Chapter 41 - Hereditary spastic paraplegia

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Abstract

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurologic disorders with the common feature of prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. The HSPs exist not only in “pure” forms but also in “complex” forms that are associated with additional neurologic and extraneurologic features. The HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified. Numerous studies elucidating the molecular pathogenesis underlying HSPs have highlighted the importance of basic cellular functions – especially membrane trafficking, mitochondrial function, organelle shaping and biogenesis, axon transport, and lipid/cholesterol metabolism – in axon development and maintenance. An encouragingly small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways present compelling targets for future therapies.

Introduction

Human voluntary movement utilizes the pyramidal motor system, a long and winding, multisynaptic central nervous system (CNS) pathway that extends from the cerebral motor cortex to neuromuscular junctions, innervating skeletal muscles (Fig. 41.1). Distances traversed by corticospinal and lower motor neurons are among the furthest of any neurons in the body, with the longest axons responsible for regulating lower-limb muscles extending up to 1 meter. This length facilitates the rapid relay of action potentials, enabling timely voluntary movement. However, complex cellular machineries are needed for sorting, packaging, and distributing proteins, cytoskeletal elements, lipids, organelles, and other molecules over such long distances, creating vulnerabilities that can manifest as motor dysfunction in neurologic disorders (Blackstone, 2012).

The hereditary spastic paraplegias (HSPs) comprise a large and diverse group of inherited neurologic disorders, with a defining and unifying feature of prominent lower-extremity spasticity due to an axonopathy of the longest corticospinal nerves (Blackstone, 2012; Fink, 2014; Klebe et al., 2015; Tesson et al., 2015). Historically, HSPs have been bisected into “pure” and “complex” (or “complicated”) forms. “Pure” forms are characterized by prominent spasticity (with often severe hypertonia and usually more mild weakness) of the lower limbs without significant other findings, with the exception of modest urinary symptoms and impaired distal vibratory sensation. “Complex” forms are associated with additional, often prominent, features (Harding, 1983). These can include neuropathy, seizures, parkinsonism, cognitive impairment, amyotrophy, short stature, and visual abnormalities, among others. This classification scheme has always been somewhat subjective, and complex HSPs can overlap clinically with other disorders characterized primarily by symptoms such as cerebellar ataxia, neuropathy, motor neuron disease, cognitive impairment, and leukodystrophy.

Dramatic advances in DNA sequencing technologies have facilitated the identification of numerous HSP genes that comprise autosomal-dominant, autosomal-recessive, and X-linked inheritances; de novo and mitochondrial DNA mutations have also been described. In fact, HSPs are among the most genetically diverse Mendelian disorders, with > 70 distinct spastic gait genetic loci (SPG1–78) and around 60 genes already identified (Blackstone, 2012; Klebe et al., 2015; Tesson et al., 2015); these numbers will certainly continue to rise. To diagnose HSP, molecular genetic testing is increasingly employed, and indeed genetic classification has largely supplanted historic clinical classification schemes (Table 41.1). Importantly, prominent lower-extremity spasticity is often observed in diseases classified outside of the formal SPG nomenclature, particularly in hereditary motor and sensory neuropathies, parkinsonism, cerebral palsies with spastic quadriplegia, motor neuron diseases, spastic ataxias, and spinocerebellar ataxias.

Section snippets

Differential diagnosis

The predominant clinical finding in patients with pure HSP is mostly symmetric, often severe, progressive spasticity in the legs. Weakness is typically milder than the hypertonia. Deep tendon reflexes are exaggerated in the lower extremities, with extensor plantar responses, crossed adductor signs, and ankle clonus commonly seen. A significant proportion of patients have some degree of distal sensory loss, particularly of vibratory sensation at the great toes. Urinary symptoms, including

Genetic epidemiology

HSPs are present in populations throughout the world, with a pooled global average prevalence of about 1.8 per 100,000, though this varies widely by geography (Ruano et al., 2014). For instance, a large, population-based, cross-sectional study in southeast Norway reported a total prevalence of 7.4 per 100,000 (Erichsen et al., 2009), while an even larger study in Portugal found a prevalence of 4.1 per 100,000 (Coutinho et al., 2013). Autosomal-dominant forms of HSP prevail in these and most

Neuropathology

Fundamentally, HSPs are length-dependent disorders of long axons, particularly those of corticospinal neurons, although long sensory fibers in the ascending dorsal column tracts are often involved as well. Spinocerebellar tracts appear less affected (Behan and Maia, 1974). Most patients with HSP (particularly pure forms) have a normal lifespan, and many HSP genes have been described relatively recently, so a limited number of neuropathologic evaluations of genetically confirmed, pure HSPs have

Common cellular themes

The confusion and disarray one might expect from so many genetic forms of HSP have been mollified significantly by the fact that the proteins encoded by these genes segregate rather nicely into a much smaller group of common pathogenic themes at the cellular level (Table 41.2; Blackstone, 2012).

Membrane modeling and organelle morphogenesis

Many HSP proteins are involved in the intracellular trafficking, distribution, biogenesis, and/or shaping of membrane compartments, which is not surprising given the extreme length and polarity of corticospinal axons. In fact, this is an important subgroup, since mutations in genes responsible for autosomal-dominant SPG4, SPG3A, and SPG31 comprise about half of HSP cases in North America and Northern Europe. Furthermore, loss-of-function mutations in the two most common autosomal-recessive

Bone morphogenetic protein (BMP) signaling

Several proteins associated with HSPs regulate signaling pathways known to be important for axon function. One compelling candidate that cuts across HSP categories and is widely implicated in neurodegenerative diseases is BMP signaling (Bayat et al., 2011). BMPs are ligands of the transforming growth factor-β superfamily, and BMP signaling has crucial roles in many developmental processes. HSP-associated mutations are found in at least six proteins – atlastin-1, NIPA1 (SPG6), acetyl-CoA

Motor-based transport

Shaping and positioning organelles, signaling complexes, and other molecules properly within highly polarized neurons depend on motor proteins. Thus, it is not surprising that several kinesin motors are mutated in HSPs. Mutations in the KIF5A gene encoding kinesin heavy-chain 5A in families with SPG10 have provided direct evidence for motor-based transport impairments in HSPs (Reid et al., 2002; Goizet et al., 2009). KIF5 proteins are ATP-dependent motors that move cargoes in the anterograde

Mitochondrial function

Mitochondrial dysfunction has been implicated in a host of developmental and degenerative neurologic disorders, broadly manifesting clinically as peripheral neuropathies, movement disorders, myopathies, visual disturbances, and cognitive disability (DiMauro et al., 2013). Given this fundamental link to neurologic disease, it is perhaps surprising that so few HSP genes encode proteins directly associated with mitochondrial functions. Two mitochondrial proteins mutated in HSPs are paraplegin

Axon pathfinding

Among the first HSP mutations described were in the L1CAM gene. Loss-of-function mutations in L1CAM are implicated in X-linked, early-onset, complicated HSP (SPG1) as well as other X-linked syndromes, including MASA (for mental retardation, aphasia, shuffling gait, and adducted thumbs), hydrocephalus, and agenesis of the corpus callosum (Jouet et al., 1994; Weller and Gärtner, 2001). There is corticospinal tract impairment in each of these disorders, and they are often considered together along

Hypo- and dysmyelination

A distinguishing feature of axons in the CNS and peripheral nervous system is an insulating myelin sheath, a specialization that increases the speed of electrical impulse propagation. Schwann cells supply myelin for peripheral neurons, while oligodendrocytes myelinate axons of CNS neurons. Spastic paraplegia as a symptom of dysmyelination in the CNS is fairly common; for instance, this occurs in multiple sclerosis and a variety of acquired and inherited leukodystrophies. Hence, it is not

Nucleotide metabolism

Recently, mutations in several genes involved in purine nucleotide metabolism have been identified in both complex and pure forms of HSP: AMPD2 (SPG63), ENTPD1 (SPG64), and NT5C2 (SPG65) (Novarino et al., 2014). Purine nucleotides are neuroprotective and play roles in ischemic and developing brain, so alterations in their levels could sensitize neurons to different types of stressors. More mechanistic insight into this disease pathway is eagerly anticipated.

Treatment

With a diagnosis of HSP established, most often by genetic studies, treatment is a major consideration. At the present time, therapy is predominantly symptomatic (Fink, 2014). Physical therapy, stretching, and activity are mainstays of treatment, seeking to maintain mobility and avoid complications from inactivity or falls. Spasticity can also sometimes be relieved by baclofen, either oral or intrathecal, and tizanidine. Botulinum toxin injections can be useful for weakening select muscles to

Conclusions

With the falling cost and increasing throughput of next-generation exome and whole-genome sequencing technologies, many additional genes for HSPs and related disorders will likely be uncovered over the next few years. With compelling cellular pathogenic mechanisms already identified, pharmacologic manipulation of these pathways and evaluations in cellular and animal preclinical models will be increasingly possible. Currently, BMP signaling, microtubule stability, lipid metabolism, and

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