Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

Completed

• Conditions: Muscular Dystrophy; Spinal Muscular Atrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Neuromuscular Disease; Charcot-Marie-Tooth Disease; Peroneal Muscular Atrophy; Motor Neuron Disease
• Interventions: Other: sample collection

• Registration Number: NCT02532244
• Lead Sponsor: Nemours Children's Clinic

Brief Summary

The goal of this study is to establish a genetic registry of patients with early-onset motor neuron and neuromuscular diseases. The investigators will collect samples from patients with a motor neuron or a neuromuscular disorder and their family members. The samples to be collected will be obtained using minimally invasive (whole blood) means. The research team will then extract high quality genomic DNA or RNA from these samples and use it to identify and confirm novel gene mutations and to identify genes which regulate the severity of motor neuron/neuromuscular diseases.

Detailed Description

Diseases affecting the motor unit--which is composed of the motor neuron, its myelin sheath and its innervated muscle fibers--are a diverse, heterogeneous group having heterogeneous clinical presentations and genetic causes. Many of these disorders have a inherited component. In some cases, the genetics underlying a given neuromuscular/motor neuron disease, like spinal muscular atrophy (SMA) or Duchenne muscular dystrophy, are well characterized. There are, however, disorders whose genetic basis has yet to be determined or genetically characterized diseases which harbor novel mutations. The purpose of this genetic registry is to catalogue early-onset motor neuron and neuromuscular disorders and to determine their genetic bases. With samples obtained from this registry, the investigators will be able to provide a genetic diagnosis for a specific neuromuscular/motor neuron disease which will lead to better care for those patients affected by these diseases.

Many of these disorders have a wide spectrum of phenotypic variability. For example, the severity of SMA is quite variable even though it is caused by the loss of a single gene, i.e. survival motor neuron 1 (SMN1). The number of copies of the duplicated gene survival motor neuron 2 (SMN2) dictates phenotypic severity in SMA. In this study, the research team will also identify potential modifiers of phenotypic severity for specific disorders like SMA and Charcot-Marie-Tooth (CMT) disease. With the identification of novel modifier genes, the investigators will be able to more accurately predict disease outcomes and the investigators will also have novel targets for the development of therapeutic agents for these diseases.

Study Timeline

• Study Start: 2015-06
• Study First Submitted: 2015-08-21
• Study First Submitted QC: 2015-08-24
• Study First Posted: 2015-08-25
• Status Verified: 2024-12
• Primary Completion: 2024-12-18
• Study Completion: 2024-12-18
• Last Update Submitted: 2024-12-18
• Last Update Posted: 2024-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 230

Inclusion Criteria

• Diagnosis of motor neuron/neuromuscular disease confirmed by neurologist
• Be seen by one of the study investigators

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Exclusion Criteria

• not seen by one of the study investigators

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
sample collection	sample collection	Each participant will have blood drawn for genetic analysis and for establishment of a lymphoblastoid cell line.

Primary Outcome Measures

Name	Time	Method
genetic diagnosis	up to 2 years	The genetic basis for the subject's condition will be verified/determined by Sanger sequencing of DNA sample

Secondary Outcome Measures

Name	Time	Method
target gene protein levels	up to 2 years	The relative amounts of the disease-gene-specific protein will be measured using immunoblot.
target gene mRNA levels	up to 2 years	The relative levels of the disease gene-specific messenger ribonucleic acid (mRNA) will be measured using quantitative PCR.
SMN2 copy number	up to 2 years	The number of copies of the SMN2 gene will be determined using array digital PCR.
SMN1 copy number	up to 2 years	The number of copies of the SMN1 gene will be determined using array digital polymerase chain reaction (PCR).

Trial Locations

Locations (3)

Nemours Children's Hospital Delaware; 🇺🇸 Wilmington, Delaware, United States

Nemours Children's Specialty Care; 🇺🇸 Jacksonville, Florida, United States

Nemours Children's Hospital Orlando; 🇺🇸 Orlando, Florida, United States