New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Julie Pilliod, Sébastien Moutton, Julie Lavie, Elise Maurat, Christophe Hubert, Nadège Bellance, Mathieu Anheim, Sylvie Forlani, Fanny Mochel, Karine N'Guyen, Christel Thauvin-Robinet, Christophe Verny, Dan Milea, Gaëtan Lesca, Michel Koenig, Diana Rodriguez, Nada Houcinat, Julien Van-Gils, Christelle M. Durand, Agnès Guichet, Magalie Barth, Dominique Bonneau, Philippe Convers, Elisabeth Maillart, Lucie Guyant-Marechal, Didier Hannequin, Guillaume Fromager, Alexandra Afenjar, Sandra Chantot-Bastaraud, Stéphanie Valence, Perrine Charles, Patrick Berquin, Caroline Rooryck, Julie Bouron, Alexis Brice, Didier Lacombe, Rodrigue Rossignol, Giovanni Stevanin, Giovanni Benard, Lydie Burglen, Alexandra Durr, Cyril Goizet, Isabelle Coupry
Ann Neurol.. 2015-11-14; 78(6): 871-886
DOI: 10.1002/ana.24509

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1. Ann Neurol. 2015 Dec;78(6):871-86. doi: 10.1002/ana.24509. Epub 2015 Nov 14.

New practical definitions for the diagnosis of autosomal recessive spastic ataxia
of Charlevoix-Saguenay.

Pilliod J(1), Moutton S(1)(2), Lavie J(1), Maurat E(1), Hubert C(3), Bellance
N(1), Anheim M(4)(5)(6), Forlani S(7), Mochel F(7)(8), N’Guyen K(9),
Thauvin-Robinet C(10), Verny C(11), Milea D(12), Lesca G(13), Koenig M(14),
Rodriguez D(15)(16)(17), Houcinat N(2), Van-Gils J(2), Durand CM(1), Guichet
A(18), Barth M(18), Bonneau D(18), Convers P(19), Maillart E(20), Guyant-Marechal
L(21), Hannequin D(21), Fromager G(22), Afenjar A(15)(23), Chantot-Bastaraud
S(15)(23), Valence S(15)(17), Charles P(7), Berquin P(24), Rooryck C(1)(2),
Bouron J(2), Brice A(7)(8), Lacombe D(1)(2), Rossignol R(1), Stevanin
G(7)(8)(25), Benard G(1), Burglen L(15)(16)(23), Durr A(7)(8), Goizet C(1)(2),
Coupry I(1).

Author information:
(1)Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux,
Bordeaux, France.
(2)Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux,
France.
(3)Functional Genomics Center, University of Bordeaux, Bordeaux, France.
(4)Neurology Service, Strasbourg University Hospitals, Strasbourg, France.
(5)Molecular Cell Biology Genetics Institute, INSERM U964/CNRS UMR7104,
University of Strasbourg, Illkirch-Graffenstaden, France.
(6)Strasbourg Federation of Translational Medicine, University of Strasbourg,
Illkirch-Graffenstaden, France.
(7)Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of
Paris, Paris, France.
(8)Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne
Universities-Pierre and Marie Curie University, Paris, France.
(9)Department of Medical Genetics, Timone Hospital, Marseille, France.
(10)Genetics Center, Dijon University Hospital Center, Dijon, France.
(11)Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM
U1083, University Hospital Center, Angers, France.
(12)Ophthalmology Service, Angers University Hospital Center, Angers, France and
Singapore National Eye Centre, Singapore Eye Research Institute, Duke-National
University of Singapore, Singapore.
(13)Genetics Service, Lyon University Hospital Center, Lyon, France.
(14)Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University
Hospital Center, Montpellier, France.
(15)Rare Diseases Reference Center “Defects and Congenital Diseases of the
Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris,
France.
(16)Robert Debré Hospital, INSERM U1141, Paris, France.
(17)Genetics Service, Armand Trousseau Hospital, Public Hospital Network of
Paris, Paris, France.
(18)Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network
of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
(19)Nantes Angers le Mans University and Department of Biochemistry and Genetics,
University Hospital Center, Angers, France.
(20)Clinical Neurophysiology Service, Saint-Étienne University Hospital Center,
Saint-Étienne, France.
(21)Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of
Paris, Paris, France.
(22)Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France.
(23)Neurologist, Caen, France.
(24)Amiens University Hospital Center, Pediatric Neurology Activity Center,
Amiens, France.
(25)Laboratory of Neurogenetics, Practical School of Higher Studies, Paris,
France.

OBJECTIVE: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is
caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose
function remains unknown, despite the description of numerous protein domains and
the recent focus on its potential role in the regulation of mitochondrial
physiology. This study aimed to identify new mutations in a large population of
ataxic patients and to functionally analyze their cellular effects in the
mitochondrial compartment.
METHODS: A total of 321 index patients with spastic ataxia selected from the
SPATAX network were analyzed by direct sequencing of the SACS gene, and 156
patients from the ATAXIC project presenting with congenital ataxia were
investigated either by targeted or whole exome sequencing. For functional
analyses, primary cultures of fibroblasts were obtained from 11 patients carrying
either mono- or biallelic variants, including 1 case harboring a large deletion
encompassing the entire SACS gene.
RESULTS: We identified biallelic SACS variants in 33 patients from SPATAX, and in
5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent
alteration of the mitochondrial network was observed in 10 of the 11 patients
tested.
INTERPRETATION: Our results permit extension of the clinical and mutational
spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial
network anomalies could be used as a trait biomarker for the diagnosis of ARSACS
when SACS molecular results are difficult to interpret (ie, missense variants and
heterozygous truncating variant). Based on our findings, we propose new
diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria.

© 2015 American Neurological Association.

DOI: 10.1002/ana.24509
PMID: 26288984 [Indexed for MEDLINE]

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