Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

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.

Study Overview

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

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 Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Matthew ER Butchbach, Ph.D.; Phone Number: 302-298-7366; Email: Matthew.Butchbach@nemours.org
• Study Contact Backup: Name: Kimberly Klipner, M.S.; Phone Number: 302-651-4088; Email: Kimberly.Klipner@nemours.org

Study Locations

• United States
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Recruiting
      • Nemours Children's Hospital Delaware
      • Contact: Matthew ER Butchbach, Ph.D.; Phone Number: 302-298-7366; Email: Matthew.Butchbach@nemours.org
      • Sub-Investigator: Robert Heinle, M.D.
      • Sub-Investigator: Jason Howard, M.D.
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Recruiting
      • Nemours Children's Specialty Care
      • Contact: Matthew ER Butchbach, Ph.D.; Phone Number: 302-298-7266; Email: Matthew.Butchbach@nemours.org
    • Orlando, Florida, United States, 32827
      • Recruiting
      • Nemours Children's Hospital Orlando
      • Contact: Matthew ER Butchbach, Ph.D.; Phone Number: 302-298-7366; Email: Matthew.Butchbach@nemours.org
      • Sub-Investigator: Omer Abdul Hamid, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll children diagnosed with a motor neuron or neuromuscular disease as well as their parents and/or siblings as well as adults with childhood-onset motor neuron or neuromuscular diseases.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
sample collection; Each participant will have blood drawn for genetic analysis and for establishment of a lymphoblastoid cell line.	Other: sample collection; collection of blood

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
SMN2 copy number	The number of copies of the SMN2 gene will be determined using array digital PCR.	up to 2 years
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
target gene protein levels	The relative amounts of the disease-gene-specific protein will be measured using immunoblot.	up to 2 years

Collaborators and Investigators

• Sponsor: Nemours Children's Clinic
• Investigators: Principal Investigator: Matthew ER Butchbach, Ph.D., Nemours Children's Clinic

Publications and helpful links

General Publications

• 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):439-446. doi: 10.1016/j.nmd.2017.02.002. Epub 2017 Feb 6.
• 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 measured by array digital PCR. Mol Genet Genomic Med. 2015 Jul;3(4):248-57. doi: 10.1002/mgg3.141. Epub 2015 Mar 21.
• 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. Genet Med. 2020 May;22(5):945-953. doi: 10.1038/s41436-020-0754-0. Epub 2020 Feb 18.
• 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/s41598-020-76893-7.
• 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/s10048-020-00630-5. Epub 2021 Jan 7.
• 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/biology11060824.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: August 21, 2015
• First Submitted That Met QC Criteria: August 24, 2015
• First Posted (Estimated): August 25, 2015

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: distal hereditary motor neuronopathy
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Stomatognathic Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Muscular Disorders, Atrophic; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Muscular Dystrophies; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Tooth Diseases; Neuromuscular Diseases; Nerve Compression Syndromes; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy
• Other Study ID Numbers: 764456

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: De-identified information will be shared once the data are published.

Drug and device information, study documents

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