Natural History Study - Mitochondrial Disease

Mitochondrial Encephalomyopathies and Mental Retardation: Investigations of Clinical Syndromes Associated With MtDNA Point Mutations

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.

Study Overview

• Status: Recruiting
• Conditions: MELAS or m.3243 A>G Mitochondrial DNA Mutation Carrier

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.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Kris Engelstad, MS; Phone Number: 2123056834; Email: ke4@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
      • Contact: Kris Engelstad, MS; Phone Number: '-212-305-6834; Email: ke4@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• 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).

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
mtDNA mutation; m.3243 A>G carriers and their maternal relatives Other mutations in the mitochondrial genome may be included
Control; controls (people not maternally related to mutation carriers) Preference is for married in relatives

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI/MRS	Evaluate structure and function in brain and muscle	2-3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	Evaluate various biomarkers of disease progression	2-3 years
Motor skills	6 minute walk test to evaluate motor skills	2-3 years
Cognitive function	Evaluate cognitive function through neuropsychological testing	2-3 years
Clinical symptoms	Evaluate clinical symptoms through medical history questionnaires and physical exam	2-3 years
Mutation load	Evaluate heteroplasmy through blood,urine and skin fibroblast evaluations	2-3 years

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Michio Hirano, MD, mh29@cumc.columbia.edu

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• general website for our available clinical studies

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2004
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: February 14, 2012
• First Posted (Estimated): February 15, 2012

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 22, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: mitochondria; MELAS; mitochondrial DNA mutation; mtDNA mutation; mitochondrial DNA; m.3243A>G mutation
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Mitochondrial Diseases; Cerebral Small Vessel Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; MELAS Syndrome
• Other Study ID Numbers: AAAB1425; 5P01HD032062 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: When applicable, manuscript(s) regarding data will be submitted for publication

Drug and device information, study documents

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