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

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.