Research on National and International Levels

The initial phase of the SP-CERN aims to establish the center of excellence sites and organize national and international collaboration. The network will establish research infrastructure, will harmonize research protocols with international partners, connect patients and families affected by HSP/PLS, and build collaborations with partners in the biotechnology and pharmaceutical industry. The central infrastructure includes a prospective, longitudinal natural history study, a comprehensive repository of biospecimen and cell lines, and a state-of-the art genomics platform.

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Research Highlights

Establish key research infrastructure: The SP-CERN will support the development of the registry and natural history study across the whole age span, a biobank, and a genome archive

Define clinical outcome measures and biomarkers: The SP-CERN will develop and test clinician-reported outcome measures, patient-reported outcome measures, measures of quality of life, wearable sensors to measure motor function, and blood and CSF-based biomarkers

Establish a state-of-the art genomics platform: Since the introduction of next generation sequencing, the rate of discovery of the genetic basis of HSP has accelerated, including new genetic causes of HSP, unbiased measurement of variant frequencies in known disease genes, establishment o phenotype/genotype relationships and molecular spectra, definition of genetic factors that modigy disease. We will facilitate collaboration and tolls that will allow datasets from multiple clinical and research sites to be integrated and interrogated.

Facilitate the clinical testing of novel therapies: Targeted therapies, including those targeting specific genes or mutations, are under development of several subtypes of HSP and have entered clinical testing for some. To facilitate the development of targeted therapies for HSP and PLS, SP-CERN investigators will design and conduct high quality natural history studies covering both the pediatric and adult age groups.

Train the next generation of clinicians and scientists: The SP-CERN has depth and breadth of expertise to train the next generation of clinicians and scientists to drive basic science research in order to develop new therapies, to perform the clinical trials and to introduce novel therapies into routine clinical practice.

Synchronize and harmonize research worldwide: Global collaboration is essential for rare disease research. The SP-CERN will harmonize all research efforts with similar consortia in Europe, Asia, South America, and Africa to help accelerate basic and clinical research on HSP and PLS on a global level.

Publications

• High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
  January 17, 2024 by Afshin Saffari
  Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adapter protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia characterized by mislocalization of […]
• The hereditary spastic paraplegias
  August 24, 2023 by John K Fink
  The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, […]
• Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia
  July 24, 2023 by Julian E Alecu
  CONCLUSIONS: pNfL is a potential disease marker in AP-4-HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.
• High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia
  July 3, 2023 by Afshin Saffari
  Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect novel therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adaptor protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia, characterized by mislocalization […]
• The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders
  February 9, 2023 by Afshin Saffari
  In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants […]
• The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15
  October 31, 2022 by Afshin Saffari
  In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While […]
• Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST
  September 14, 2022 by Alisa Mo
  CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.
• Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants
  August 17, 2022 by Dustin L Gable
  Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be […]
• De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations
  August 4, 2022 by Julian E Alecu
  Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and […]
• Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis
  July 1, 2022 by Julian Emanuel Alecu
  Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the […]
• Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia
  March 29, 2022 by Dwayne J Byrne
  Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain […]
• Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons
  March 29, 2022 by Peng-Peng Zhu
  Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1-86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the […]
• An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG7, SPG11, and SPG15
  March 25, 2022 by Geert Vander Stichele
  CONCLUSIONS: This is the first epidemiological model of HSP prevalence at the genetic subtype-level reported at multiple geographic levels. This study offers additional data to better capture the burden of illness due to mutations in common genes causing HSP, that can inform public health policy and healthcare service planning, especially in regions with higher estimated […]
• AP-4-mediated axonal transport controls endocannabinoid production in neurons
  February 26, 2022 by Alexandra K Davies
  The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the […]
• Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons
  January 13, 2022 by Zhenyu Chen
  Hereditary spastic paraplegias are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive hereditary spastic paraplegias, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the […]