Motor neuron diseasesHereditary spastic paraplegia: More than an upper motor neuron disease
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.
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Spastic Paraplegia 4
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2022, Current Opinion in NeurobiologyCitation Excerpt :However, leg spasticity is also present in numerous other genetic diseases, such as leukodystrophies (e.g. X-linked adrenoleukodystrophy) or motoneuron diseases (e.g. amyotrophic lateral sclerosis) further extending the genetic heterogeneity of this group of diseases. Such genetic diversity is associated with wide clinical variability, varying from isolated pyramidal symptoms in the legs, that is, primarily first motoneuron involvement, to a complex combination of first and second motoneuron involvement associated with various other neurological symptoms, such as cognitive impairment, cerebellar ataxia, and peripheral neuropathy [2]. Such pure to complex variability depends, at least partially, on the nature of the mutated gene, suggesting that genetics is the primary driver of the nature of symptoms in HSP patients (Figure 1).