Objective: We aim to define the prevalence and phenotypic spectrum of movement disorders in Niemann-Pick Disease Type C (NPC), track motor and functional progression using the NPC Severity Scale (NPCSS), and integrate genetic data to clarify genotype–phenotype correlations.

Background: NPC is a rare, progressive neurodegenerative disorder with phenotypic variability, ranging from neonatal cholestatic liver disease to adult-onset neuropsychiatric presentations. Movement disorders (MD) are a hallmark feature but large-scale characterization remains limited.

Method: Data from the International Niemann-Pick Disease Registry (INPDR), a multicenter international registry of over 350 individuals with NPC, were analyzed. Participants across the lifespan were included. Demographic, clinical, and genetic variables were reviewed, and descriptive statistics summarized the prevalence and patterns of MD. The INPDR operates under institutional ethical approval with informed consent from participants or legal guardians. This study was approved by the local research ethics board. We thank the INPDR Registry Investigators for their contributions and support.

Results: The cohort comprised 350 participants, with a mean age at inclusion of 20 years (range: 17 weeks–69 years) and a mean age at diagnosis of 14 years (range: birth–67 years). Phenotypes included neonatal rapidly fatal (4%), early infantile (19%), late infantile (22%), juvenile (23%), adult (23%), visceral-only (3%), and unknown (6%). Movement disorder were present in 186 participants (53%). Dystonia (77%) and ataxia (70%) were most common, followed by abnormal muscle tone (40%) and cataplexy (38%), with mixed MD phenotypes frequently observed.

Genetic testing (n=240) identified 220 distinct variants. Compound heterozygosity predominated (82%), while homozygosity (12%) was more frequent in early-onset disease. The c.3182T>C variant was common across most phenotypes.

Conclusion: NPC exhibits marked clinical and genetic heterogeneity. MD affect approximately half of individuals, most commonly dystonia and ataxia, often in combination and varying by phenotype. Compound heterozygosity predominates, while homozygosity may be associated with more severe, early-onset disease. Registry-based characterization improves understanding of NPC and may inform diagnosis, prognosis, and clinical management.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterizing-movement-disorders-in-niemann-pick-disease-type-c-a-registry-based-analysis-with-findings-from-the-international-niemann-pick-disease-registry-inpdr/