A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

Marie Coutelier, Giulia Coarelli, Marie-Lorraine Monin, Juliette Konop, Claire-Sophie Davoine, Christelle Tesson, Rémi Valter, Mathieu Anheim, Anthony Behin, Giovanni Castelnovo, Perrine Charles, Albert David, Claire Ewenczyk, Mélanie Fradin, Cyril Goizet, Didier Hannequin, Pierre Labauge, Florence Riant, Pierre Sarda, Yves Sznajer, François Tison, Urielle Ullmann, Lionel Van Maldergem, Fanny Mochel, Alexis Brice, Giovanni Stevanin, Alexandra Durr
Brain. 2017-04-21; 140(6): 1579-1594
DOI: 10.1093/brain/awx081

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1. Brain. 2017 Jun 1;140(6):1579-1594. doi: 10.1093/brain/awx081.

A panel study on patients with dominant cerebellar ataxia highlights the
frequency of channelopathies.

Coutelier M(1)(2)(3)(4)(5)(6), Coarelli G(1)(2)(3)(4)(7), Monin ML(7), Konop
J(1)(2)(3)(4)(6), Davoine CS(1)(2)(3)(4), Tesson C(1)(2)(3)(4)(6), Valter
R(1)(2)(3)(4)(6), Anheim M(8)(9)(10), Behin A(11), Castelnovo G(12), Charles
P(7), David A(13), Ewenczyk C(7), Fradin M(14)(15), Goizet C(16)(17), Hannequin
D(18), Labauge P(19), Riant F(20), Sarda P(21), Sznajer Y(22), Tison F(23),
Ullmann U(24), Van Maldergem L(25)(26), Mochel F(1)(2)(3)(4)(7)(27), Brice
A(1)(2)(3)(4)(7), Stevanin G(1)(2)(3)(4)(6)(7), Durr A(1)(2)(3)(4)(7); SPATAX

Author information:
(1)INSERM U 1127, 75013, Paris, France.
(2)Centre National de la Recherche Scientifique UMR 7225, 75013, Paris, France.
(3)UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités,
75013, Paris, France.
(4)Institut du Cerveau et de la Moelle Epinière, 75013, Paris, France.
(5)Laboratory of Human Molecular Genetics, de Duve Institute, Université
catholique de Louvain, 1200, Brussels, Belgium.
(6)Ecole Pratique des Hautes Etudes, PSL Research University, 75014, Paris,
(7)Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière,
Assistance Publique – Hôpitaux de Paris, 75013, Paris, France.
(8)Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de
Strasbourg, 67200, Strasbourg, France.
(9)Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, 67100,
Strasbourg, France.
(10)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC),
INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67400, Illkirch, France.
(11)AP-HP, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut
de Myologie, GHU Pitié-Salpêtrière, 75013, Paris, France.
(12)Service de Neurologie, Centre Hospitalier Universitaire Caremeau, 30900,
Nîmes, France.
(13)Service de Génétique Médicale Centre Hospitalier Universitaire de Nantes,
44093, Nantes, France.
(14)Service de Génétique Médicale, CHU de Rennes, 35033, Rennes, France.
(15)Service de Génétique Médicale, Centre Hospitalier de Saint Brieuc, 22000,
Saint-Brieuc, France.
(16)INSERM U1211, Université de Bordeaux, Laboratoire Maladies Rares, Génétique
et Métabolisme, 33000, Bordeaux, France.
(17)CHU Bordeaux, Service de Génétique Médicale, 33000, Bordeaux, France.
(18)Service de Génétique, Service de Neurologie, Inserm U1079, Rouen University
Hospital, 76031, Rouen, France.
(19)Service de Neurologie, Hopital Gui de Chauliac, CHU de Montpellier, 34295,
Montpellier Cedex 5, France.
(20)Assistance Publique – Hôpitaux de Paris, Groupe Hospitalier
Lariboisiere-Fernand Widal, Laboratoire de Génétique, 75010, Paris, France.
(21)Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHU de
Montpellier, 34295 Montpellier, France.
(22)Cliniques Universitaires Saint-Luc, Centre for Human Genetics, 1200,
Brussels, Belgium.
(23)Institut des Maladies Neurodégénératives, CHU de Bordeaux, Université de
Bordeaux, CNRS UMR 5293, 33076, Bordeaux, France.
(24)Centre de génétique humaine, Institut de Pathologie et de Génétique, 6041,
Gosselies, Belgium.
(25)Centre de Génétique Humaine, Université de Franche-Comté, 25000, Besançon,
(26)Centre de Référence pour les Maladies Métaboliques, Université de Liège,
4000, Liège, Belgium.
(27)Neurometabolic Research Group, University Pierre and Marie Curie, 75013,
Paris, France.

Comment in
Brain. 2018 Apr 1;141(4):e22.
Brain. 2018 Apr 1;141(4):e23.

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic
background, with mutations in 34 genes identified so far. This large amount of
implicated genes accounts for heterogeneous clinical presentations, making
genotype-phenotype correlations a major challenge in the field. While
polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1,
ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in
large cohorts, there is a need for comprehensive assessment of frequency and
phenotype of more ‘conventional’ ataxias. After exclusion of CAG/polyglutamine
expansions in spinocerebellar ataxia genes in 412 index cases with dominantly
inherited cerebellar ataxias, we aimed to establish the relative frequencies of
mutations in other genes, with an approach combining panel sequencing and TaqMan®
polymerase chain reaction assay. We found relevant genetic variants in 59
patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n =
16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11)
were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7)
came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5,
FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants
were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to
channelopathies had a significantly earlier age at onset with an average of 24.6
years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and
37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was
significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001),
though for similar functional stages, indicating slower progression of the
disease. Of interest, intellectual deficiency was more frequent in channel
spinocerebellar ataxias, while cognitive impairment in adulthood was similar
among the three groups. Similar differences were found among a single gene group,
comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22
patients with CACNA1A point mutations, which had lower average age at onset (25.2
versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower
severity indexes (0.39 versus 0.44), indicating slower progression of the
disease. In conclusion, we identified relevant genetic variations in up to 15% of
cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and
confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm
genotype-phenotype correlations that are important for genetic counselling and of
possible prognostic value.

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DOI: 10.1093/brain/awx081
PMID: 28444220 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus