Jean Muller
  • Francois Severac
  • Jean Louis Mandel
  • Wahiba Hamza
  • Traki Benhassine
  • Lamia Ali-Pacha
  • Meriem Tazir
  • Alexandra Durr
  • Marie-Lorraine Monin
  • Cyril Mignot
  • Perrine Charles
  • Lionel Van Maldergem
  • Ludivine Chamard
  • Christel Thauvin-Robinet
  • Vincent Laugel
  • Lydie Burglen
  • Patrick Calvas
  • Marie-Céline Fleury
  • Christine Tranchant
  • Mathieu AnheimEmail author
  • Michel Koenig
Original Communication

Abstract

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55–0.98) p < 0.001] confirming the algorithm’s reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

Keywords

Recessive ataxia Next generation sequencing Neurogenetics Electromyography 

Notes

Acknowledgments

Sequencing was performed by the IGBMC Microarray and Sequencing platform a member of the “France Génomique” consortium (ANR-10-INBS-0009). This study was supported by funds from the Agence Nationale pour la Recherche-Maladies Rares and Maladies Neurologiques et Psychiatriques (ANR-09-MNPS-001-01 to M.K. and A.D.) the ANR/E-rare JTC 2011 “Euro-SCAR” (2011-RARE-004-01 to M.K.) and the Agence de la Biomédecine (to J.-L.M.). M.R. was supported by a fellowship from the “Journées de Neurologie de Langue Française”.

Compliance with ethical standards

Financial disclosure

The authors declare no financial disclosure related to the research covered by this article. Martial Mallaret received travel grants from Ipsen and Merz. Mathieu Anheim received honoraria and travel grants from Actelion.

Conflicts of interest

None.

Supplementary material

415_2016_8112_MOESM1_ESM.docx (25 kb)
Supplementary file: A-Panel of 57 ataxia mutated genes (in alphabetical order). B- Variants Analysis of NGS data. C-Clinical and molecular data of the patients without evaluation by the clinical practice-based algorithm. D- Comparative clinical data from patients with a molecular diagnosis (positive patients) and without (negative patients) in our series (DOCX 26 kb)

References

  1. 1.
    Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M (2010) Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace. Eastern France: implications for clinical management Neurogenetics 11:1–12PubMedGoogle Scholar
  2. 2.
    Németh AH, Kwasniewska AC, Lise S, Parolin Schnekenberg R, Becker EB, Bera KD, Shanks ME, Gregory L, Buck D, Zameel Cader M, Talbot K, de Silva R, Fletcher N, Hastings R, Jayawant S, Morrison PJ, Worth P, Taylor M, Tolmie J, O’Regan M; UK Ataxia Consortium, Valentine R, Packham E, Evans J, Seller A, Ragoussis J (2013) Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain 136:3106–3118CrossRefPubMedGoogle Scholar
  3. 3.
    Anheim M, Tranchant C, Koenig M (2012) The autosomal recessive cerebellar ataxias. N Engl J Med 366:636–646CrossRefPubMedGoogle Scholar
  4. 4.
    Redin C, Le Gras S, Mhamdi O, Geoffroy V, Stoetzel C, Vincent MC, Chiurazzi P, Lacombe D, Ouertani I, Petit F, Till M, Verloes A, Jost B, Chaabouni HB, Dollfus H, Mandel JL, Muller J (2012) Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet 49:502–512CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Geoffroy V, Pizot C, Redin C, Piton A, Vasli N, Stoetzel C, Blavier A, Laporte J, Muller J (2015) VaRank: a simple and powerful tool for ranking genetic variants. PeerJ 3:e796. doi: 10.7717/peerj.796 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hamza W, Ali Pacha L, Hamadouche T, Muller J, Drouot N, Ferrat F, Makri S, Chaouch M, Tazir M, Koenig M, Benhassine T (2015) Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia. BMC Med Genet 16:36CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Schmitz-Hübsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schöls L, Szymanski S, van de Warrenburg BP, Dürr A, Klockgether T, Fancellu R (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720CrossRefPubMedGoogle Scholar
  8. 8.
    Renaud M, Anheim M, Kamsteeg EJ, Mallaret M, Mochel F, Vermeer S, Drouot N, Pouget J, Redin C, Salort-Campana E, Kremer HP, Verschuuren-Bemelmans CC, Muller J, Scheffer H, Durr A, Tranchant C, Koenig M (2014) Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol 71:1305–1310CrossRefPubMedGoogle Scholar
  9. 9.
    Gros-Louis F, Dupré N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA (2007) Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet 39:80–85CrossRefPubMedGoogle Scholar
  10. 10.
    Synofzik M, Soehn AS, Gburek-Augustat J, Schicks J, Karle KN, Schüle R, Haack TB, Schöning M, Biskup S, Rudnik-Schöneborn S, Senderek J, Hoffmann KT, MacLeod P, Schwarz J, Bender B, Krüger S, Kreuz F, Bauer P, Schöls L (2013) Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis 8:41CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schöls L, Sequeiros J, Goizet C, Marelli C, Le Ber I, Koht J, Gazulla J, De Bleecker J, Mukhtar M, Drouot N, Ali-Pacha L, Benhassine T, Chbicheb M, M’Zahem A, Hamri A, Chabrol B, Pouget J, Murphy R, Watanabe M, Coutinho P, Tazir M, Durr A, Brice A, Tranchant C, Koenig M (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 132:2688–2698CrossRefPubMedGoogle Scholar
  12. 12.
    Lagier-Tourenne C, Tazir M, López LC, Quinzii CM, Assoum M, Drouot N, Busso C, Makri S, Ali-Pacha L, Benhassine T, Anheim M, Lynch DR, Thibault C, Plewniak F, Bianchetti L, Tranchant C, Poch O, DiMauro S, Mandel JL, Barros MH, Hirano M, Koenig M (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 82:661–672CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mollet J, Delahodde A, Serre V, Chretien D, Schlemmer D, Lombes A, Boddaert N, Desguerre I, de Lonlay P, de Baulny HO, Munnich A, Rötig A (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, de Coo R, van der Kooi A, Smeets H (2010) Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10:510–515CrossRefPubMedGoogle Scholar
  15. 15.
    Horvath R, Czermin B, Gulati S, Demuth S, Houge G, Pyle A, Dineiger C, Blakely EL, Hassani A, Foley C, Brodhun M, Storm K, Kirschner J, Gorman GS, Lochmüller H, Holinski-Feder E, Taylor RW, Chinnery PF (2012) Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry 83:174–178CrossRefPubMedGoogle Scholar
  16. 16.
    Blumkin L, Leshinsky-Silver E, Zerem A, Yosovich K, Lerman-Sagie T, Lev D (2014) Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability. JIMD Rep 12:103–107CrossRefPubMedGoogle Scholar
  17. 17.
    Mignot C, Apartis E, Marques Durr A, Lourenço C, Charles P, Devos D, Moreau C, de Lonlay P, Drouot N, Burglen L, Kempf N, Nourisson E, Chantot-Bastaraud S, Lebre AS, Rio M, Chaix Y, Bieth E, Roze E, Bonnet I, Canaple S, Rastel C, Brice A, Rötig A, Desguerre I, Tranchant C, Koenig M, Anheim M (2013) Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression. Orphanet J Rare Dis 8:173CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Liu YT, Hersheson J, Plagnol V, Fawcett K, Duberley KE, Preza E, Hargreaves IP, Chalasani A, Laurá M, Wood NW, Reilly MM, Houlden H (2014) Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J Neurol Neurosurg Psychiatry 85:493–498CrossRefPubMedGoogle Scholar
  19. 19.
    Méneret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E, Tranchant C, Rivaud-Péchoux S, Degos B, Benyahia B, Suarez F, Maisonobe T, Koenig M, Durr A, Stern MH, Dubois d’Enghien C, Fischer A, Vidailhet M, Stoppa-Lyonnet D, Grabli D, Anheim M (2014) The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia. Neurology 83:1087–1095CrossRefPubMedGoogle Scholar
  20. 20.
    H’mida-Ben Brahim D, M’zahem A, Assoum M, Bouhlal Y, Fattori F, Anheim M, Ali-Pacha L, Ferrat F, Chaouch M, Lagier-Tourenne C, Drouot N, Thibaut C, Benhassine T, Sifi Y, Stoppa-Lyonnet D, N’Guyen K, Poujet J, Hamri A, Hentati F, Amouri R, Santorelli FM, Tazir M, Koenig M (2011) Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays. J Neurol 258:56–67CrossRefPubMedGoogle Scholar
  21. 21.
    Lionnet C, Carra C, Ayrignac X, Levade T, Gayraud D, Castelnovo G, Besson G, Androdias G, Vukusic S, Confavreux C, Zaenker C, De Seze J, Collongues N, Blanc F, Tranchant C, Wallon D, Hannequin D, Gerdelat-Mas A, Brassat D, Clanet M, Zephir H, Outteryck O, Vermersch P, Labauge P (2014) Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects. Rev Neurol (Paris) 170:445–453CrossRefGoogle Scholar
  22. 22.
    Synofzik M, Smets K, Mallaret M, Di Bella D, Gallenmüller C, Baets J, Schulze M, Magri S, Sarto E, Mustafa M, Deconinck T, Haack T, Züchner S, Gonzalez M, Timmann D, Stendel C, Klopstock T, Durr A, Tranchant C, Sturm M, Hamza W, Nanetti L, Mariotti C, Koenig M, Schöls L, Schüle R, de Jonghe P, Anheim M, Taroni F, Bauer P (2016) SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large scale multi-centre study. Brain 139:1378–1393CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Martial Mallaret
    • 1
    • 2
    • 3
  • Mathilde Renaud
    • 2
    • 3
    • 4
  • Claire Redin
    • 2
  • Nathalie Drouot
    • 2
  • Jean Muller
    • 2
    • 5
  • Francois Severac
    • 6
  • Jean Louis Mandel
    • 2
    • 5
    • 7
  • Wahiba Hamza
    • 8
  • Traki Benhassine
    • 8
  • Lamia Ali-Pacha
    • 9
  • Meriem Tazir
    • 9
    • 10
  • Alexandra Durr
    • 11
    • 12
  • Marie-Lorraine Monin
    • 13
  • Cyril Mignot
    • 13
  • Perrine Charles
    • 14
  • Lionel Van Maldergem
    • 15
  • Ludivine Chamard
    • 16
  • Christel Thauvin-Robinet
    • 17
  • Vincent Laugel
    • 18
  • Lydie Burglen
    • 19
  • Patrick Calvas
    • 20
  • Marie-Céline Fleury
    • 3
  • Christine Tranchant
    • 2
    • 3
    • 4
  • Mathieu Anheim
    • 2
    • 3
    • 4
    Email author
  • Michel Koenig
    • 21
  1. 1.Service de NeurologieCentre Hospitalier de HaguenauHaguenauFrance
  2. 2.Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)INSERM-U964/CNRS-UMR7104/Université de StrasbourgIllkirchFrance
  3. 3.Department of Neurology, Movement Disorders UnitHôpital de HautepierreStrasbourg cedexFrance
  4. 4.Fédération de Médecine Translationnelle de Strasbourg (FMTS)Université de StrasbourgStrasbourgFrance
  5. 5.Laboratoire de Génétique Médicale, UMR_S INSERM U1112, IGMA, Faculté de MédecineUniversité de StrasbourgStrasbourgFrance
  6. 6.Laboratoire de Biostatistique et d’Informatique Médicale, Faculté de MédecineHôpitaux Universitaires de StrasbourgStrasbourgFrance
  7. 7.Chaire de Génétique HumaineCollège de FranceIllkirchFrance
  8. 8.Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences BiologiquesUSTHBAlgiersAlgeria
  9. 9.Département de NeurologieCentre hospitalier universitaire Mustapha PachaAlgiersAlgeria
  10. 10.Laboratoire de NeurosciencesUniversité d’AlgerAlgiersAlgeria
  11. 11.Fédération de Génétique, Hôpital de la Pitié-SalpêtrièreAssistance Publique-Hôpitaux de ParisParisFrance
  12. 12.Institut du cerveau et de la moelle épinière, INSERM U1127/CNRS UMR7225Université de Paris VIParisFrance
  13. 13.Département de Génétique et de Cytogénétique, Hôpital de la Pitié-SalpêtrièreAssistance Publique-Hôpitaux de ParisParisFrance
  14. 14.Département de Neurologie, Hôpital de la Pitié-SalpêtrièreAssistance Publique-Hôpitaux de ParisParisFrance
  15. 15.Centre de Génétique HumaineUniversité de Franche-ComtéBesançonFrance
  16. 16.Research Memory Center (CMRR), CHU BesançonBesançonFrance
  17. 17.Centre de Génétique, Hôpital d’Enfants, CHU Dijon and EA4271Université de BourgogneDijonFrance
  18. 18.Hôpital de HautepierreNeuropédiatrie, Hôpitaux Universitaires de StrasbourgStrasbourg cedexFrance
  19. 19.Centre de Référence Malformations et Maladies congénitales du Cervelet, INSERM U1141Assistance Publique-Hôpitaux de ParisParisFrance
  20. 20.Service de Génétique Médicale, Pavillon Ch LefebvreHôpital Purpan-CHU de ToulouseToulouse CedexFrance
  21. 21.Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche CliniqueUniversité de MontpellierMontpellierFrance

Personalised recommendations