Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.
Giovanni Stevanin
(1, 2)
,
Hamid Azzedine
(1)
,
Paola Denora
(1)
,
Amir Boukhris
(1, 3)
,
Meriem Tazir
(4)
,
Alexander Lossos
(5)
,
Alberto Luis Rosa
(6)
,
Israela Lerer
(7)
,
Abdelmadjid Hamri
(8)
,
Paulo Alegria
(9)
,
José Loureiro
(10)
,
Masayoshi Tada
(11)
,
Didier Hannequin
(12, 13, 14)
,
Mathieu Anheim
(15)
,
Cyril Goizet
(16)
,
Victoria Gonzalez-Martinez
(17)
,
Isabelle Le Ber
(1)
,
Sylvie Forlani
(1)
,
Kiyoshi Iwabuchi
(18)
,
Vardiela Meiner
(7)
,
Goekhan Uyanik
,
Anne Kjersti Erichsen
(19)
,
Imed Feki
(3)
,
Florence Pasquier
(20)
,
Soreya Belarbi
(4)
,
Vitor T Cruz
(10)
,
Christel Depienne
(1, 2)
,
Jeremy Truchetto
(1)
,
Guillaume Garrigues
(17)
,
Chantal Tallaksen
(21)
,
Christine Tranchant
(22, 23)
,
Masatoyo Nishizawa
(11)
,
José Vale
(9)
,
Paula Coutinho
(10)
,
Filippo M Santorelli
(24)
,
Chokri Mhiri
(3)
,
Alexis Brice
(1, 2, 2)
,
Alexandra Durr
(1)
1
Neurologie et thérapeutique expérimentale
2 CHU Pitié-Salpêtrière [AP-HP]
3 Department of neurology
4 Service de Neurologie
5 Department of Neurology
6 Laboratorio de Biologia Cellular y Molecular
7 Department of Human Genetics
8 Service de Neurologie
9 Serviçio Neurologia
10 Departamento de Neurologia
11 Department of Neurology
12 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
13 Service de neurologie [Rouen]
14 Department of Genetics
15 Neurology Department
16 Service de génétique médicale
17 Département de neurologie [Montpellier]
18 Neurological Clinic of Yokohama
19 Department of Histopathology
20 Département de neurologie [Lille]
21 Department of Neurology
22 Département de Neurologie
23 Service de Neurologie [Strasbourg]
24 Unit of Molecular Medicine
2 CHU Pitié-Salpêtrière [AP-HP]
3 Department of neurology
4 Service de Neurologie
5 Department of Neurology
6 Laboratorio de Biologia Cellular y Molecular
7 Department of Human Genetics
8 Service de Neurologie
9 Serviçio Neurologia
10 Departamento de Neurologia
11 Department of Neurology
12 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
13 Service de neurologie [Rouen]
14 Department of Genetics
15 Neurology Department
16 Service de génétique médicale
17 Département de neurologie [Montpellier]
18 Neurological Clinic of Yokohama
19 Department of Histopathology
20 Département de neurologie [Lille]
21 Department of Neurology
22 Département de Neurologie
23 Service de Neurologie [Strasbourg]
24 Unit of Molecular Medicine
Giovanni Stevanin
- Fonction : Auteur
- PersonId : 758031
- ORCID : 0000-0001-9368-8657
- IdRef : 119149982
Didier Hannequin
- Fonction : Auteur
- PersonId : 842408
Goekhan Uyanik
- Fonction : Auteur
Christel Depienne
- Fonction : Auteur
- PersonId : 757923
- ORCID : 0000-0002-7212-9554
- IdRef : 150923163
Alexis Brice
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 1104774
- ORCID : 0000-0002-0941-3990
- IdRef : 050512935
Connectez-vous pour contacter l'auteur
Alexandra Durr
- Fonction : Auteur
- PersonId : 758970
- ORCID : 0000-0002-8921-7104
- IdRef : 148675018
Résumé
Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 +/- 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.