Clinical trial NCT01532791: Natural History Study - Mitochondrial Disease
Official title: Mitochondrial Encephalomyopathies and Mental Retardation: Investigations of Clinical Syndromes Associated With MtDNA Point Mutations
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: MELAS or m.3243 A>G Mitochondrial DNA Mutation Carrier
Keywords: MELAS
mitochondrial DNA mutation
mtDNA mutation
mitochondrial DNA
mitochondria
m.3243A>G mutation
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-02-15
Enrollment: 300
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Carriers of the m.3243A\>G mitochondrial DNA point mutation, and their maternal relatives (carrier status documentation not required.). All patients suspected of having an mtDNA point mutation regardless of age, health status, gender, race, or ethnicity will be evaluated. The minimal age of entry into the study will be 4 years or older. We will also evaluate controls (often these are married in relatives).

Brief summary: Carriers of the m.3242A\>G mutation often have clinical symptoms which can include migraines, seizures, strokes, hearing loss, balance issues, gastrointestinal issues, and many other symptoms. The investigators would like to learn more about these disorders and have designed a "Natural History Study" to monitor these conditions over time so that physicians and scientists can not only understand the problems that patients have, but work on developing treatments. The focus of the current work is to evaluate known mutation carriers of the m.3243A\>G (mitochondrial DNA) and their maternal relatives (carrier status not a requirement for participation). Paternal relatives will serve as controls. This study involves no treatment.

Detailed description: The purpose of this study is to investigate the neurological and biochemical consequences of the m.3243 A\>G mutation. Mitochondria are the powerhouses of the cell and are controlled by nuclear genetic material (DNA) and mitochondrial (mt) DNA. Mitochondrial DNA mutations impair mitochondrial function, and cause cellular energy failure. These mutations, when present in high abundance, cause neurological signs and symptoms that are clinically obvious. The investigators hypothesize that these mutations, when present in lesser abundance, will cause measurable alterations in the patient's neuropsychological profile and cerebral energy profile. This study does not involve any experimental or approved therapy. The investigators will evaluate the patient's condition with blood/urine tests, neurological exam, MRI/MRS, questionnaires, motor skills functioning, serum and urine biomarkers, and genetic testing.

Eligibility criteria: Inclusion Criteria:

Known carrier of a the m.3243 A\>G mitochondrial mutation, ,or Maternally related to someone who carries the m.3243A\>G mitochondrial mutation.

A family member who is not maternally related to someone who carries the m.3243A\>G mitochondrial mutation

Exclusion Criteria:

* Younger than 4 years of age
* No confirmed m.3243 A\>G mitochondrial DNA mutation in the family.

Primary outcomes:
measure: MRI/MRS
timeFrame: 2-3 years
Secondary outcomes:
measure: Biomarkers
timeFrame: 2-3 years
measure: Motor skills
timeFrame: 2-3 years
measure: Cognitive function
timeFrame: 2-3 years
measure: Clinical symptoms
timeFrame: 2-3 years
measure: Mutation load
timeFrame: 2-3 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
affiliation: dcd1@columbia.edu
name: Darryl De Vivo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Weiduschat N, Kaufmann P, Mao X, Engelstad KM, Hinton V, DiMauro S, De Vivo D, Shungu D. Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology. 2014 Mar 4;82(9):798-805. doi: 10.1212/WNL.0000000000000169. Epub 2014 Jan 29.
citation: Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, Battista V, Koenigsberger DY, Pascual JM, Shanske S, Sano M, Mao X, Hirano M, Shungu DC, Dimauro S, De Vivo DC. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011 Nov 29;77(22):1965-71. doi: 10.1212/WNL.0b013e31823a0c7f. Epub 2011 Nov 16.
citation: Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K, Naini A, De Vivo DC, DiMauro S. Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A. 2009 Feb 15;149A(4):584-7. doi: 10.1002/ajmg.a.32703.
citation: Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Battista V, Koenigsberger DY, Pascual JM, Sano M, Hirano M, DiMauro S, Shungu DC, Mao X, De Vivo DC. Protean phenotypic features of the A3243G mitochondrial DNA mutation. Arch Neurol. 2009 Jan;66(1):85-91. doi: 10.1001/archneurol.2008.526.