AMPD3, OMIM*102772, AMP Deaminase DeficiencyNCT06092346

A Natural History Study Seeks to Understand the Clinical, Genomic, Pharmacological, Laboratory, and Dietary Determinates of Pyrimidine and Purine Metabolism Disorders

An observational study of AMPD3, OMIM*102772, AMP Deaminase Deficiency and AK1, OMIM *103000, Adenylate Kinase Deficiency, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

Background: Pyrimidine and purine metabolism disorders (DPPMs) affect how the body metabolizes chemicals called pyrimidines and purines. DPPMs can cause dysfunctions throughout the body, especially in the brain, blood, kidneys, and immune system. Read more about this study

Who is it for?: Ages 1 month to 100 years
Conditions the study is for: AMPD3, OMIM*102772, AMP Deaminase Deficiency, AK1, OMIM *103000, Adenylate Kinase Deficiency, AMPD1, OMIM *102770, Myopathy Due to Myoadenylate Deaminase Deficiency
How many people: 999 participants
Where: 1 siteUnited States
Study dates: 19 Dec 2023to 1 Jan 2099
Phase: Observational

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 100 years
All sexes
No healthy volunteers
Child, Adult, Older adult

Study population: There are three populations that will be included in this study: 1. Subjects with known, suspected or uncharacterized DPPMs; 2. Family members of study subjects; 3. Healthy Volunteers;

Who may be able to join

There are three populations that will be included in this study: subjects with known DPPM, family members of study subjects, and healthy controls.
In order to be eligible to participate in this study as a subject with a known DPPM an individual must meet all following criteria:
At least one month of age;
A medical history that, based on the preponderance of clinical, laboratory, biochemical, and/or genomic evidence is consistent with DPPMs;
Clinical findings that can be used to suspect disorders of purine and pyrimidine metabolism will include, but not be limited to the presence of congenital malformations, neurological, behavioral, immunological, rheumatological, hematological, renal involvement; gout; and recurrent rhabdomyolysis in one or more family members.
Laboratory findings may include but not limited to elevated CPK (recurrent rhabdomyolysis); neutropenia, lymphopenia, anemia, thrombocytopenia; and immunodeficiency.

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Biochemical evidence may encompass but not limited to persistent laboratory abnormalities in blood and urinary urate (a terminal product of purine degradation); blood and urinary beta-alanine (a terminal product of pyrimidine degradation); characteristic findings on plasma amino acid profiles (elevated plasma aspartate and glycine); elevated orotic acid on the urine organic acid assay; presence of urate crystals in urine; abnormal findings on the purine and pyrimidine panels (e.g. plasma and urine purines \& pyrimidines biochemical panels at Mayo, PUPYP and PUPYU).
Genomic evidence may include the presence of pathogenic and likely pathogenic variants in genes known or plausibly linked to the pathways of the de novo synthesis, degradation, and salvage of purines \& pyrimidines. Participants with variants of unknown significance in the said genes may be invited to participate in the protocol, if they have clinical, laboratory and biochemical evidence consistent with DPPMs.
Have a primary metabolic or genetic physician, or primary care provider; and
Ability of the subject, parent/s (in the case of children), or a Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
In order to be eligible to participate in this study as an unaffected family member of a subject with known DPPM, an individual must meet all the following criteria:
At least one month of age;
Relationship either by blood or marriage, to an individual enrolled or about to be enrolled in the study with known DPPM;
Likelihood, in the expert opinion of the study team, that analysis of a sample from the individual would advance genetic or functional analysis of the affected relative s possible condition; and
Ability of the subject, parent/s (in the case of children), or an LAR to understand and the willingness to sign a written informed consent document.
If during the consenting/assenting procedure, review of medical and family history and physical exam, clinical suspicion arises that a family member has symptoms of DPPMs, additional review and/or studies may be recommended to clarify the clinical status.
Participants must have a routine clinical care team outside of NIH to enroll in this study.
In order to be eligible to participate in this study as an unrelated healthy volunteer, an individual must meet all the following criteria:
No personal or family history of DPPMs;
At least one month old;
No symptoms of DPPMs;
Likelihood, in the expert opinion of the study team, that a sample from the individual would advance the functional analysis of the DPPM under study;
And ability of the subject, parent/s (in the case of children), or an LAR to understand and the willingness to sign a written informed consent document.
Participants must have a routine clinical care team outside of NIH to enroll in this study.

Who cannot join

Individuals meeting the following exclusion criteria are not eligible for the study:
Unrelated volunteers who are unaffected with DPPM but have intellectual disability due to other causes, such that they cannot provide informed consent without a guardian/LAR, will not be enrolled in this study. Affected individuals and family member(s) of individuals with DPPM can participate in the study when appropriate informed consent is obtained (with aide of parents/guardian/LAR/bioethics review when necessary).
Intercurrent or chronic conditions which in the opinion of the investigators, can then interfere with the interpretation of research studies (e.g. ongoing cancer treatment resulting in bone marrow suppression in a patient with DPPM also presenting with bone marrow suppression).
Pregnant participants as unaffected family members or as unrelated healthy volunteers are not able to join the protocol during the pregnancy.
Individuals without a routine clinical care team outside of the NIH cannot enroll in this study. We will ask the participants for the name of clinical care team prior to enrollment.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Oleg A Shchelochkov, M.D. contact

(301) 435-2944

PurineandPyrimidine@mail.nih.gov

United States1 site, 1 recruiting

National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
Shannon Haines, 240-987-8298, shannon.haines@nih.gov
NIH Clinical Center Office of Patient Recruitment (OPR), (800) 411-1222 ext. TTY dial 711, ccopr@nih.gov
Recruiting

Other trials in United States

About this study

Official title: Prospective Study of the Clinical, Genomic, Pharmacological, Laboratory, and Dietary Determinates of Pyrimidine and Purine Metabolism Disorders

Background:

Pyrimidine and purine metabolism disorders (DPPMs) affect how the body metabolizes chemicals called pyrimidines and purines. DPPMs can cause dysfunctions throughout the body, especially in the brain, blood, kidneys, and immune system. People with DPPMs might have no symptoms, mild symptoms, or they may have severe, chronic symptoms, that can be fatal. DPPMs are not well understood, and researchers want to learn more about what causes them and how to treat them.

Objective:

To learn more about factors that affect DPPMs by comparing test results from affected, uaffected family members, and healthy people.

Eligibility:

Three types of participants are needed: people aged 1 month and older with DPPMs; their family members who do not have DPPMs; and healthy volunteers.

Design:

Participants with DPPMs will come to the clinic once a year; some may be asked to come more often. At each visit, all affected participants will have a physical exam and give samples of blood, urine, saliva, and stool. Depending on their symptoms, they may also have other procedures, such as:

Swabs of their skin and inside the mouth.

Tests of their heart, kidney, brain, and nerve function.

Questionnaires about what they eat.

Dental exams, and exams of their hearing and vision.

Tests of their learning ability.

Monitoring of their physical activity.

Imaging scans.

Photographs of their face and body.

These tests may be spread over up to 7 days. Affected participants may remain in the study indefinitely if they wish to.

Healthy volunteers and family members will have 1 study visit. They will have a physical exam and may be asked to give blood, urine, saliva, and stool samples.

Read the detailed description

Study Description:

This study will explore the natural history and mechanisms of novel or known but incompletely characterized disorders of pyrimidine and purine metabolism (DPPMs). Eligible participants will be ascertained by identifying biochemical abnormalities in the levels of purines, pyrimidines and related compounds in body fluids, abnormal activity of enzymes, and/or identifying pathogenic variants in genes linked to purines and pyrimidine metabolism. We will collect participants DNA for genetic and genomic analyses, body fluids for biochemical analysis, blood and tissue samples for enzyme analysis, gastrointestinal samples for microbiome analysis. Some participants may undergo skin biopsy. Study subjects will be offered medical, laboratory, and imaging studies at the NIH Clinical Research Center consistent with the standards of care. Collected data will be analyzed to improve understanding of the natural history, develop statistical prediction models, identify and validate novel biomarkers.

Objectives:

Primary Objective: To describe features of novel and poorly characterized DPPMs.

Secondary Objectives: To identify genomic, clinical, pharmacological, laboratory, and dietary factors associated with variable outcomes in subjects affected by DPPMs.

Endpoints:

Primary Endpoint: Identify genomic variants, laboratory parameters, image findings, microbiome variables, nutritional and medication history of DPPMs.

Secondary Endpoints: Identify disease parameters associated with variable clinical outcomes (e.g., frequency of hospitalizations, survival, quality of life, function).

Conditions: AMPD3, OMIM*102772, AMP Deaminase Deficiency, AK1, OMIM *103000, Adenylate Kinase Deficiency, AMPD1, OMIM *102770, Myopathy Due to Myoadenylate Deaminase Deficiency, TPMT, OMIM *187680, Thoipurines, Poor Metabolism of, IMPDH1, OMIM *146690, Retinitis Pigmentosa Type 10, Leber Congenital Amauriosis Type 11, APRT, OMIM *102600, Adenine Phosphoribosyltransferase Deficiency
Keywords: Pyrimidine and Purine Metabolism Disorders
Medical subject headings: Adenosine monophosphate deaminase deficiency, Adenine phosphoribosyltransferase deficiency, Lesch-Nyhan Syndrome, Xanthinuria, Type I, Arts syndrome, Charcot-Marie-Tooth Disease, Pontocerebellar Hypoplasia, Inosine Triphosphatase Deficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT06092346
Study group	Role	What they receive
Family Member of a subject with known or suspected DPPM		1. At least one month of age;2. Relationship either by blood or marriage, to an individual enrolled or about to be enrolled in the study with known or suspected DPPM;3. Likelihood, in the expert opinion of the study team, that analysis of a sample from the individual would advance genetic or functional analysis of the affected relative s possiblecondition; and4. Ability of the subject, parent/s (in the case of children), or an LAR to understand and the willingness to sign a written informed consent document.5. If during the consenting/assenting procedure, clinical suspicion arises that a family member has symptoms of the diagnosed DPPMs, additional review and/or studies may be requested to clarify the clinical status before enrolling a family member as an unaffected participant.
Healthy Volunteers		1. No personal or family history of DPPMs;2. At least one month old;3. No symptoms of DPPMs;4. Likelihood, in the expert opinion of the study team, that a sample from the individual would advance the functional analysis of the DPPM under study; 5. And ability of the subject, parent/s (in the case of children), or an LAR to understand and the willingness to sign a written informed consent document.
Subjects with known or suspected or uncharacterized DPPMs		1. Regardless of gender, at least one month of age;2. A medical history that, in the expert opinion of the study team, is consistent with the DPPM; 3. Have a primary metabolic or genetic physician, or primary care provider; and 4. Ability of the subject, parent/s (in the case of children), or a Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.

What is being measured

The primary outcome is the main question the study is designed to answer.

TP describe features of poorly characterized and novel DPPMs.
DPPMs demonstrate significant inter- and intra-familial variability. We hypothesize that differences in clinical outcomes are the result of differences in the genomic, laboratory, and nutritional determinates. A proportion of subjects with biochemical evidence of DPPMs do not have molecular confirmation, suggesting locus heterogeneity and the opportunity to identify novel DPPMs.
Measured: indefinite

Secondary outcomes (1)

To identify genomic, clinical, pharmacological, laboratory, and dietary factors associated with variable outcomes in subjects affected by DPPMs.
The vast majority of DPPMs lack effective and definitive treatments. Identification of response biomarkers and candidate surrogate endpoints associated with clinical meaningful outcomes will enable future clinical trials for novel genomic medicines.
Measured: indefinite

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

19 Dec 20231 Jan 2099

First posted23 Oct 2023
Study start19 Dec 2023
Primary completion1 Jan 2099 (estimated)
Study completion1 Jan 2099 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (7)Papers the sponsor has linked to this study.
Other trials for AMPD3, OMIM*102772, AMP Deaminase DeficiencyStudies 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: 999 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT06092346
Sponsor's protocol ID: 10001625
Other IDs: 001625-HG
Status last verified: 14 Aug 2026
First submitted: 19 Oct 2023
Last updated: 19 Aug 2026
Results posted: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Publications

Shchelochkov OA, Manoli I, Juneau P, Sloan JL, Ferry S, Myles J, Schoenfeld M, Pass A, McCoy S, Van Ryzin C, Wenger O, Levin M, Zein W, Huryn L, Snow J, Chlebowski C, Thurm A, Kopp JB, Chen KY, Venditti CP. Severity modeling of propionic acidemia using clinical and laboratory biomarkers. Genet Med. 2021 Aug;23(8):1534-1542. doi: 10.1038/s41436-021-01173-2. Epub 2021 May 18.
PubMed 34007002
Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O'Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M; NIH Intramural Sequencing Center Group; Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, Nyhan WL, Biesecker LG, Venditti CP. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. doi: 10.1038/ng.908.
PubMed 21841779
Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of purine metabolism: clinical update and therapies. J Inherit Metab Dis. 2014 Sep;37(5):669-86. doi: 10.1007/s10545-014-9731-6. Epub 2014 Jun 28.
PubMed 24972650
Shchelochkov OA, Manoli I, Sloan JL, Ferry S, Pass A, Van Ryzin C, Myles J, Schoenfeld M, McGuire P, Rosing DR, Levin MD, Kopp JB, Venditti CP. Chronic kidney disease in propionic acidemia. Genet Med. 2019 Dec;21(12):2830-2835. doi: 10.1038/s41436-019-0593-z. Epub 2019 Jun 28.
PubMed 31249402
Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis. 2014 Sep;37(5):687-98. doi: 10.1007/s10545-014-9742-3. Epub 2014 Jul 17.
PubMed 25030255
Chu Y, Sun S, Huang Y, Gao Q, Xie X, Wang P, Li J, Liang L, He X, Jiang Y, Wang M, Yang J, Chen X, Zhou C, Zhao Y, Ding F, Zhang Y, Wu X, Bai X, Wu J, Wei X, Chen X, Yue Z, Fang X, Huang Q, Wang Z, Huang R. Metagenomic analysis revealed the potential role of gut microbiome in gout. NPJ Biofilms Microbiomes. 2021 Aug 9;7(1):66. doi: 10.1038/s41522-021-00235-2.
PubMed 34373464
Han ST, Kim AC, Garcia K, Schimmenti LA, Macnamara E, Network UD, Gahl WA, Malicdan MC, Tifft CJ. PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation. Mol Genet Metab. 2022 Mar;135(3):221-229. doi: 10.1016/j.ymgme.2022.01.103. Epub 2022 Feb 1.
PubMed 35144859