Clinical features and management of hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions. Keywords: hereditary spastic paraplegia, spastic paraplegia, muscle spasticity, genetics, mutation. RESUMOParaplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.Palavras-chave: paraplegia espástica hereditária, paraplegia espástica, espasticidade muscular, genética, mutação.

Hereditary spastic paraplegia from 1880 to 2017: an historical review

“…Harding also shed light on the importance of examining first degree relatives who considered themselves asymptomatic, as that practice unraveled AD-HSP in five of the 22 kindreds in this work 30 . She also reinforced the knowledge that spasticity, and not weakness, is the main source of disability in this scenario, an aspect that remains useful in differentiating HSP from other myelopathies 5,31 . Harding' s major contribution to the field of HSP was published in The Lancet journal in 1983 32 .…”

“…On the other hand, a complex or complicated clinical picture, characterized by the presence of other neurological or non-neurological dysfunctions, is more frequently found in AR-HSP or X-linked HSP 1, 2, 3, 4 . These features encompass, for example, ataxia, parkinsonism, peripheral neuropathy, cognitive dysfunction, cataracts, and icthyosis 1,2,3,4,5,6,7 . The diagnosis of an inherited spastic paraplegia is based essentially on the clinical picture, together with the investigation of other, potentially affected, members of the kindred.…”

“…Some conditions that can mimic HSP are: human T-lymphotropic virus-related myelopathy, primary progressive multiple sclerosis, vitamin B12 deficiency, copper deficiency, spinal cord tumors or malformations and degenerative disorders of the spine 4,5,6,7 . The presence of a family history or consanguinity strengthens the possibility of a hereditary condition; its absence, on the contrary, should not dissuade the clinician from the diagnosis 1,2,3,4,5,6,7 . An apparently isolated case can be related to the occurrence of mildly affected family members, incomplete penetrance, false paternity or de novo mutations, for example.…”

“…In the last three decades, advances in molecular genetics have revealed that HSPs constitute a large and heterogeneous group of diseases 4,5 . The knowledge of the key historical marks of HSPs may assist neurologists in understanding why a common ground of spasticity and weakness of the lower limbs has evolved into more than 80 different genetic subtypes.…”

Novel FA2H mutation in a girl with familial spastic paraplegia

“…Increasing awareness about this group of clinically and genetically diverse inherited disorders is especially important for patients and researchers nowadays, since there is rapid progression on the field. Detection of new causative genes, proteins and its mechanisms may bring treatment perspectives in the near future as well as provide clues about other similar neurodegenerative diseases of the motor system [10]. In conclusion, having an updated database in nonsense variants related to HSPs will offer more clinical advantages to carriers, who are considered as having a more aggressive development of HSP.…”