The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism

National Human Genome Research Institute (NHGRI)500 enrolled

Overview

The Metabolism, Infection and Immunity (MINI) Study is a longitudinal natural history study at the National Institutes of Health (NIH) that aims to define the relationship between infection, immunity and clinical decline in individuals with mitochondrial disease. Mitochondrial diseases are a group of disorders caused by problems with the cell s ability to produce energy. Infection in individuals with mitochondrial disease can lead to worsening clinical symptoms, particularly neurologic symptoms. Goals: The main goal of our study is to understand the relationship between infection and clinical decline in patients with mitochondrial disease. Mitochondrial diseases can affect many different parts of the body, including the immune system and its ability to respond to infection. Therefore, we perform a comprehensive evaluation of participants including a detailed immunologic assessment. We are not testing any new medicine or procedure to treat or cure IEM or mitochondrial diseases. However, by understanding the relationship between infection and mitochondrial disease, we hope to develop treatments in the future. At the NIH, we are interested in research. Although we do provide advice and care for people enrolled in our study, we are not able to take over the long-term care of participants. To enroll in our study, you (your child) must already have a confirmed diagnosis of a mitochondrial disease. We are not able to provide a "first time" diagnosis or regular metabolic care. What is involved? Once you contact our team members, you will be asked to provide medical records to determine eligibility. Our team will review the records and notify you if you (your child is) eligible to join the study. -Onsite participation: You (your child) will be invited to visit the National Institutes of Health in Bethesda, Maryland. This first visit will typically last 3-5 days. Depending on the level of participation, additional visits may be requested. Our team members will work with you and your child to coordinate the supports needed during your stay at NIH. Study participants may be seen in the clinic, day hospital or inpatient setting. When you (your child) arrive at the NIH we will have an informed consent discussion to confirm willingness to participate, answer questions and review the risks and benefits of the study. You (your child) will meet with a physician who will ask about medical and family history and do a physical exam (like in any doctor's office). We will ask all study participants to allow us to collect urine, draw blood, swab your (your child s) nose, and perform a detailed assessment. We may suggest additional evaluations or specialty consults for some participants based on clinical manifestations, age and level of independence. We will explain these studies to you (your child). They may include items such as- imaging studies, DEXA or MRI scan, energy expenditure or metabolic testing, developmental neuropsychological logical testing, physiatry, ophthalmology, or other consults. In some cases, we may request a skin biopsy (if one has not been done). You will receive the results of your (your child's) clinical testing and notes from any clinical consultations. -Remote participation: If you (your child) are unable to travel, you (your child) may be enrolled remotely for records review, questionnaires, and telethealth exams. Blood or other samples collection may be requested in coordination with local providers or lab testing companies

Study Description: Infections are a leading cause of morbidity and mortality in children with mitochondrial (MtD) disease. This is a longitudinal natural history study of infection and immunity in children with mitochondrial disease. Objectives: This longitudinal natural history study aims to characterize biological factors that contribute to deleterious host-pathogen interactions in children with mitochondrial disease. Primary Objective: 1\) To document the relationship between infection and disease status in participants with mitochondrial disease via a natural history study. Secondary Objectives: 1. To capture descriptive and functional immunologic data in cohorts of mitochondrial participants by the collection of biologic specimens. 2. To document the vulnerability of organs affected by MtD which may manifest with dysfunction/failure during infection. Endpoints: Primary Endpoint: To provide insight into the mechanisms involved in the interplay between the immune system and mitochondrial metabolism. Secondary Endpoint: To document immunity in cohorts of mitochondrial disease patients.

Eligibility

Sex: ALLMin age: 4 WeeksMax age: 115 YearsHealthy volunteers:

Medical Language ↔ Plain English

* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Stated willingness to comply with all study procedures and availability for the duration of the study. 2. Male or female, \>4 weeks of age. 3. Diagnosis of mitochondrial disease with documented molecular evidence of disease. 4. Healthy volunteers of any gender and ethnicity \>2 years of age may also be eligible to enroll in the protocol. Healthy volunteers may be from the local community, or family members of patients with MtD. 5. Agreement to adhere to Lifestyle considerations throughout study duration. 6. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. Overall, most participants will be over the age of 2 years. Advances in genetic diagnostics coupled with earlier diagnosis of MtD has led to an increasing number of participants who could be eligible within the 1-24 month age range. Participants with MtD who are between 1-24 months of age may be enrolled on this study on a case by case basis at the discretion of the PI and clinical team. The participants clinical status and resource availability within NIH will be taken into account. The majority of the clinical team, has pediatric experience and/or are board certified in Pediatrics (PI) or Pediatric Neurology (Staff Clinician). Participants with a hospitalization immediately prior to their appointment date will be rescheduled. Rescheduled appointments will occur no earlier than 2 weeks after the hospitalization discharge date. The enrollment is requested to be 50/year with a ceiling of 500 participants: 300 MtD participants and 200 healthy volunteers. Enrollment is anticipated to be up to 50 MtD participants/year and up to 30 HV/year. Recruitment of healthy volunteers may be targeted to match age ranges and sex of MtD participants seen. We may also receive deidentified biospecimens (blood spots, blood samples, serum samples) from biorepositories such as the National Children s Study, the Mitochondrial Disease Biobank at Mayo, the biorepository at the Children s Hospital of Philadelphia, or the North American Mitochondrial Disease Consortium, to our current protocol. These samples may be used to examine the role of mitochondrial haplogroups, ancient mutations in mtDNA that help define ancestral origins, in mitochondrial disease, as well as nDNA mutations involved in mitochondrial disease. Under an MTA, we are requesting biospecimens for up to 500 participants, which will be stored indefinitely or until use. Our recruitment will remain the same since these are specimens only and not additional participants. For the Mitochondrial Disease Biobank, we mayrequest materials and patient clinical information for up to 500 individuals to help supplement our current cohort. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: 1. Lack of a local MtD provider (For participants with MtD only) 2. Pregnancy or lactation 3. Discretion and clinical judgement of the Principal Investigator

Outcomes

Primary Outcomes

To provide insight into the mechanisms involved in the interplay between the immune system and mitochondrial metabolism

By developing an understanding of immune dysfunction, targets for rational therapies may be developed for this patient population.

Time frame: Initial visit and various timepoints thereafter dependent on protocol

To document the development of adaptive immunity in cohorts of mitochondrial disease patients according to the standard of care for this vulnerable population.