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.

ClinicalTrials.Gov: Spastic Paraplegia – Centers of Excellence Research Network (SP-CERN) (NCT06553976)

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

  • by Vicente Quiroz
    Biallelic loss-of-function variants in AP4S1 cause childhood-onset hereditary spastic paraplegia. A recent report suggested that heterozygous AP4S1 variants lead to a syndrome of lower limb spasticity and dysregulation of sphincter function. We critically evaluate this claim against clinical observations in 28 heterozygous carriers of the same AP4S1 variant (NM_007077.3: c.289C>T, p.Arg97Ter). In these 14 males […]
  • by Alexandra K Brooks
    Autosomal-dominant variants in the CPT1C gene have been associated with hereditary spastic paraplegia type 73 (SPG73), which typically presents with slowly progressive lower limb weakness and spasticity and is therefore considered a pure form of hereditary spastic paraplegia. However, we report two unrelated males with novel CPT1C variants (NM_001199753.2: patient 1: c.2057_2061del (p.Ile686SerfsTer8) and patient […]
  • by Jessica P Wiseman
    Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to […]
  • by Salimata Diarra
    Hereditary spastic paraplegia (HSP) comprises a large group of neurogenetic disorders characterized by progressive lower extremity spasticity. Neurological evaluation and genetic testing were completed in a Malian family with early-onset HSP. Three children with unaffected consanguineous parents presented with symptoms consistent with childhood-onset complicated HSP. Neurological evaluation found lower limb weakness, spasticity, dysarthria, seizures, and […]
  • 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 […]
  • 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, […]
  • 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.
  • 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 […]
  • 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 […]
  • 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 […]
  • 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.
  • 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 […]
  • 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 […]
  • 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 […]
  • by Julian Alecu
    CLINICAL CHARACTERISTICS: AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged […]