Update on the Genetics of Spastic Paraplegias.
Curr Neurol Neurosci Rep. 2019-02-28; 19(4):
DOI: 10.1007/s11910-019-0930-2
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1. Curr Neurol Neurosci Rep. 2019 Feb 28;19(4):18. doi: 10.1007/s11910-019-0930-2.
Update on the Genetics of Spastic Paraplegias.
Boutry M(1)(2)(3), Morais S(1)(2)(4), Stevanin G(5)(6).
Author information:
(1)Institut du Cerveau et de la Moelle épinière, Sorbonne Université UMR_S1127,
INSERM Unit 1127, CNRS UMR7225, 75013, Paris, France.
(2)Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences
Lettres (PSL) Research University, 75013, Paris, France.
(3)Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
(4)UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal.
(5)Institut du Cerveau et de la Moelle épinière, Sorbonne Université UMR_S1127,
INSERM Unit 1127, CNRS UMR7225, 75013, Paris, France. .
(6)Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences
Lettres (PSL) Research University, 75013, Paris, France.
.
PURPOSE OF REVIEW: Hereditary spastic paraplegias are a genetically heterogeneous
group of neurological disorders. Patients present lower limb weakness and
spasticity, complicated in complex forms by additional neurological signs. We
review here the major steps toward understanding the molecular basis of these
diseases made over the last 10 years.
RECENT FINDINGS: Our perception of the intricate connections between clinical,
genetic, and molecular aspects of neurodegenerative disorders has radically
changed in recent years, thanks to improvements in genetic approaches. This is
particularly true for hereditary spastic paraplegias, for which > 60 genes have
been identified, highlighting (i) the considerable genetic heterogeneity of this
group of clinically diverse disorders, (ii) the fuzzy border between recessive
and dominant inheritance for several mutations, and (iii) the overlap of these
mutations with other neurological conditions in terms of their clinical effects.
Several hypotheses have been put forward concerning the pathophysiological
mechanisms involved, based on the genes implicated and their known function and
based on studies on patient samples and animal models. These mechanisms include
mainly abnormal intracellular trafficking, changes to endoplasmic reticulum
shaping and defects affecting lipid metabolism, lysosome physiology, autophagy,
myelination, and development. Several causative genes affect multiple of these
functions, which are, most of the time, interconnected. Recent major advances in
our understanding of these diseases have revealed unifying pathogenic models that
could be targeted in the much-needed development of new treatments.
DOI: 10.1007/s11910-019-0930-2
PMID: 30820684 [Indexed for MEDLINE]