Platt, Frances M.

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Abstract Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase ( cis- PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, Dhdds R37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. Dhdds R37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used “off-label” to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in Dhdds R37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis- PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.

Abstract Background Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded Phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code “IB1001-301”) for the chronic treatment of symptoms in adult and pediatric patients with NPC. Methods This multinational double-blind randomized placebo-controlled crossover Phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. Discussion Pre-clinical as well as observational and Phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders. Trial registrations: The trial (IB1001-301) has been registered at www.clinicaltrials.gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10).

Abstract Background: Several scales have been developed in the past two decades to evaluate Niemann-Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research. Methods: A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale.Results: Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥70% agreement or neutrality) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC.Conclusions: In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings, but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale.