Research Publications
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Schierbaum L, Gonzalez Saez-Diez E, Tam A, Rong J, Zubair U, Bernardi K, Yang K, Quiroz V, Zaman Z, Saffari A, Carty S, Agianda HAP, Alexandrescu S, Eichler F, Sveden A, Chopra M, Calame DG, Danzi MC, Zuchner S, Ebrahimi-Fakhari D. Diagnostic yield of genome sequencing in children with progressive movement disorders. Brain. 2026 Feb 5:awag050. doi: 10.1093/brain/awag050. Epub ahead of print. PMID: 41640354.
Childhood-onset movement disorders have a large range of symptoms and genetic causes. Over 500 different genes are associated with these disorders. However, standard genetic testing may not detect some of the genetic variants.
In this study, researchers evaluated the use of genome sequencing in diagnosing children with progressive movement disorders. First, the team used whole genome sequencing to identify variants in 100 children and young adults with early-onset progressive movement disorders and prior nondiagnostic testing. Then, a multidisciplinary team interpreted the variants and matched them with different phenotypes.
Results included a molecular diagnosis in 27% of cases, with candidate variants identified in an additional 33%. Short-read whole genome sequencing showed a small increase in diagnoses over exome sequencing. Most of the diagnoses were achieved through reanalysis of exome-level data. Authors note that these findings highlight the importance of repeat variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.
Agianda HAP, Kim HM, Battaglia N, Rong J, Tam A, Gonzalez Saez-Diez E, Boerkoel CF, Saffari A, Quiroz V, Schierbaum L, Zaman Z, Bernardi K, Ebrahimi-Fakhari D. Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia. Ann Clin Transl Neurol. 2026 Jan 5. doi: 10.1002/acn3.70308. Epub ahead of print. PMID: 41491634.
Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders that cause the upper motor neurons to slowly degenerate, leading to progressive muscle stiffness and leg weakness. Adaptor protein complex 4–associated HSP (AP-4-HSP) is a childhood-onset and complex form of HSP that causes mislocalization—buildup in the wrong location—of the protein ATG9A. Gradual progression of initial symptoms, similarity with other developmental conditions like cerebral palsy, and unknown significance of genetic variants can make it challenging to diagnose AP-4-HSP.
In this study, researchers investigated the ATG9A ratio as a diagnostic tool for AP-4-HSP. The team measured the mislocalization of ATG9A in eight patients with suspected AP-4-HSP and genetic variants of unknown significance.
Results demonstrated loss of AP-4 function in six of the participants, revealing new disease-causing genetic variants. Authors note that the ATG9A ratio is a useful tool for diagnosing AP-4-HSP and classifying new genetic variants, which can help determine eligibility for clinical trials and guide treatment decisions.
Agianda HAP, Alecu JE, Tam A, Kim HM, Rong J, Battaglia N, Warren K, Mannix R, Setola N, Barghigiani M, Yoon G, Takiyama Y, Moon J, Bernardi K, Yang K, Schierbaum L, Santorelli FM, Ebrahimi-Fakhari D. Longitudinal Dynamics of Plasma Neurofilament Light Chain in Hereditary Spastic Paraplegia Type 11 (HSP-SPG11) and Type 15 (HSP-ZFYVE26). Mov Disord. 2025 Dec 9. doi: 10.1002/mds.70142. Epub ahead of print. PMID: 41365832.
Hereditary spastic paraplegia (HSP) is a large group of inherited disorders that affect nerves that send messages to the muscles. HSP-SPG11 and HSP-ZFYVE26 are autosomal-recessive forms of HSP, meaning that they are caused by two mutated copies of a gene. More information is needed about measurable signs of these disorders for new therapeutic trials.
In this study, researchers evaluated plasma neurofilament light chain (pNfL) as a biomarker for HSP-SPG11 and HSP-ZFYVE26. The team analyzed pNfL levels in 57 patients with HSP, collecting clinical and biomarker data over five years.
Results showed significantly elevated baseline pNfL levels in patients with HSP, reflecting early neuroaxonal injury. However, authors note that baseline pNfL did not help predict future disease progression.
Resch D, Alecu JE, Yang K, Quiroz V, Schierbaum L, Bernardi K, Zaman Z, Agianda HAP, Rong J, Battaglia N, Carty S, Tam A, Kieslich M, Santorelli FM, González-Salazar C, França Junior MC, Ebrahimi-Fakhari D. Spectrum of Movement Disorders in Early-Onset Hereditary Spastic Paraplegia: A Study of 428 Cases. Mov Disord. Mov Disord. 2025 Dec 2. doi: 10.1002/mds.70141. Epub ahead of print. PMID: 41328529
Hereditary spastic paraplegia (HSP) is a large group of inherited disorders that affect nerves that send messages to the muscles. Individuals with early-onset HSP can experience movement disorders, but not much is known about why and how often they occur.
In this study, researchers explored the spectrum of movement disorders in early-onset HSP. The team analyzed data from 428 children and young adults with HSP, reviewing clinical characteristics and video examinations.
Results showed that movement disorders—including dystonia, parkinsonism, and ataxia—were common in childhood-onset HSP. Authors note that routine screening and management tailored to specific genotypes of movement disorders—especially dystonia—may improve functional outcomes and quality of life.
Schmidt HJD, Battaglia N, Rong J, Tam A, Carty S, Quiroz V, Yang K, Zaman Z, Schierbaum L, Bernardi K, Alecu JE, Ebrahimi-Fakhari D. Health-Related Quality of Life in Rare Forms of Childhood-Onset Hereditary Spastic Paraplegia. Ann Clin Transl Neurol. 2026 Jan;13(1):193-199. doi: 10.1002/acn3.70244. Epub 2025 Nov 6. PMID: 41199121; PMCID: PMC12790169.
Hereditary spastic paraplegia (HSP) is a large group of inherited disorders that affect nerves that send messages to the muscles. Patients with HSP commonly have difficulty walking due to muscle weakness and spasticity (muscle rigidity) in the legs. In patients with rare forms of HSP, these symptoms can be more complex, including developmental delay, intellectual disability, movement disorders, dysphagia (difficulty swallowing), or incontinence. While previous studies have examined how common forms of HSP affect health-related quality of life, less is known about the impact of rare childhood-onset forms.
In this study, researchers assessed health-related quality of life in 80 children with rare forms of HSP. Using the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) and clinician-reported outcomes, the team examined how clinical features, age, and genotype correlate with quality of life.
Results showed that CPCHILD can be used to assess many different forms of childhood-onset HSP. Lower scores were seen in children with more complex forms. Motor, autonomic, and bulbar symptoms had the largest impact. Authors note that these insights can help clinicians prioritize interventions and inform strategies to improve quality of life for children with HSP.