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


CONCLUSIONS
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.
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Julie
J
Pilliod
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.|Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Sébastien
S
Moutton
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Julie
J
Lavie
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Elise
E
Maurat
Functional Genomics Center, University of Bordeaux, Bordeaux, France.
Christophe
C
Hubert
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Nadège
N
Bellance
Neurology Service, Strasbourg University Hospitals, Strasbourg, France.|Molecular Cell Biology Genetics Institute, INSERM U964/CNRS UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France.|Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch-Graffenstaden, France.
Mathieu
M
Anheim
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
Sylvie
S
Forlani
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.|Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Fanny
F
Mochel
Department of Medical Genetics, Timone Hospital, Marseille, France.
Karine
K
N'Guyen
Genetics Center, Dijon University Hospital Center, Dijon, France.
Christel
C
Thauvin-Robinet
Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM U1083, University Hospital Center, Angers, France.
Christophe
C
Verny
Ophthalmology Service, Angers University Hospital Center, Angers, France and Singapore National Eye Centre, Singapore Eye Research Institute, Duke-National University of Singapore, Singapore.
Dan
D
Milea
Genetics Service, Lyon University Hospital Center, Lyon, France.
Gaëtan
G
Lesca
Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University Hospital Center, Montpellier, France.
Michel
M
Koenig
Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.|Robert Debré Hospital, INSERM U1141, Paris, France.|Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.
Diana
D
Rodriguez
Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Nada
N
Houcinat
Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Julien
J
Van-Gils
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Christelle M
CM
Durand
Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Agnès
A
Guichet
Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Magalie
M
Barth
Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Dominique
D
Bonneau
Nantes Angers le Mans University and Department of Biochemistry and Genetics, University Hospital Center, Angers, France.
Philippe
P
Convers
Clinical Neurophysiology Service, Saint-Étienne University Hospital Center, Saint-Étienne, France.
Elisabeth
E
Maillart
Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
Lucie
L
Guyant-Marechal
Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
Didier
D
Hannequin
Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France.
Guillaume
G
Fromager
Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.|Neurologist, Caen, France.
Alexandra
A
Afenjar
Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.|Neurologist, Caen, France.
Sandra
S
Chantot-Bastaraud
Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.|Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.
Stéphanie
S
Valence
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
Perrine
P
Charles
Amiens University Hospital Center, Pediatric Neurology Activity Center, Amiens, France.
Patrick
P
Berquin
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.|Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Caroline
C
Rooryck
Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Julie
J
Bouron
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.|Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Alexis
A
Brice
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.|Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Didier
D
Lacombe
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Rodrigue
R
Rossignol
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.|Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.|Laboratory of Neurogenetics, Practical School of Higher Studies, Paris, France.
Giovanni
G
Stevanin
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Giovanni
G
Benard
Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.|Robert Debré Hospital, INSERM U1141, Paris, France.|Neurologist, Caen, France.
Lydie
L
Burglen
Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.|Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities-Pierre and Marie Curie University, Paris, France.
Alexandra
A
Durr
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.|Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France.
Cyril
C
Goizet
Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Isabelle
I
Coupry
D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D018929:Cell Culture Techniques; D002648:Child; D015331:Cohort Studies; D005260:Female; D005347:Fibroblasts; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009128:Muscle Spasticity / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D055815:Young Adult
D015415:Biomarkers; D006360:Heat-Shock Proteins; C404403:SACS protein, human