Congenital Disorder of Glycosylation, DHDDS-CDG, DHDDS-Congenital Disorder of Glycosylation
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of the dietary supplement, nicotinamide mononucleotide (NMN), in individuals with dehydrodolichol diphosphate synthase congenital disorder of glycosylation (DHDDS-CDG). This will to contribute to knowledge that will allow healthcare providers to make informed decisions about recommending this dietary supplement in this population.
Detailed description
This is a small cohort, off label treatment study assessing the safety, and tolerability of the over-the-counter supplement, nicotinamide mononucleotide (NMN) in individuals with heterozygous DHDDS-CDG. There is no treatment currently available for this progressive disease and there is evidence that this supplement may be a viable supportive therapy. This study will assess the safety and tolerability of this supplement, as well as examine NMN's effect on clinical manifestations of DHDDS-CDG, including gait abnormalities and hand tremor. This phase 1, open-label study will have a 4 week run-in period, a treatment period of 6 months during which the participants will take 250 mg NMN daily, and an optional extension period of 6 more months. Study assessments will involve physician assessments, lab tests, physical exams, vital signs, height/weight measurements, participant goal-setting, and tests to assess gait performance and hand tremor.
Interventions
DRUGNicotinamide Mononucleotide (NMN) Nucleosidase
Name: nicotinamide mononucleotide (NMN) Form: measured powder Dose: 250 mg/day Frequency: Daily Route of administration: Oral
Sponsors
Eva Morava-Kozicz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is ≥ 4 years old * Subject has biologically and genetically proven heterozygous DHDDS-CDG. * Subject/legally authorized representative (LAR) is able to understand and provide written informed consent, and assent (as applicable) to participate in this study.
Exclusion criteria
* Subject has intellectual disability with IQ\<52 (moderate or lower IQ intellectual disability). * In the site Principal Investigator's opinion, subject has a history of intolerance to NMN or other niacin metabolite supplement that precludes the subject from participation in this study. * Subject has any of the following: * Liver failure * ALT level \>5x ULN * AST level \>5x ULN * eGFR \< 30 OR creatinine \>180 mmol/L * Subject is pregnant. * Use of investigational compounds within the previous 6 months or current enrollment in another trial involving investigational compounds. * Concomitant use of the following medications that could interact with orally administered NMN: * Aspirin * Metformin * Statins or other cholesterol-lowering drugs * In the site Principal Investigator's opinion, subject is not able or willing to comply with the trial requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) | up to 12 months | Incidence of AEs will be collected throughout the treatment period and optional long-term safety follow up period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| International Cooperative Ataxia Rating Scale (ICARS) Score | Baseline, 6 months, 12 months | Change in ICARS score from baseline to end of the treatment period (6 months) and long term follow up (12 months). The minimal score is 0 and the maximum score is 100, with a higher score indicating greater impairment as a result of ataxia. |
| Composite gait stability score (Cord walking test performance) | Baseline, 6 months, 12 months | Cord walking performance will be quantified using a standardized video-based computer vision pipeline applied to semi-structured recordings of participants walking along a straight line. Markerless pose estimation algorithms will extract time-resolved body keypoints, from which predefined gait and postural metrics will be derived, including step width variability, step length consistency, lateral deviation from the walking path, and trunk instability (e.g., standard deviation of body lean). Each metric will be summarized per recording and combined into a composite gait stability score using a prespecified algorithm. Change from baseline to 6 and 12 months will be calculated as within-subject differences in these quantitative measures, enabling objective assessment of gait abnormalities over time. |
| Composite tremor severity score (Archimedes spiral test performance) | Baseline, 6 months, 12 months | Archimedes spiral test performance will be quantified using standardized digital analysis of recorded spiral drawings. Video or image inputs will be processed to extract the drawn trajectory, and quantitative features of tremor and motor control will be computed, including line deviation from an ideal spiral template, tremor amplitude (spatial variability), frequency of oscillations, and drawing smoothness (e.g., velocity and jerk metrics). These features will be aggregated into a composite tremor severity score using a predefined scoring framework. Change from baseline to 6 and 12 months will be assessed as within-subject differences in these quantitative metrics, providing an objective measure of hand tremor severity and progression. |
Countries
United States
Contacts
CONTACTGeorgia MacDonald, MS, CGC
PRINCIPAL_INVESTIGATOREva Morava, MD, PhD
Icahn School of Medicine at Mount Sinai
Outcome results
None listed