Organic AcidemiaNCT00078078
Clinical and Laboratory Study of Methylmalonic Acidemia
An observational study of Organic Acidemia and Methylmalonic Acidemia, run by National Human Genome Research Institute (NHGRI) at 3 sites in United States.
Trial summary
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal… Read more about this study
- Who is it for?
- Ages 1 month to 115 yearsHealthy volunteers can take part
- Conditions the study is for
- Organic Acidemia, Methylmalonic Acidemia, Inborn Errors of Metabolism
- How many people
- 2,275 participants
- Where
- 3 sitesUnited States
- Study dates
- 7 Jun 2004to not given
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 115 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Individuals with methylmalonic acidemia
Who may be able to join
- Patients of any sex, ethnicity, and over 1 month of age with biochemical or genetic diagnosis of methylmalonic acidemia or cobalamin disorders are eligible to enroll in this protocol. The primary reason for expanding enrollment to young children is because individuals with cobalamin C deficiency (cblC) develop a maculopathy often in utero or early infancy yet the natural history of the disease progression in these early years has not been well defined. Our colleagues at the National Eye Institute have documented the retinal findings in the largest cohort of individuals with cblC and have developed an expertise in this disorder. A recent report suggests that early treatment may significantly improve the retinal disease and will be the focus of a future clinical trial at the NIH Clinical Center requiring a need for more natural history data from birth to early childhood. Children ages 1 month to 2 years or under 12 kg will be reviewed by the Pediatric Consult Service prior to scheduling and if approved will be evaluated in the outpatient clinic for limited evaluations blood draw, eye exam, consults. Affected infants that are not approved by the Pediatric Consult Service or are not stable enough to travel may enroll remotely by telemedicine to include in natural history data collection, such as medical history and laboratory result sharing and interpretation, molecular genetic testing, genetic counseling, nutrition consult with dietary food log analysis, neurocognitive assessments. Affected individuals of any of the other disorders under study, younger than 2 years may be evaluated at Children s National Medical Center (CNMC) as part of an evolving agreement in the Translational Program in Pediatrics, if they are deemed eligible for participation by the NIH team and the CNMC team. Patients will be diagnosed based on a determination of MMA and homocysteine levels in plasma and urine. Most will have their complementation class known or pending. Molecular genetic analyses to determine mutations will be expected to have been performed prior to acceptance into the study. Some patients who have not yet had these laboratory tests will be admitted to the protocol based upon metabolic parameters and clinical history. This latter category of patients might include individuals with a suspected genetic but unknown type of MMA.
Who cannot join
- The PI/AI may decline to enroll a patient for reasons such as being medically unstable, residing in a hospital, sub-optimal metabolic control or for any concerns arising after review of the laboratory and clinical data; any patient who requires dialysis once or more/week and weighs <40 kg; any patient who is being treated for an intercurrent infection with antibiotics or has evidence of an acute infection and has metabolic symptoms; any patient who does not have a regular/local metabolic, genetic or endocrine physician and/or a family physician, pediatrician, or internist; any patient who may be metabolically unstable but not acutely ill; and any patient or family who may not be able to institute recommendations for appropriate testing and care before visiting the NIH. Each family may be contacted by the NIH team prior to a pending admission to confirm that the patient is metabolically stable and ready to visit the NIH in a state of relative health, with an adequate supply of special formulas, medications, supplements, and if needed, medical equipment such as feeding pumps and replacement parts for feeding tubes. A subset of participants will be enrolled in the tissue collection part of the study only (i.e. if they are too sick to travel).
- Pregnant women may be eligible to enroll in the study if they are affected with methylmalonic acidemia or a cobalamin disorder or are family members of an affected subject. Pregnant women are not excluded because it is important to learn more about the effects of these disorders in pregnant participants and the fetus. This research involves no more than minimal risk to the fetus. Affected subjects who are pregnant or become pregnant during their participation on the study will not be withdrawn, but will be excluded from some procedures until the pregnancy is concluded. Affected subjects who are pregnant may undergo procedures as part of their clinical care, including blood draws, genetic studies, and consultations, according to the clinical judgement of the clinical team. Pregnant participants will be excluded from some procedures such as stable isotope, GFR testing, and MRI until the pregnancy is concluded.
- Patients with methylmalonic acidemia or cobalamin disorders of any age, sex and ethnicity, undergoing a transplantation surgery at UPMC Children s Hospital of Pittsburgh, are eligible to participate in the tissue collection arm of the study. Pregnant women will be excluded from tissue collection at the UPMC Children s Hospital of Pittsburgh.
- For the healthy volunteers, eligibility criteria include individuals that are age 18 and over.
- Exclusion criteria include: women who are pregnant, individuals being treated with antibiotics, individuals with kidney or liver disease, individuals on a special diet such as a high protein diet or taking protein supplements and individuals with severe claustrophobia or other anxiety disorders.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 2 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
- Recruiting
UPMC Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, 15224
James Squires, 412-692-5180, james.squires2@chp.edu
- Completed
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - (cblC, cblD, cblF, cblJ and cblX) - and are also heterogenous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes.
In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed. In this small group of patients, CSF metabolite monitoring may be used to adjust therapy.
Read more
The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials.
The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children's National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal Investigator of the CNMC location Individuals may also enroll in the tissue collection only part of the study at the UPMC Children's Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.
Read the detailed description
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with mut, cblA, and cblB classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - (cblC, cblD, cblF, cblJ and cblX) - and are also heterogeneous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine and/or malonic acid in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes.
In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions and outpatient evaluations will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing.
The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials. The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children s National Medical Center (CNMC) site, pending approval by Dr. Chapman, the Principal Investigator of the CNMC location. Individuals may also enroll in the tissue collection only part of the study at the UPMC Children s Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.
- Keywords
- Organic Acidemia, Cobalamin, Vitamin B12, Methylmalonic Acidemia, Hyperhomocysteinemia, Natural History, MMA, Metabolic Disease
- Medical subject headings
- Methylmalonic acidemia, Metabolism, Inborn Errors, Hyperhomocysteinemia, Metabolic Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Methylmalonic Acidemia | Individuals with methylmalonic acidemia |
What is being measured
The primary outcome is the main question the study is designed to answer.
Natural history to assess long term complications of disease
assessing the complications of MMA during a week long evaluation with imaging, labs and consultations
Measured: ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Feb 2004 (estimated)
- Study start7 Jun 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Organic AcidemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 2,275 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Charles P Venditti, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00078078
- Sponsor's protocol ID
- 040127
- Other IDs
- 04-HG-0127
- Status last verified
- 8 Sep 2026
- First submitted
- 18 Feb 2004
- Last updated
- 29 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Study is observational natural history study that is ongoing with no defined endpoints.
Publications
Manoli I, Sysol JR, Epping MW, Li L, Wang C, Sloan JL, Pass A, Gagne J, Ktena YP, Li L, Trivedi NS, Ouattara B, Zerfas PM, Hoffmann V, Abu-Asab M, Tsokos MG, Kleiner DE, Garone C, Cusmano-Ozog K, Enns GM, Vernon HJ, Andersson HC, Grunewald S, Elkahloun AG, Girard CL, Schnermann J, DiMauro S, Andres-Mateos E, Vandenberghe LH, Chandler RJ, Venditti CP. FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight. 2018 Dec 6;3(23):e124351. doi: 10.1172/jci.insight.124351.
PubMed 30518688Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med. 2016 Apr;18(4):386-95. doi: 10.1038/gim.2015.102. Epub 2015 Aug 13.
PubMed 26270765Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [updated 2022 Sep 8]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1231/
PubMed 20301409Manoli I, Sysol JR, Head PE, Epping MW, Gavrilova O, Crocker MK, Sloan JL, Koutsoukos SA, Wang C, Ktena YP, Mendelson S, Pass AR, Zerfas PM, Hoffmann V, Vernon HJ, Fletcher LA, Reynolds JC, Tsokos MG, Stratakis CA, Voss SD, Chen KY, Brown RJ, Hamosh A, Berry GT, Chen XS, Yanovski JA, Venditti CP. Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation. JCI Insight. 2024 Feb 22;9(4):e174097. doi: 10.1172/jci.insight.174097.
PubMed 38271099Manoli I, Pass AR, Harrington EA, Sloan JL, Gagne J, McCoy S, Bell SL, Hattenbach JD, Leitner BP, Duckworth CJ, Fletcher LA, Cassimatis TM, Galarreta CI, Thurm A, Snow J, Van Ryzin C, Ferry S, Mew NA, Shchelochkov OA, Chen KY, Venditti CP. 1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA). Genet Med. 2021 Aug;23(8):1522-1533. doi: 10.1038/s41436-021-01143-8. Epub 2021 Apr 5.
PubMed 33820958Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25 [updated 2021 Dec 16]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1328/
PubMed 20301503Manoli I, Gebremariam A, McCoy S, Pass AR, Gagne J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. J Inherit Metab Dis. 2023 Jul;46(4):554-572. doi: 10.1002/jimd.12636. Epub 2023 Jun 6.
PubMed 37243446Harrington EA, Sloan JL, Manoli I, Chandler RJ, Schneider M, McGuire PJ, Calcedo R, Wilson JM, Venditti CP. Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia. Hum Gene Ther. 2016 May;27(5):345-53. doi: 10.1089/hum.2015.092. Epub 2016 Mar 22.
PubMed 26790480Caterino M, Chandler RJ, Sloan JL, Dorko K, Cusmano-Ozog K, Ingenito L, Strom SC, Imperlini E, Scolamiero E, Venditti CP, Ruoppolo M. The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers. Mol Biosyst. 2016 Feb;12(2):566-74. doi: 10.1039/c5mb00736d.
PubMed 26672496Ktena YP, Ramstad T, Baker EH, Sloan JL, Mannes AJ, Manoli I, Venditti CP. Propofol administration in patients with methylmalonic acidemia and intracellular cobalamin metabolism disorders: a review of theoretical concerns and clinical experiences in 28 patients. J Inherit Metab Dis. 2015 Sep;38(5):847-53. doi: 10.1007/s10545-015-9816-x. Epub 2015 May 19.
PubMed 25985870Raval DB, Merideth M, Sloan JL, Braverman NE, Conway RL, Manoli I, Venditti CP. Methylmalonic acidemia (MMA) in pregnancy: a case series and literature review. J Inherit Metab Dis. 2015 Sep;38(5):839-46. doi: 10.1007/s10545-014-9802-8. Epub 2015 Jan 8.
PubMed 25567501Baker EH, Sloan JL, Hauser NS, Gropman AL, Adams DR, Toro C, Manoli I, Venditti CP. MRI characteristics of globus pallidus infarcts in isolated methylmalonic acidemia. AJNR Am J Neuroradiol. 2015 Jan;36(1):194-201. doi: 10.3174/ajnr.A4087. Epub 2014 Sep 4.
PubMed 25190203Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13552-7. doi: 10.1073/pnas.1302764110. Epub 2013 Jul 29.
PubMed 23898205O'Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, Manoli I, Venditti CP, Snow J. Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics. 2012 Jun;129(6):e1541-51. doi: 10.1542/peds.2011-1715. Epub 2012 May 21.
PubMed 22614770Hauser NS, Manoli I, Graf JC, Sloan J, Venditti CP. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr. 2011 Jan;93(1):47-56. doi: 10.3945/ajcn.110.004341. Epub 2010 Nov 3.
PubMed 21048060
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders
- ClinicalTrials.gov ID
- NCT00078078
- Acronym / sponsor ID
- 040127
- Keywords
- Organic Acidemia, Cobalamin, Vitamin B12, Methylmalonic Acidemia, Hyperhomocysteinemia, Natural History, MMA, Metabolic Disease
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 2,275 participants (estimated)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 7 Jun 2004 (actual)
- First posted
- 19 Feb 2004 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - (cblC, cblD, cblF, cblJ and cblX) - and are also heterogenous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes.
In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed. In this small group of patients, CSF metabolite monitoring may be used to adjust therapy.
The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials.
The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children's National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal Investigator of the CNMC location Individuals may also enroll in the tissue collection only part of the study at the UPMC Children's Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.
Detailed description
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with mut, cblA, and cblB classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - (cblC, cblD, cblF, cblJ and cblX) - and are also heterogeneous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine and/or malonic acid in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes.
In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions and outpatient evaluations will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing.
The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials. The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children s National Medical Center (CNMC) site, pending approval by Dr. Chapman, the Principal Investigator of the CNMC location. Individuals may also enroll in the tissue collection only part of the study at the UPMC Children s Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Methylmalonic Acidemia | – | –Individuals with methylmalonic acidemia |
Who may qualify
- Ages
- 1 month to 115 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Individuals with methylmalonic acidemia
Key inclusion criteria (1 listed)
- Patients of any sex, ethnicity, and over 1 month of age with biochemical or genetic diagnosis of methylmalonic acidemia or cobalamin disorders are eligible to enroll in this protocol. The primary reason for expanding enrollment to young children is because individuals with cobalamin C deficiency (cblC) develop a maculopathy often in utero or early infancy yet the natural history of the disease progression in these early years has not been well defined. Our colleagues at the National Eye Institute have documented the retinal findings in the largest cohort of individuals with cblC and have developed an expertise in this disorder. A recent report suggests that early treatment may significantly improve the retinal disease and will be the focus of a future clinical trial at the NIH Clinical Center requiring a need for more natural history data from birth to early childhood. Children ages 1 month to 2 years or under 12 kg will be reviewed by the Pediatric Consult Service prior to scheduling and if approved will be evaluated in the outpatient clinic for limited evaluations blood draw, eye exam, consults. Affected infants that are not approved by the Pediatric Consult Service or are not stable enough to travel may enroll remotely by telemedicine to include in natural history data collection, such as medical history and laboratory result sharing and interpretation, molecular genetic testing, genetic counseling, nutrition consult with dietary food log analysis, neurocognitive assessments. Affected individuals of any of the other disorders under study, younger than 2 years may be evaluated at Children s National Medical Center (CNMC) as part of an evolving agreement in the Translational Program in Pediatrics, if they are deemed eligible for participation by the NIH team and the CNMC team. Patients will be diagnosed based on a determination of MMA and homocysteine levels in plasma and urine. Most will have their complementation class known or pending. Molecular genetic analyses to determine mutations will be expected to have been performed prior to acceptance into the study. Some patients who have not yet had these laboratory tests will be admitted to the protocol based upon metabolic parameters and clinical history. This latter category of patients might include individuals with a suspected genetic but unknown type of MMA.
Key exclusion criteria (5 listed)
- The PI/AI may decline to enroll a patient for reasons such as being medically unstable, residing in a hospital, sub-optimal metabolic control or for any concerns arising after review of the laboratory and clinical data; any patient who requires dialysis once or more/week and weighs <40 kg; any patient who is being treated for an intercurrent infection with antibiotics or has evidence of an acute infection and has metabolic symptoms; any patient who does not have a regular/local metabolic, genetic or endocrine physician and/or a family physician, pediatrician, or internist; any patient who may be metabolically unstable but not acutely ill; and any patient or family who may not be able to institute recommendations for appropriate testing and care before visiting the NIH. Each family may be contacted by the NIH team prior to a pending admission to confirm that the patient is metabolically stable and ready to visit the NIH in a state of relative health, with an adequate supply of special formulas, medications, supplements, and if needed, medical equipment such as feeding pumps and replacement parts for feeding tubes. A subset of participants will be enrolled in the tissue collection part of the study only (i.e. if they are too sick to travel).
- Pregnant women may be eligible to enroll in the study if they are affected with methylmalonic acidemia or a cobalamin disorder or are family members of an affected subject. Pregnant women are not excluded because it is important to learn more about the effects of these disorders in pregnant participants and the fetus. This research involves no more than minimal risk to the fetus. Affected subjects who are pregnant or become pregnant during their participation on the study will not be withdrawn, but will be excluded from some procedures until the pregnancy is concluded. Affected subjects who are pregnant may undergo procedures as part of their clinical care, including blood draws, genetic studies, and consultations, according to the clinical judgement of the clinical team. Pregnant participants will be excluded from some procedures such as stable isotope, GFR testing, and MRI until the pregnancy is concluded.
- Patients with methylmalonic acidemia or cobalamin disorders of any age, sex and ethnicity, undergoing a transplantation surgery at UPMC Children s Hospital of Pittsburgh, are eligible to participate in the tissue collection arm of the study. Pregnant women will be excluded from tissue collection at the UPMC Children s Hospital of Pittsburgh.
- For the healthy volunteers, eligibility criteria include individuals that are age 18 and over.
- Exclusion criteria include: women who are pregnant, individuals being treated with antibiotics, individuals with kidney or liver disease, individuals on a special diet such as a high protein diet or taking protein supplements and individuals with severe claustrophobia or other anxiety disorders.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Natural history to assess long term complications of disease
Time frame: ongoing
assessing the complications of MMA during a week long evaluation with imaging, labs and consultations
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2026.
- Background: PubMed 30518688Manoli I, Sysol JR, Epping MW, Li L, Wang C, Sloan JL, Pass A, Gagne J, Ktena YP, Li L, Trivedi NS, Ouattara B, Zerfas PM, Hoffmann V, Abu-Asab M, Tsokos MG, Kleiner DE, Garone C, Cusmano-Ozog K, Enns GM, Vernon HJ, Andersson HC, Grunewald S, Elkahloun AG, Girard CL, Schnermann J, DiMauro S, Andres-Mateos E, Vandenberghe LH, Chandler RJ, Venditti CP. FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight. 2018 Dec 6;3(23):e124351. doi: 10.1172/jci.insight.124351.
- Background: PubMed 26270765Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med. 2016 Apr;18(4):386-95. doi: 10.1038/gim.2015.102. Epub 2015 Aug 13.
- Background: PubMed 20301409Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [updated 2022 Sep 8]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1231/
- Background: PubMed 38271099Manoli I, Sysol JR, Head PE, Epping MW, Gavrilova O, Crocker MK, Sloan JL, Koutsoukos SA, Wang C, Ktena YP, Mendelson S, Pass AR, Zerfas PM, Hoffmann V, Vernon HJ, Fletcher LA, Reynolds JC, Tsokos MG, Stratakis CA, Voss SD, Chen KY, Brown RJ, Hamosh A, Berry GT, Chen XS, Yanovski JA, Venditti CP. Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation. JCI Insight. 2024 Feb 22;9(4):e174097. doi: 10.1172/jci.insight.174097.
- Background: PubMed 33820958Manoli I, Pass AR, Harrington EA, Sloan JL, Gagne J, McCoy S, Bell SL, Hattenbach JD, Leitner BP, Duckworth CJ, Fletcher LA, Cassimatis TM, Galarreta CI, Thurm A, Snow J, Van Ryzin C, Ferry S, Mew NA, Shchelochkov OA, Chen KY, Venditti CP. 1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA). Genet Med. 2021 Aug;23(8):1522-1533. doi: 10.1038/s41436-021-01143-8. Epub 2021 Apr 5.
- Background: PubMed 20301503Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25 [updated 2021 Dec 16]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1328/
- Derived from this study: PubMed 37243446Manoli I, Gebremariam A, McCoy S, Pass AR, Gagne J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. J Inherit Metab Dis. 2023 Jul;46(4):554-572. doi: 10.1002/jimd.12636. Epub 2023 Jun 6.
- Derived from this study: PubMed 26790480Harrington EA, Sloan JL, Manoli I, Chandler RJ, Schneider M, McGuire PJ, Calcedo R, Wilson JM, Venditti CP. Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia. Hum Gene Ther. 2016 May;27(5):345-53. doi: 10.1089/hum.2015.092. Epub 2016 Mar 22.
- Derived from this study: PubMed 26672496Caterino M, Chandler RJ, Sloan JL, Dorko K, Cusmano-Ozog K, Ingenito L, Strom SC, Imperlini E, Scolamiero E, Venditti CP, Ruoppolo M. The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers. Mol Biosyst. 2016 Feb;12(2):566-74. doi: 10.1039/c5mb00736d.
- Derived from this study: PubMed 25985870Ktena YP, Ramstad T, Baker EH, Sloan JL, Mannes AJ, Manoli I, Venditti CP. Propofol administration in patients with methylmalonic acidemia and intracellular cobalamin metabolism disorders: a review of theoretical concerns and clinical experiences in 28 patients. J Inherit Metab Dis. 2015 Sep;38(5):847-53. doi: 10.1007/s10545-015-9816-x. Epub 2015 May 19.
- Derived from this study: PubMed 25567501Raval DB, Merideth M, Sloan JL, Braverman NE, Conway RL, Manoli I, Venditti CP. Methylmalonic acidemia (MMA) in pregnancy: a case series and literature review. J Inherit Metab Dis. 2015 Sep;38(5):839-46. doi: 10.1007/s10545-014-9802-8. Epub 2015 Jan 8.
- Derived from this study: PubMed 25190203Baker EH, Sloan JL, Hauser NS, Gropman AL, Adams DR, Toro C, Manoli I, Venditti CP. MRI characteristics of globus pallidus infarcts in isolated methylmalonic acidemia. AJNR Am J Neuroradiol. 2015 Jan;36(1):194-201. doi: 10.3174/ajnr.A4087. Epub 2014 Sep 4.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No. Study is observational natural history study that is ongoing with no defined endpoints.
Related trials for Organic Acidemia
RecruitingObservational study
Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia
Metabolic Disease, Propionic Acidemia
Recruiting
At Home Ammonia Monitoring of Inborn Errors of Ammonia Metabolism
Urea Cycle Disorders, Organic Acidemias
RecruitingPhase 1/2
A Study to Assess the Long-term Safety and Clinical Activity of mRNA-3927 in Participants Previously Enrolled in the mRNA-3927-P101 Study
Propionic Acidemia
RecruitingPhase 1/2
Open-Label Study of mRNA-3927 in Participants With Propionic Acidemia
Propionic Acidemia
RecruitingObservational study
Systemic Biomarkers of Brain Injury From Hyperammonemia
Urea Cycle Disorder, Organic Acidemia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Charles P Venditti, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Organic Acidemia and Methylmalonic Acidemia, run by National Human Genome Research Institute (NHGRI) at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jennifer L Sloan, Ph.D. ((301) 443-9055, jsloan@mail.nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Natural history to assess long term complications of disease (time frame: ongoing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00078078, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2026.