Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex.
Brain. 2018-11-23; 141(12): 3331-3342
DOI: 10.1093/brain/awy285
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1. Brain. 2018 Dec 1;141(12):3331-3342. doi: 10.1093/brain/awy285.
Spastic paraplegia due to SPAST mutations is modified by the underlying mutation
and sex.
Parodi L(1), Fenu S(1), Barbier M(1), Banneau G(1), Duyckaerts C(1)(2), Tezenas
du Montcel S(3)(4), Monin ML(1), Ait Said S(1), Guegan J(1), Tallaksen
CME(1)(5)(6), Sablonniere B(7)(8), Brice A(1), Stevanin G(1)(9), Depienne
C(1)(10), Durr A(1); SPATAX network.
Collaborators: Abada M, Anheim M, Bonneau D, Charles P, Clavelou P, Coarelli G,
Coutinho P, Debs R, Elleuch N, Ewenczyk C, Feki I, Ferrer X, Fontaine B, Goizet
C, Guyant-Marechal L, Hannequin D, Heide S, Kassar A, Labauge P, Lagueny A, Le
Ber I, Lenglet T, Maldergem L, Marelli C, Nguyen K, Rodriguez D, Stojkovic T,
Tataru A, Tchikviladze M, Tranchant C, Vandenberghe N.
Author information:
(1)Institut du Cerveau et de la Moelle épinière (ICM), INSERM, CNRS, Assistance
Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Pitié-Salpêtrière
University Hospital, Paris, France.
(2)Raymond Escourolle Department of Neuropathology, Pitié-Salpêtrière University
Hospital, Paris, France.
(3)Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière University
Hospital, Biostatistics and Medical Informatics Unit and Clinical Research Unit,
Paris, France.
(4)Sorbonne Universités, UMR S1136, Institut Pierre Louis d’Epidémiologie et de
Santé Publique, Paris, France.
(5)Department of Neurology, Oslo University Hospital, Oslo, Norway.
(6)Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo,
Norway.
(7)Lille University, Inserm, CHU Lille, UMR-S 1172 – JPArc – Centre de Recherche
Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.
(8)CHU Lille, Institut de Biochimie et Biologie Moléculaire, Centre de Biologie
Pathologie et Génétique, Lille, France.
(9)Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences et Lettres (PSL)
Research Univeristy, Neurogenetics Group, Paris, France.
(10)Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Comment in
Brain. 2019 Jul 1;142(7):e31.
Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by
progressive distal degeneration of the corticospinal tracts. Among the 79 loci
and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST,
which encodes spastin, responsible for SPG4, are the most frequent cause of both
familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype
associated with restricted involvement of the corticospinal tracts and posterior
columns of the spinal cord. It is rarely associated with additional neurological
signs. However, both age of onset and severity of the disorder are extremely
variable. Such variability is both intra- and inter-familial and may suggest
incomplete penetrance, with some patients carrying mutations remaining
asymptomatic for their entire life. We analysed a cohort of 842 patients with
SPG4-HSP to assess genotype-phenotype correlations. Most patients were French
(89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized
by a bimodal distribution, with high inter-familial and intra-familial
variability, especially concerning first-degree relatives. Penetrance of the
disorder was 0.9, complete after 70 years of age. Penetrance was lower in females
(0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more
frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations
(missense, frameshift, splice site, nonsense, and deletions) were located in the
AAA cassette of spastin, impairing its microtubule-severing activity. A
comparison of the missense and truncating mutations revealed a significantly
lower age at onset for patients carrying missense mutations than those carrying
truncating mutations, explaining the bimodal distribution of the age at onset.
The age at onset for patients carrying missense mutations was often before 10
years, sometimes associated with intellectual deficiency. Neuropathological
examination of a single case showed degeneration of the spinocerebellar and
spinocortical tracts, as well as the posterior columns. However, there were
numerous small-diameter processes among unusually large myelinated fibres in the
corticospinal tract, suggesting marked regeneration. In conclusion, this large
cohort of 842 individuals allowed us to identify a significantly younger age at
onset in missense mutation carriers and lower penetrance in females, despite a
more severe disorder. Neuropathology in one case showed numerous small fibres
suggesting regeneration.
DOI: 10.1093/brain/awy285
PMID: 30476002 [Indexed for MEDLINE]