molecular bases of response to copper treatment in menkes disease, related phenotypes, and unexplained copper deficiency

Conditions: Menkes Disease; Occipital Horn Syndrome; Unexplained Copper Deficiency

Summary: menkes disease and occipital horn syndrome are two forms of copper deficiency that must be diagnosed and treated very early in life to prevent serious developmental problems. however, these and other forms of copper deficiency are not very well understood, and further research is needed to determine whether certain treatments are useful in treating copper deficiency. one such treatment is copper histidine, a copper replacement that can be injected directly into the body to avoid absorption through the gastrointestinal tract. this study will investigate the effectiveness, side effects, and dosage of copper histidine treatment for patients with copper deficiency. it will also collect medical history information from patients to allow researchers to study possible genetic and nongenetic origins of copper deficiency. this study will include 100 subjects, all of whom will be children and adults who have been diagnosed with menkes disease, occipital horn syndrome, or other unexplained copper deficiency. patients will receive a prescribed dose of copper histidine, which will be administered daily as an injection. during the study, patients will be admitted to the nih clinical center on an outpatient basis to evaluate their response to the copper histidine treatment. these evaluations will take place every 8 months, with a final evaluation performed after 3 years of treatment. during the outpatient visits, patients will be required to give blood and urine samples for testing and undergo ultrasound testing. they will also undergo brain mri scans at the initial visit and at the 16-month and 36-month visits. patients who agree will give additional blood samples for genetic research purposes.

study description: the purpose of this study is to allow currently enrolled participants to complete their three-year course of subcutaneous copper histidinate treatment under the protocol. we hypothesize that subcutaneous injections of this drug will raise serum copper levels and ceruloplasmin levels in enrolled participants, improve neurodevelopmental and neurological outcomes, and reduce mortality compared to untreated affected subjects. objectives: -primary objective: evaluate responses to copper histidinate treatment for clinical care. endpoints: -completion of three years treatment by 13 remaining subjects study population: the 13 remaining subjects phase: clinical care/treatment only description of sites/facilities enrolling participants: the study will occur at the nih clinical center description of study intervention: the study intervention is administration of copper histidinate in dose(s) prescribed as follows: 250 microgram sc b.i.d. in infants up to 12 months of age, and 250 microgram sc q.d. for infants and children older than 12 months. the total duration of copper histidinate treatment will not exceed three years. study duration: the estimated time from when the study opens to enrollment until completion is approximately 151 months (02/27/2009-09/30/2021). (may end sooner pending fda new drug approval.) participant duration: the time it will take for each individual participant to complete all participant visits is approximately 36 months. there are 13 subjects with a total of 31 visits to complete.

Eligibility criteria:
* inclusion criteria: in order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. provision of signed and dated informed consent form by parent or legal guardian, or the subject himself/herself. 2. male or female, aged 0 to 80 years. 3. diagnosed with classic menkes disease, occipital horn syndrome (ohs), or unexplained copper deficiency. 4. serum copper level results between 0 and 75 mg/dl (normal range 80-180 microgram/dl). 5. ability to adhere to the prescribed subcutaneous copper histidinate injection regimen. 6. willingness to comply with all study visits and procedures. exclusion criteria: an individual who meets any of the following criteria will be excluded from participation in this study: 1. pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (e.g., serum creatinine \>1.0 mg/dl) 2. history of bleeding diatheses 3. pregnancy or lactation 4. diagnosis of wilson disease 5. any disease or condition that, in the opinion of the investigator, has a high probability of precluding the patient from completing the study or where the patient cannot or will not appropriately comply with study requirements 6. participation in any other investigational trial in which receipt of investigational drug or device occurred within 30 days prior to screening for this study 7. history of diagnosed drug or alcohol dependence within the previous 3 years 8. any disease process that may adversely affect gastrointestinal absorption, e.g. celiac sprue 9. chronic/severe cardiac disease (applies to adult subjects only) that could make participating in a clinical trial physically demanding, including but not limited to cardiac insufficiency, arrhythmias, bradycardia, or hypotension, unless associated with other features of dysautonomia, as in ohs. 10. history of cerebrovascular accident (applies to adult subjects only) that could make participating in a clinical trial difficult for the subject. adults who are, or who may be, unable to consent will not be allowed to participate in this study. this is because we did not encounter subjects in this category for whom enrollment would be necessary or appropriate in our previous studies (90-ch-0149, 90-n-0149) with this ind. the main populations to be recruited are 1) pediatric subjects under 18 years of age with inherited copper transport disorders, and 2) non-cognitively-impaired adults with unexplained copper deficiency. nih employees are eligible to participate in this protocol if they meet the inclusion criteria and have no exclusion criteria. recruitment, enrollment and compensation of nih employee subjects will be consistent with the guidelines for the inclusion of employees in nih intramural research studies (december 2015) and nih policy manual chapter 2300-630-3, "leave policy for nih employees participating in nih medical research studies". the consenting research team member will make the nih information sheet on employee research participation available to staff members who are considering enrolling. if the individual requesting to participate in the protocol is a co-worker, the consent from the nih staff member (co-worker) will not be obtained by the staff member s direct supervisor but by another research staff member approved for obtaining informed consent who is not a co-worker. neither participation nor refusal to participate as a subject in this protocol will have an effect, either beneficial or adverse, on the participant s employment or position at nih. employee subjects' privacy and confidentiality will be respected by protocol and consenting staff the same as for all subjects participating in research protocols. however, all subjects will be made aware that there are limits to these protections.

Keywords: copper deficiency menkes disease neurodegeneration occipital horn syndrome copper