An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models

Abstract

Aims: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments. Methods: A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period. Results: A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1, DDHD1, C19orf12, GBA2, TECPR2, DDHD2, C12orf65, REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the "HSPome." Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds. Conclusion: The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.The term "hereditary spastic paraplegia" (HSP) is applied to a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs.There is marked genetic heterogeneity in HSP, with at least 55 genes and 72 loci identified thus far. The mode of inheritance can be autosomal dominant, autosomal recessive, X-linked, or maternal.

Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells

“…Hereditary spastic paraplegia (HSP) is an inherited, progressive neurodegenerative condition causing spasticity and weakness in the lower limbs as a consequence of corticospinal tract degeneration ( Hedera et al, 2005 ; Salinas et al, 2008 ; Kumar et al, 2015 ). Mutations in SPG7 and SPAST are the most common causes of HSP.…”

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

“…The underlying pathophysiology of HSP remains poorly understood and it is likely that this varies according to genotype (2). There are >64 HSP associated genes and 13 HSP associated loci identified to date and this number will continue to grow with the advent of next generation sequencing (3, 4).…”

Sorting of Arabidopsis NRAMP3 and NRAMP4 depends on adaptor protein complex AP4 and a dileucine‐based motif

“…This is in line with results obtained for mammalian AP4. In humans, disruptions in AP4 are linked to a subtype of hereditary spastic paraplegias (HSP), irrespective of which subunit is affected by the mutation (reviewed in Kumar et al) . In addition, patients with mutations in either AP4ß, μ or ε, show decreased protein levels of both AP4ß and AP4ε .…”

“…In humans, disruptions in AP4 are linked to a subtype of hereditary spastic paraplegias (HSP), irrespective of which subunit is affected by the mutation (reviewed in Kumar et al). 52 In addition, patients with mutations in either AP4ß, μ or ε, show decreased protein levels of both AP4ß and AP4ε. [53][54][55][56][57] The fact that developmental defects of Arabidopsis mutants lacking the ß-subunit of AP4 resemble those of ap4μ mutants corresponds to the results obtained in human patients.…”