Characterization of DupEx2 Duchenne Muscular Dystrophy (DMDDup2)

Characterization of the Phenotypic Diversity in DupEx2 Duchenne Muscular Dystrophy and Identification of Predictive/Prognostic Markers

To characterize the clinical phenotype and possible predictive/prognostic factors of patients with Duchenne muscular dystrophy (DMD) due to duplication of exon 2 (Dup2). Specifically, we aim 1) to describe the progression of motor, respiratory and cardiac function; 2) to enquire if the phenotypic spectrum of Dup2 is milder than classic DMD, 3) to perform whole genome sequencing (WGS) to characterize DNA breakpoints to correlate with the phenotype; 4) to collect material for future proteomic/transcriptomic studies.

Background/Rationale DMD is caused by mutations in the DMD gene and in 11% of cases is due to duplications. The most promising therapeutic approaches include mutation-specific therapies. Notably, there is increasing evidence that specific groups of mutations may underlie different disease trajectories compared to the "average" DMD population. It is thus mandatory to have more information on genotype-phenotype correlations and patterns of progression related to different genotypes.

Dup2 is the most common DMD duplication and the only one for which a AAV-mediated exon skipping study is ongoing. Despite most case series and databases ascribe Dup2 to severe phenotype, our preliminary findings sustain that these patients have collectively a milder progression of the disease and in 1/3 of cases a significantly milder phenotype. Moreover, our attempts to reveal mechanism involved in attenuating the phenotype would confute the hypothesis of alternative spicing transcripts as previously described for DMD with deletion of exon 2.

Research design and methods Clinical information regarding a cohort of 26 Italian Dup2 patients will be collected. Differences in time to loss of ambulation compared to a DMD control group will be achieved. Finally, we will retrieve DNA for correlative WGS studies.

Anticipated output We expect that Dup2 patients present a milder DMD phenotype , which might be predicted by genomic studies.

Study Overview

• Status: Recruiting
• Conditions: Muscular Dystrophy, Duchenne

Detailed Description

The primary clinical endpoint is time to loss of ambulation (LOA).

Secondary endpoints include:

1. The change over time of the following functional measurements:

   1.1 Motor function: The 6 Minute Walk test (6MWT) and North Star Ambulatory Assessment (NSAA) including sub-items such as Time to Rise from the floor.

   1.2 Respiratory function: Forced Vital Capacity (FVC) Liters (L) and % of predicted; time to FVC% < 50%. Time to Nocturnal Ventilation initiation.

   1,3 Cardiac function: Left ventricular ejection fraction (EF) as measured by echocardiogram.

2. To characterize DNA breakpoints in mild vs severe phenotypes

• Study Type: Observational
• Enrollment (Estimated): 26

Contacts and Locations

• Study Contact: Name: Stefano C Previtali, MD; Phone Number: 00390226433036; Email: neuromuscolare@hsr.it
• Study Contact Backup: Name: Alberto A Zambon, MD; Phone Number: 00390226431; Email: neuromuscolare@hsr.it

Study Locations

• Italy
  • Milano, Italy, 20132
    • Recruiting
    • Dept. of Neurology, IRCCS Ospedale San Raffaele
    • Contact: Stefano C Previtali, MD; Phone Number: 00390226433036; Email: neuromuscolare@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Italian DMD patients with Dup2 mutation

Description

Inclusion Criteria:

• pediatric and adult DMD patients harboring a genetically confirmed duplication of the exon 2 in the dystrophin gene

Exclusion Criteria:

• patients lacking genetic confirmation of Dup2 mutation

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age at loss of ambulation	Age at loss of ambulation	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time test for motor function	The 6 Minute Walk test (6MWT) and North Star Ambulatory Assessment (NSAA) including sub-items such as Time to Rise from the floor.	12 months
Respiratory function	Forced Vital Capacity (FVC) Liters (L) and % of predicted; time to FVC% < 50%. Time to Nocturnal Ventilation initiation	12 months

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Principal Investigator: Stefano C Previtali, MD, IRCCS Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2022
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): January 31, 2025

Study Registration Dates

• First Submitted: March 18, 2024
• First Submitted That Met QC Criteria: March 22, 2024
• First Posted (Actual): March 29, 2024

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: OSRSCP-GUP21006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No