Overview

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.

Eligibility

• INCLUSION CRITERIA:

        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.
               -  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.
        EXCLUSION CRITERIA:
        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.