Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

Amyotrophic Lateral Sclerosis Clinical Trial

Official title:

Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02532244
• Other study ID #: 764456
• Status: Recruiting
• Start date: June 2015
• Est. completion date: December 2025

Study information

• Verified date: March 2024
• Source: Nemours Children's Clinic
• Contact: Matthew ER Butchbach, Ph.D.
• Phone: 302-298-7366
• Email: Matthew.Butchbach[@]nemours.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Month and older

Eligibility

Inclusion Criteria:

• Diagnosis of motor neuron/neuromuscular disease confirmed by neurologist

• Be seen by one of the study investigators

Exclusion Criteria:

• not seen by one of the study investigators

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Atrophy
• Charcot-Marie-Tooth Disease
• Hereditary Sensory and Motor Neuropathy
• Motor Neuron Disease
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Muscular Dystrophies
• Muscular Dystrophy
• Nerve Compression Syndromes
• Neuromuscular Disease
• Neuromuscular Diseases
• Peroneal Muscular Atrophy
• Spinal Muscular Atrophy
• Spinal Muscular Atrophy With Respiratory Distress 1
• Tooth Diseases

Intervention

Other:
• sample collection
collection of blood

Locations

Country	Name	City	State
United States	Nemours Children's Specialty Care	Jacksonville	Florida
United States	Nemours Children's Hospital Orlando	Orlando	Florida
United States	Nemours Children's Hospital Delaware	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Nemours Children's Clinic

Country where clinical trial is conducted

United States, 

References & Publications (6)

Chen X, Sanchis-Juan A, French CE, Connell AJ, Delon I, Kingsbury Z, Chawla A, Halpern AL, Taft RJ; NIHR BioResource; Bentley DR, Butchbach MER, Raymond FL, Eberle MA. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Ge — View Citation

Jiang L, Lin R, Gallagher S, Zayac A, Butchbach MER, Hung P. Development and validation of a 4-color multiplexing spinal muscular atrophy (SMA) genotyping assay on a novel integrated digital PCR instrument. Sci Rep. 2020 Nov 16;10(1):19892. doi: 10.1038/s — View Citation

Pinto A, Cunha C, Chaves R, Butchbach MER, Adega F. Comprehensive In Silico Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy. Biology (Basel). 2022 May 27;11(6):824. doi: 10.3390/biology1106 — View Citation

Stabley DL, Harris AW, Holbrook J, Chubbs NJ, Lozo KW, Crawford TO, Swoboda KJ, Funanage VL, Wang W, Mackenzie W, Scavina M, Sol-Church K, Butchbach ME. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measure — View Citation

Stabley DL, Holbrook J, Harris AW, Swoboda KJ, Crawford TO, Sol-Church K, Butchbach MER. Establishing a reference dataset for the authentication of spinal muscular atrophy cell lines using STR profiling and digital PCR. Neuromuscul Disord. 2017 May;27(5): — View Citation

Stabley DL, Holbrook J, Scavina M, Crawford TO, Swoboda KJ, Robbins KM, Butchbach MER. Detection of SMN1 to SMN2 gene conversion events and partial SMN1 gene deletions using array digital PCR. Neurogenetics. 2021 Mar;22(1):53-64. doi: 10.1007/s10048-020-0 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	genetic diagnosis	The genetic basis for the subject's condition will be verified/determined by Sanger sequencing of DNA sample	up to 2 years
Secondary	SMN1 copy number	The number of copies of the SMN1 gene will be determined using array digital polymerase chain reaction (PCR).	up to 2 years
Secondary	SMN2 copy number	The number of copies of the SMN2 gene will be determined using array digital PCR.	up to 2 years
Secondary	target gene mRNA levels	The relative levels of the disease gene-specific messenger ribonucleic acid (mRNA) will be measured using quantitative PCR.	up to 2 years
Secondary	target gene protein levels	The relative amounts of the disease-gene-specific protein will be measured using immunoblot.	up to 2 years