Elsevier

Revue Neurologique

Volume 173, Issue 5, May 2017, Pages 352-360
Revue Neurologique

Motor neuron diseases
Hereditary spastic paraplegia: More than an upper motor neuron disease

https://doi.org/10.1016/j.neurol.2017.03.034Get rights and content

Abstract

Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis.

Introduction

Hereditary spastic paraplegias (HSPs) were first described in the late 1800s by German neurologist Adolf Strümpell through observations of degeneration of spinal cord nerve fibers in two brothers presenting with gait disorders and spasticity in the lower limbs.

The latest estimate of the global prevalence of HSPs is 1–5:100,000 population, depending on the country [1], although there is still no information on its incidence in large parts of the world. HSPs refer to a very heterogeneous group of diseases, and the literature on HSPs highlights the extreme complexity that characterizes them, including both the observable set of clinical features in affected patients and their underlying genetic features.

The neurodegeneration that characterizes HSP patients is the result of a progressive distal axonopathy that mainly involves the corticospinal tracts, leading to spasticity of the lower limbs when walking, the hallmark of the disease. Moreover, a wide range of neurological and extraneurological features can be manifested by HSP patients that sometimes overlap with those of other diseases.

A high degree of genetic diversity underlies the observed phenotypic heterogeneity, with more than 70 loci and 50 genes involved in the onset of HSPs that can be inherited through autosomal-dominant and -recessive, X-linked and maternal modes of transmission [2].

No treatment is yet available to prevent or slow the neural degeneration. Drug therapy to alleviate spasticity, coupled with physiotherapy and rehabilitation, is therefore the only current strategy to ameliorate patients’ quality of life (QoL).

Section snippets

Clinical classification and diagnosis

HSPs were initially classified into two groups, pure and complex (complicated), based on the clinical phenotype. In pure HSP forms, pyramidal signs predominantly affect the lower limbs, causing spasticity, weakness and, in some cases, sphincter disturbances [3]. The major features that define this pure form on neurological examination include increased lower-limb muscle tone (especially in the hamstrings, quadriceps, gastrocnemius–soleus and adductors) and weakness (in the iliopsoas, hamstrings

Genetics of HSPs

Linkage analysis was the first strategy to allow the identification of genomic regions harboring causative genes of HSPs. The subsequent introduction of next-generation sequencing (NGS) revolutionized the genetic diagnosis of HSPs: the combination of NGS and the use of screening panels of genes involved in HSPs, or allelic diseases, greatly increased the power of genetic diagnosis and is now steadily increasing the number of new candidate genes. Yet, despite these advances, the difficulty in

HSPs: UMN and LMN degeneration

Neurodegeneration in HSPs involves primarily sensory and corticospinal tract axons, and arises through a progressive ‘dying-back’ process starting from the distal ends of the axons [16]. The gradual retraction of UMN axons progressively impairs and dysregulates the synapse between UMNs and LMNs. Leg spasticity, weakness, hypertonia and hyperreflexia subsequently appear due to the lack of communication between the two neuronal partners.

However, such neurodegeneration can affect either only UMNs,

Conclusion

Based on the fact that the motor neuron degeneration underlying HSPs can involve both UMN and LMN axons, the present attempt was made to classify each form of HSP based on the motor neurons affected. HSPs arise following the dying-back degeneration of UMN axons of the corticospinal tracts. The combination of both UMN and LMN degeneration is detectable in some forms of HSP, leading to a phenotype that is rather more ALS-like, with muscular atrophy and muscle weakness as the main symptoms of LMN

Disclosure of interest

The authors declare that they have no competing interest.

Acknowledgements

The work of the author is supported by grants from the European Union (7th FP NEUROMICS, E-Rare Neurolipid and Prepare), the VERUM Foundation, the Agence Nationale de la Recherche (SPATAX-QUEST) and the Programme Hospitalier de Recherche Clinique.

References (66)

  • K. Neveling et al.

    Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy

    Am J Hum Genet

    (2013)
  • I. Grigoriev et al.

    Rab6 regulates transport and targeting of exocytotic carriers

    Dev Cell

    (2007)
  • E.C. Oates et al.

    Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia

    Am J Hum Genet

    (2013)
  • L. Ruano et al.

    The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies

    Neuroepidemiology

    (2014)
  • A.E. Harding

    Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families

    J Neurol Neurosurg Psychiatry

    (1981)
  • G. Novarino et al.

    Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

    Science

    (2014)
  • C. Tesson et al.

    Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology

    Hum Genet

    (2015)
  • J. Pilliod et al.

    New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay

    Ann Neurol

    (2015)
  • M. Jouet et al.

    X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene

    Nat Genet

    (1994)
  • D. Bonneau et al.

    X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus

    J Med Genet

    (1993)
  • A. Caballero Oteyza et al.

    Motor protein mutations cause a new form of hereditary spastic paraplegia

    Neurology

    (2014)
  • M. Coutelier et al.

    Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia

    Brain J Neurol

    (2015)
  • E. Panza et al.

    ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

    Brain J Neurol

    (2016)
  • S. Klebe et al.

    Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

    Brain J Neurol

    (2012)
  • C. Blackstone

    Cellular pathways of hereditary spastic paraplegia

    Annu Rev Neurosci

    (2012)
  • G.C. Deluca et al.

    The extent of axonal loss in the long tracts in hereditary spastic paraplegia

    Neuropathol Appl Neurobiol

    (2004)
  • T. Mannen et al.

    Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: its clinical significance

    J Neurol Neurosurg Psychiatry

    (1977)
  • J. Hazan et al.

    Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia

    Nat Genet

    (1999)
  • N. Fonknechten et al.

    Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia

    Hum Mol Genet

    (2000)
  • C. Depienne et al.

    Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases

    J Med Genet

    (2006)
  • J. Hazan et al.

    Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p

    Hum Mol Genet

    (1994)
  • A. Hentati et al.

    Linkage of a locus for autosomal dominant familial spastic paraplegia to chromosome 2p markers

    Hum Mol Genet

    (1994)
  • A. Dürr et al.

    Spastic Paraplegia 4

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