Clinical trial NCT02532244: Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
Official title: Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Spinal Muscular Atrophy
Charcot-Marie-Tooth Disease
Muscular Dystrophy
Spinal Muscular Atrophy With Respiratory Distress 1
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Neuromuscular Disease
Peroneal Muscular Atrophy
Keywords: distal hereditary motor neuronopathy
Lead sponsor: Nemours Children's Clinic
Sponsor class: OTHER
First posted: 2015-08-25
Enrollment: 230
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: genetic diagnosis
timeFrame: up to 2 years
Secondary outcomes:
measure: SMN1 copy number
timeFrame: up to 2 years
measure: SMN2 copy number
timeFrame: up to 2 years
measure: target gene mRNA levels
timeFrame: up to 2 years
measure: target gene protein levels
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Wilmington
country: United States
facility: Nemours Children's Hospital Delaware
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Children's Specialty Care
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital Orlando
state: Florida
Study officials:
affiliation: Nemours Children's Clinic
name: Matthew ER Butchbach, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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):439-446. doi: 10.1016/j.nmd.2017.02.002. Epub 2017 Feb 6.
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 measured by array digital PCR. Mol Genet Genomic Med. 2015 Jul;3(4):248-57. doi: 10.1002/mgg3.141. Epub 2015 Mar 21.
citation: 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.
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/s41598-020-76893-7.
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/s10048-020-00630-5. Epub 2021 Jan 7.
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/biology11060824.