Review Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches Samuel Shribman, Evan Reid, Andrew H Crosby, Henry Houlden, Thomas T Warner Lancet Neurol 2019; 18: 1136–46 Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases Published Online characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features, July 31, 2019 and imaging abnormalities vary substantially according to the affected gene and differentiating HSP from other http://dx.doi.org/10.1016/ genetic diseases associated with spasticity can be challenging. Next generation sequencing-based gene panels are S1474-4422(19)30235-2 now widely available but have limitations and a molecular diagnosis is not made in most suspected cases. Reta Lila Weston Institute of Neurological Studies Symptomatic management continues to evolve but with a greater understanding of the pathophysiological basis of (S Shribman MA, individual HSP subtypes there are emerging opportunities to provide targeted molecular therapies and personalised Prof T T Warner PhD), and medicine. Department of Neuromuscular Diseases (Prof H Houlden PhD), UCL Queen Square Institute of Introduction initially be misdiagnosed as cerebral palsy. The spasticity, Neurology, London, UK; The hereditary spastic paraplegias (HSPs) are a het­ which can be slightly asymmetrical, occurs in the absence Cambridge Institute for erogeneous group of monogenic neurological diseases of limb weakness and is only demonstrable on walking. Medical Research and with a combined prevalence of two to five cases per Asymptomatic upper limb hyperreflexia without spasticity Department of Medical 1,2 Genetics, University of 100 000 individuals worldwide. They are characterised by is common and a brisk jaw jerk can occasionally be Cambridge, Cambridge, UK length­dependent corticospinal tract and dorsal column seen.8 Urinary symptoms related to detrusor instability (E Reid PhD); and The Institute degeneration that manifests with the core clinical fea­ or detrusor sphincter dyssynergia are frequent, usually of Biomedical and Clinical tures of bilateral lower limb spasticity, hyperreflexia, and occurring later in the disease course.9 Asymptomatic, or Science, University of Exeter 3 Medical School, Exeter, UK extensor plantar responses. HSPs can present in infancy, mildly symptomatic, impairment of vibration sensation (Prof A H Crosby PhD childhood, adolescence, or adulthood. Autosomal domin­ caused by dorsal column degeneration is also com­ Correspondence to ant, autosomal recessive, or X­linked modes of inheri tance mon, whereas central pathways conveying other sensory Prof Thomas T Warner, Reta Lila 4 are reported, with 13–40% of cases being sporadic (ie, with modalities are less often involved. Weston Institute of Neurological 4,5 no family history). Additional neurological features such as cognitive Studies, UCL Queen Square Institute of Neurology, London, The genetic classification for HSP is based on sequen­ impair ment, ataxia, dysarthria, neuropathy, or seizures WC1N 1PJ, UK tial numbering of chromosomal loci or specific genes, are seen in more than half of cases and can be the [email protected] as they were identified, using a spastic paraplegia gene presenting feature.4 The clinical classification proposed by (SPG) designation. Up to 79 SPG genes have been Harding10 divides HSP cases on this basis into pure or described so far. Many of these have only been identified complicated, later revised to pure or complex. These in single families, and so are perhaps best regarded as specific clinical features are sometimes helpful for dif­ HSP candidate genes.6 Several other groups of mono­ ferentiating the underlying cause; although substan­ genic neurological diseases, other than HSP, are associ­ tial phenotypic vari ation can occur between individuals ated with spasticity, usually in the context of other cardinal with the same SPG type or specific mutation, and some clinical features, and are not the focus of this Review. features can be subtle or subclinical, or only emerge later Despite the selective use of next­generation sequencing­ in the disease course.7,11 The association between various based HSP gene panels or whole­exome sequencing, a different clinical features and the majority of SPG types, genetic diag nosis is not made in 51–71% of all suspected up to SPG78, has been reviewed before.12 Here, we cover cases of HSP, with or without a positive family history.4,5,7,8 the more common HSPs encountered in clinical pract­ This Review focuses on the more common HSPs ice divided according to inheritance patterns—given that encountered in clinical practice, highlighting clinical, a positive family history can immediately narrow the neuro imaging, and neurophysiological features. We des­ differential diagnosis. cribe how to approach the diagnosis of a suspected case of HSP in the era of next­generation sequencing and propose Autosomal-dominant HSP subtypes a simple diagnostic algorithm using clinical and neuro­ The SPG4 subtype is the most common HSP. This subtype imaging features. We then discuss symptomatic treat­ is associated with mutations in SPAST and is inherited as ments and the potential emerging therapeutic options an autosomal dominant trait.13–15 It accounts for up to for spec ific causes of HSP based on their underlying a third of all HSP cases, including 60% of autosomal molecular mechanisms. dominant cases and 15% of sporadic cases.4 The mean age of onset is 31·7 years but cases have been reported with Clinical characteristics onset of up to 70 years, and it usually presents with isolated Most cases present with a slowly progressive gait dis­ lower limb spasticity, with or without bladder or sen­ turbance of insidious onset. Onset in early childhood sory dysfunction.8 In a cohort of 196 patients of mostly can manifest with delayed motor milestones and might German origin, ataxia or peripheral motor involvement 1136 www.thelancet.com/neurology Vol 18 December 2019 Review were seen in 5–10% of cases and cognitive involvement, Investigations extra pyramidal involvement, dysarthria, or dysphagia were seen in fewer than 5% of cases.4 Structural The SPG3A subtype is the second most common Cervical spondylosis MRI autosomal dominant HSP. This subtype is associated Neoplasia (spinal or parasagittal) MRI with mutations in ATL1 and constitutes around 5–10% of Chiari malformation MRI autosomal dominant HSP cases that test negative for Atlanto-axial subluxation MRI SPAST mutations.8 Similarly, it usually presents with Tethered cord37 MRI isolated lower limb spasticity, with or without bladder or Vascular sensory dysfunction; however, an axonal motor neuro­ Dural arteriovenous malformation MRI, angiography pathy is seen in up to 25% of cases.4 The mean age Inflammatory of onset for SPG3A is considerably lower than SPG4 Primary progressive multiple sclerosis MRI, CSF (5·6 years vs 31·7 years), meaning that ATL1 and SPAST Infectious mutations occur with roughly equal frequency in auto­ HTLV1 MRI, CSF, HTLV1 serology somal dominant HSP presenting in the first decade of HIV MRI, CSF, HIV serology life, whereas autosomal dominant HSP present ing after Neurosyphilis MRI, CSF, syphilis serology the fourth decade is unlikely to be caused by ATL1.4 Metabolic The SPG31 subtype is the third most common auto­ Vitamin B12 deficiency MRI, vitamin B12, methylmalonic somal dominant HSP and is associated with mutations acid and homocysteine in REEP1.16,17 Like SPG3A, it usually presents as a pure concentrations pheno type, with or without bladder or sensory dysfunc­ Copper deficiency MRI, serum copper tion, but is associated with an axonal neuropathy in up to Toxic 50% of cases.18 It appears to have a bimodal distribution Lathyrism History with peaks in the first and fourth decades, although onset Neurodegenerative in a nonagenarian has been reported, and the age of Primary lateral sclerosis38 MRI, electromyogram onset can also vary greatly within individual families.19 Iatrogenic Sev eral patients with SPG31 have been reported to have Radiation myelopathy39 MRI, history COX­deficient fibreson muscle biopsy, which suggests Table adopted from Salinas and colleagues3. HTLV1=human T-lymphocytic virus 1. mitochondrial dysfunction.18 Table 1: Acquired causes of slowly progressive spastic paraplegia and key Autosomal recessive HSP subtypes diagnostic investigations The SPG11 subtype is one of the most prevalent auto­ somal recessive HSPs. It is associated with mutations in in men than in women.23 It usually manifests with a SPG11 and accounts for up to 8% of all HSP cases, with combination of lower limb spasticity, which can be a higher prevalence in populations with considerable relatively mild, and cerebellar ataxia.24 Cerebellar signs consan guinity.1,5 It presents between the ages of 4 years were seen in 57–90% of people and dysarthria in 37–76% and 36 years. The phenotype can vary between family of individuals at presentation in the two largest cohorts of members but is invariably complex. Most cases present 42 patients from England and 49 patients from the with cog nitive impairment or learning difficulties with Netherlands.23,25 A waddling gait, associated with proximal lower limb spasticity emerging later, typically in the second myopathic weakness, is also common, and progressive decade.20 More than 50% of patients develop dysarthria, external ophthalmoplegia is also seen, and can be a useful ataxia, axonal motor neuropathy,