New findings made
This huge study of 842 SPG4 HSPers in France made the following new findings:
a significantly younger age at onset in missense SPG4 mutation carriers (under 10 years)
fewer females than males with an SPG4 mutation develop HSP symptoms, despite the condition generally being more severe in females
one case showed numerous small fibres suggesting nerve regeneration.
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.
SOURCE: Brain. 2018 Dec 1;141(12):3331-3342. doi: 10.1093/brain/awy285. PMID: 30476002
Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex.
Parodi L1, Fenu S1, Barbier M1, Banneau G1, Duyckaerts C1,2, Tezenas du Montcel S3,4, Monin ML1, Ait Said S1, Guegan J1, Tallaksen CME1,5,6, Sablonniere B7,8, Brice A1, Stevanin G1,9, Depienne C1,10, Durr A1; SPATAX network.
- 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.
- Raymond Escourolle Department of Neuropathology, Pitié-Salpêtrière University Hospital, Paris, France.
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière University Hospital, Biostatistics and Medical Informatics Unit and Clinical Research Unit, Paris, France.
- Sorbonne Universités, UMR S1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France.
- Department of Neurology, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
- Lille University, Inserm, CHU Lille, UMR-S 1172 – JPArc – Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.
- CHU Lille, Institut de Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie et Génétique, Lille, France.
- Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences et Lettres (PSL) Research Univeristy, Neurogenetics Group, Paris, France.
- Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.