Copper Histidinate for Menkes Disease

Table of Contents

1. What Menkes Disease Is
2. The ATP7A Gene and Copper Trapped in the Gut
3. Why the First Weeks of Life Matter
4. What Copper Histidinate Is and Why It Goes Under the Skin
5. Survival Results in the Pooled Trials
6. What Starting Early or Late Changed
7. Regulatory Status
8. Side Effects Measured
9. Kidney Findings
10. What Copper Treatment Has Not Fixed
11. What Is Not Known
12. Key Research Papers
13. Connections
14. Featured Videos

What Menkes Disease Is

Menkes disease is a disorder of copper handling that affects many body systems. The main features are progressive damage to the brain and nerves, weak connective tissue, and the sparse, kinky hair that gave the condition its old name, kinky hair disease. Reviews describe severely affected patients as usually dying before their third birthday (Tümer and Møller 2010). Untreated children develop failure to thrive and developmental delay that usually begin at 6 to 8 weeks of age (Kaler 2014).

Copper matters because several enzymes cannot work without it. Copper helps build connective tissue, and it is the working part of dopamine-beta-hydroxylase, the enzyme that makes the nerve signal norepinephrine. Partial loss of that enzyme is a chemical hallmark of Menkes disease, and it is the basis of one diagnostic blood test (Kaler 2008).

How common it is

• The Food and Drug Administration review gives a United States estimate of 1 in 50,000 to 1 in 250,000 live male births.
• Older counts from confirmed clinical cases ranged from 1 in 40,000 to 1 in 354,507.
• A 2020 genetic database analysis predicted 1 in 34,810 live male births with Menkes disease or a related ATP7A disorder, and as many as 1 in 8,664 when predicted harmful missense variants were added. These are calculations from variant frequencies, not counted patients, and the authors said a newborn screening pilot would be needed to confirm them (Kaler 2020).

How it is inherited

The disease is X-linked recessive. The ATP7A gene sits on the X chromosome, at band Xq13.3. A boy has one X chromosome, so one faulty copy causes disease, and the great majority of patients are male (Tümer and Møller 2010). Girls and women with one faulty copy are carriers and are rarely affected. In the largest reported group, covering 517 families, 9 carriers with normal chromosomes were neurologically affected, and their symptoms were generally milder than those of boys with the same variant (Møller 2012).

Faults in the same gene also cause milder conditions. Occipital horn syndrome mainly affects connective tissue, and a rarer ATP7A motor neuropathy resembles a form of Charcot-Marie-Tooth disease (Kaler 2011).

The ATP7A Gene and Copper Trapped in the Gut

In 1993, three research groups reported the gene responsible in the same issue of one journal (Vulpe 1993; Chelly 1993; Mercer 1993), mapped to band Xq13.3. One group found that it coded for a protein of about 1,500 amino acids resembling a bacterial copper pump. That protein, ATP7A, uses energy to carry copper across cell membranes.

The Food and Drug Administration review describes two of its jobs that explain the disease:

• Getting copper out of the gut. ATP7A moves copper from the cells lining the intestine into the blood. When it fails, copper from food reaches those cells but cannot move on normally, so the rest of the body runs short.
• Getting copper into the brain. ATP7A also moves copper across the blood-brain barrier. Copper injections can normalize blood levels, but whether they refill the brain depends on the mutation and other factors (Kaler 2014).

ATP7A also pumps surplus copper out of cells. Its failure produces an odd pattern, described in the same review: copper builds up inside the cells of almost all tissues except the liver and brain, while the copper-dependent enzymes that need it go short. The kidney is one of the places copper collects, which is why kidney monitoring features in the safety findings below.

Blood tests reflect the shortage. Children with the disease have low serum copper and low ceruloplasmin, the main copper-carrying protein in blood (see the copper test and the ceruloplasmin test).

Why the First Weeks of Life Matter

The damage appears to begin before birth. Studies of fetal tissue and placenta point to abnormal copper distribution before delivery, even though newborns with the disease appear neurologically normal (Haddad 2012). That leaves a short period when a baby looks well but copper is already short.

Early diagnosis is the difficulty. A Japanese study found that abnormal hair growth was noted in the newborn period in 20 of 69 patients, prolonged jaundice in 16 of 67, and feeding difficulty in 3 of 18. Only three patients saw a physician for these signs as newborns, and none was diagnosed then. The mean age at diagnosis was 8.7 months. The seven patients treated early were those with a family history, identified before or soon after birth (Fujisawa 2022).

Tests that could find it sooner

• Blood chemistry. In a United States study of 81 infants at risk, 46 had the abnormal pattern of plasma nerve-signal chemicals that points to low dopamine-beta-hydroxylase activity, and follow-up showed the test had high sensitivity and specificity (Kaler 2008).
• Targeted DNA testing from dried blood spots. In a proof-of-concept study, the method identified the disease-causing variant in 21 of 22 samples, or 95.5% (Parad 2020).
• Whole genome sequencing from dried blood spots. A 2026 study of 24 people with known ATP7A variants detected all of them. Those authors describe the treatment window as the first 4 to 6 weeks of life (Kaler 2026).

These are studies of known cases and at-risk infants. A population-wide newborn screening result for Menkes disease was not found in the records read for this page.

What Copper Histidinate Is and Why It Goes Under the Skin

Copper histidinate is a complex of one copper atom held by two molecules of L-histidine, an essential amino acid (see Histidine). The approved product is a sterile blue powder. Each single-dose vial holds 2.9 mg of copper histidinate, equal to 0.5 mg of elemental copper, and is mixed with salt solution before use.

The reason for the injection comes directly from the disease. Copper swallowed by mouth has to pass through the gut lining, which is the step that fails. The federal prescribing label describes the subcutaneous route as a way to bypass the impaired absorption. The label states that the absolute bioavailability of the injection has not been determined.

In the pivotal trials, children under 1 year were given 1.45 mg twice daily, and children aged 1 year and older were given 1.45 mg once daily. The label says a trained caregiver may give the injection at home if a clinician finds that appropriate, and it lists rotating injection sites to lower the risk of fat changes under the skin.

What it does to blood levels

The label reports these means in treated children:

• Serum copper: 30 mcg/dL at baseline, 114 mcg/dL at 12 months, and 63 mcg/dL at 36 months.
• Serum ceruloplasmin: 12 mg/dL at baseline, 33 mg/dL at 12 months, and 20 mg/dL at 36 months.

Both rise and then drift down over the three years. The review notes that the link between a given ceruloplasmin level and survival or kidney injury has not been precisely established.

Before approval, it was made locally

Copper histidine injections were in use for decades before any approved product existed. Hospitals in several countries prepared them on site, including in Mexico, where three children received 250 mcg doses for 30 days with no relevant undesirable effects reported (Flores-Pulido 2019), and in Thailand (Panichsillaphakit 2022). A 2025 laboratory study reported that the original formulation degraded above 8°C, and that changing the copper-to-histidine ratio from 1:2 to 1:3 stabilized it (Guzman 2025).

Survival Results in the Pooled Trials

The main evidence comes from a pooled analysis of two open-label, single-arm clinical trials, compared with an untreated external control group gathered under an amendment to the second trial. There was no randomization. Analysis was limited to children with severe ATP7A variants (duplication, deletion, nonsense or canonical splice junction) who were born after 1999. That left 83 children: 66 treated and 17 untreated. Of the 83, 81 were boys. Treatment ran for up to 3 years, with survival status tracked longer. The 17 controls were children with no significant neurological signs at about 4 weeks of age who lived at least 4 weeks after diagnosis. Their median age at diagnosis was 4.7 months.

Children treated within 4 weeks of birth

This was the primary analysis. Age was corrected for prematurity, and the median age at the first dose was 0.4 months.

• Alive at last report: 16 of 31 treated (52%) against 2 of 17 untreated (12%).
• Median survival: 177.1 months, about 14.8 years, against 17.6 months. The range around the treated figure is wide: its lower limit is 33 months and its upper limit could not be estimated.
• Risk of death: hazard ratio 0.22 (95% confidence interval 0.10 to 0.49), which the label expresses as a 78% reduction.
• Long survival: 15 treated children (48%) survived more than 6 years and 7 (23%) more than 12 years. No untreated child survived more than 6 years.

Children treated after 4 weeks

This was the secondary analysis. The median age at the first dose was 7.1 months, and the range ran to 31.4 months.

• Alive at last report: 12 of 35 treated (34%) against 2 of 16 untreated (12%).
• Median survival: 62.4 months, about 5.2 years, against 20.7 months, about 1.7 years.
• Risk of death: hazard ratio 0.27 (0.12 to 0.57), a 73% reduction.
• Long survival: 11 treated children (31.4%) survived more than 6 years and 1 (2.9%) more than 12 years. No untreated child survived more than 6 years.

Earlier reports from the same research program

• 2008: among 12 newborns who began copper within 22 days of birth, survival was 92% at a median follow-up of 4.6 years. In 15 historical late-treated patients, it was 13% at a median follow-up of 1.8 years. Two of the 12 had normal development and brain myelin (Kaler 2008). The follow-up times and comparison group differ, so the two percentages are not a like-for-like contest.
• 2014: among 60 people in the phase 1/2 trial, those treated before symptoms (35 people) did significantly better on gross motor, fine motor, personal-social and language development, and had greater head growth. Weight and height did not differ significantly. Deaths by age 3 were 28.6% in the group treated before symptoms and 50% in the older, symptomatic group (Kaler 2014).

How much weight the comparison can carry

The agency's published integrated review lists the limits itself: no randomization, an external control group, and significant data-quality issues. Several of its findings bear on how to read the numbers.

• Milder cases may have been counted. An intermediate form of the disease cannot be told apart from the classic form except by how long the child lives, and it may bring longer survival regardless of treatment. The reviewers judged that the treated groups likely included such children and that this likely affected survival.
• The benefit shrank but remained under stress testing. When reviewers removed up to 32% of the longest-surviving early-treated children, the median fell to 37.3 months and the hazard ratio became 0.36 (0.16 to 0.80). Removing 34% of the late-treated group gave 29.6 months and a hazard ratio of 0.47 (0.22 to 1.00).
• Data reliability was questioned. A clinical inspection documented significant data reliability concerns. The reviewers reported that a robust survival benefit remained after excluding the affected patients.
• The agency's conclusion. The reviewers found the evidence adequate for a survival benefit in classic Menkes disease, stating that a large effect on an objective outcome, in a rapidly fatal rare disease with no other therapy known to improve survival, outweighed the limitations.

What Starting Early or Late Changed

The trial results point the same way as smaller reports: earlier starts go with better outcomes. Median survival was 177.1 months with treatment in the first 4 weeks and 62.4 months with a later start. These two groups were not randomly assigned, so the gap is not a clean measure of the effect of timing alone.

A 2019 guideline, built by a systematic review of 13 articles using the GRADE method, concluded that copper-histidine is effective at raising survival and lowering neurological burden if started in the newborn period. Its authors wrote that recent evidence suggested efficacy only when treatment starts within days of birth, and that genotype is not a basis for deciding who is treated (Vairo 2019). The later agency analysis differs on one point: it reported a survival gain in the group treated after 4 weeks too.

The severity of the gene fault appears to matter alongside timing:

• In the 2008 study, the two children with normal development had ATP7A variants that left some function: one with partial pump activity and one allowing some correct splicing (Kaler 2008).
• A child with a nonsense variant had a strong response to early copper, and laboratory tests showed that small amounts of working protein were still being made (Kaler 2009).
• The oldest reported surviving patient, 37 years old with few neurological symptoms, had early and long-term copper and a missense variant that spared copper transport (Tümer 2017).
• At the other end, a fetus with a variant that left no detectable protein received copper histidine in the womb from 31.5 weeks of pregnancy. Fetal copper rose from 17 to 45 mcg/dL and ceruloplasmin from 39 to 122 mg/L, yet the baby had low muscle tone and delay and died of respiratory failure at 5.5 months. This is one case (Haddad 2012).

Regulatory Status

• United States: approved January 12, 2026, for Menkes disease in pediatric patients, according to the agency's approval letter for application 211241. The agency's records list it as a new molecular entity under priority review with orphan status, and the letter grants a rare pediatric disease priority review voucher. A published drug profile also gives January 2026 (Blair 2026).
• The first decision was not an approval. The agency issued a complete response letter on September 30, 2025. The review attributes this to unresolved compliance concerns at a manufacturing facility. On the clinical data, the reviewers had already concluded that benefits outweighed risks. The application was resubmitted on November 14, 2025.
• Limit in the label: not indicated for occipital horn syndrome. The review explains that these patients generally have normal or slightly low copper, so added copper is unlikely to help and raises the risk of accumulation.
• Required follow-up: the letter records a postmarketing commitment to run a trial of serum copper and ceruloplasmin at the recommended doses, with the trial completion date listed as April 2030.
• European Union: the European Commission granted orphan designation (Blair 2026). Orphan designation is not marketing approval, and approval in Europe was not confirmed in the sources read.
• Other countries: status was not confirmed.

Side Effects Measured

The pooled safety data cover 129 treated children aged 0 to 48 months, with a median exposure of 24 months. The trials had no comparison group for safety, because adverse events were not systematically collected from the untreated children. The list below therefore shows what happened during treatment, not what the drug caused. Many of these events are also part of the disease.

Events in at least 7% of treated children

• Pneumonia: 38 (30%)
• Viral infection: 35 (27%)
• Respiratory failure: 30 (23%), including cardiopulmonary failure in 11 (9%)
• Seizure: 29 (23%)
• Bacterial infection: 26 (20%), including kidney and urinary tract infection in 12 (9%)
• Bleeding: 23 (18%)
• Low blood pressure: 20 (16%)
• Vomiting: 19 (15%)
• Fast heart rate, fever, fluid depletion, fractures and shortness of breath: 16 each (12%)
• Raised liver enzymes: 13 (10%)
• Diarrhea: 13 (10%)
• Fungal infection: 12 (9%)
• Anemia: 11 (9%)
• Reaction at the injection site: 9 (7%)

The label's central warning

The label warns of copper accumulation, with potential kidney injury, liver dysfunction and blood abnormalities. It says the risk is greater in the first two years of life, when the kidneys and liver are immature. It lists no contraindications, and it describes laboratory monitoring every 6 weeks for the first 6 months, every 3 months for the next 18 months, and every 6 months after that, with changes to dosing if results are abnormal.

Other measured findings

• Serious outcomes. Fatal serious events occurred in 25.6% of the pooled trial population. In a separate ongoing expanded access program, 13 of 66 children (19.7%) died. The reviewers considered those deaths likely due to the disease rather than the drug.
• High copper levels. Four children in the safety population had dosing changed. In one, serum copper reached 211 mcg/dL and the drug was paused for 2 weeks. Another reached 220 mcg/dL after a period of three-times-daily dosing given for a low level.
• In juvenile rats with normal copper. Thirteen weeks of injections caused kidney tubular necrosis, liver cell death, inflammation and fibrosis, spleen changes and lower red cell measures at the top dose. No dose without adverse effects could be identified in these rats.
• Liver over the long term in one patient. A single report found normal liver copper concentrations over 8 years of treatment (Kroepfl 2006).
• A worsening on treatment in one patient. A patient with occipital horn syndrome and a motor neuropathy had severe worsening on copper histidinate and recovered quickly when it was withdrawn. The authors proposed copper accumulation in motor neurons as the mechanism (Natera-de Benito 2021).

Kidney Findings

The kidney receives special attention because children with this disease tend to store copper there, and because the drug adds more copper. The agency's reviewers concluded that kidney injury cannot be ruled out as a risk of the drug. They also said it is unknown whether the abnormal kidney results seen were due to the drug or to the disease, given open-label data of limited quality.

Numbers in the pooled trials

• Creatinine, a blood marker of kidney filtering: above 0.5 mg/dL in 23 of 129 children (17.8%). It rose to at least 1.5 times baseline in 7 of 60 with data (11.7%), and to at least 2 times and 3 times baseline in 1 of 60 each (1.7%).
• Urine beta-2 microglobulin, a marker of tubule injury: above 75 mg/L in 6 children (4.7%). Reviewing the cases, the agency found no clear link to the drug.
• Very low bicarbonate: no recorded value below 12 mmol/L.
• Kidney dysfunction events: the sponsor identified 9 cases, 2 of them serious. Reviewers judged both serious cases unrelated to the drug. One occurred with norovirus and dehydration, the other with necrotizing colitis and sepsis.
• Acute kidney injury: a narrow search found 4 cases. Two were judged unlikely to be related, and for the other two the relationship is unknown.
• Renal tubular acidosis: one child was moved to every-other-day dosing over concern about this form of acid imbalance.

In the expanded access program

Acute kidney injury was reported in 4 of 66 children, 3 of them serious. Two of the serious events were considered unlikely to be drug-related, one attributed to sepsis and vancomycin exposure and one occurring with a bladder rupture. Narratives were unavailable for the other two.

What the label says to watch for

The label lists new or worsening non-anion gap metabolic acidosis as a possible sign of renal tubular acidosis. It also lists raised urine beta-2 microglobulin and new low phosphate, sodium or potassium as possible signs of proximal tubule toxicity, and decreased kidney function or new protein in the urine as possible signs of glomerular injury.

Kidney and urinary problems reported in the disease

Urinary tract and kidney problems are reported as the disease progresses, which makes the drug's contribution harder to separate. One case report describes a 4-year-old with bladder diverticula, recurrent infection, kidney stones, a ruptured ureter and tubular dysfunction (Hui 2021). An autopsy of a child treated with copper histidine who died at age 10 also found bladder diverticula (George 2001).

What Copper Treatment Has Not Fixed

Long survival has not meant full recovery. Published reports show which problems tend to remain:

• Connective tissue. Four boys treated from early infancy and followed 10 to 20 years had normal or near-normal intellectual development, yet developed many severe bodily features of occipital horn syndrome, including severe drops in blood pressure on standing in 2. The authors, writing in 1998, regarded the treatment as experimental (Christodoulou 1998). The autopsy at age 10 showed skeletal and blood vessel disease and bladder diverticula, with minimal brain pathology (George 2001).
• Treatment started after symptoms. In 12 Korean patients who began at a mean age of 7.3 months, 7 died before age 5 and the others had severe developmental impairment. The authors suggested that delayed therapy and severe variants might explain this (Kim 2015).
• Mixed results in single cases. A boy who started at 15 months became seizure-free and his skin and hair darkened, but severe delays continued (Sheela 2005). A boy who started at 4 months had his hair and ceruloplasmin improve, while seizures, development and bone thinning worsened, and he died at 9.5 months (Panichsillaphakit 2022). In 4 Indian children treated after a long delay, the authors reported improved skin, hair, muscle tone and weight gain (Yoganathan 2017).
• Quality of life. A survey of 16 parents found an overall quality of life score of 29.14 and no statistically significant link between copper histidine treatment and scores (p = 0.914). This was a small, single-time-point survey, not a treatment trial (Rozensztrauch 2023).
• Blood pressure regulation in adults. Treatment gaps have prompted other research. A crossover trial of droxidopa enrolled 3 adult men, 2 with Menkes disease and 1 with occipital horn syndrome, and reported better norepinephrine levels and less diastolic blood pressure drop on tilt testing (Kaler MM 2026).

What Is Not Known

• The true size of the benefit. No randomized trial exists, and the comparison depends on 17 untreated children gathered through requests to patient groups and a professional society and through referrals.
• Who will respond. Severity cannot be reliably predicted from genotype, per the agency's review, and the intermediate form is recognized only in hindsight.
• The effect on development in the approved evidence. The label's efficacy section reports overall survival. It makes no claim about development, even though the earlier trial reports do.
• Long-term organ safety. Exposure data are limited to a median of 24 months, safety data were open-label and incomplete, and the link between blood levels and kidney injury has not been precisely established. Animal studies for cancer risk and fertility have not been done.
• The right level to aim for. The exposure-response relationship has not been fully characterized, which the postmarketing trial of blood levels is meant to help inform.
• Use in pregnancy and breastfeeding. The label reports no available data.
• The effect of newborn screening. DNA methods look technically feasible in known cases, but population results were not found.
• Gene therapy in people. In mice, adding gene therapy to copper histidinate gave 53.3% long-term survival with a brain-fluid route (Haddad 2018) and 95% with an intravenous route (Venkataraman 2025). Those authors propose human trials. Mouse results may not carry over to infants.

Decisions about treatment for an individual child belong with the clinicians managing that child.

Key Research Papers

1. Blair HA. Copper Histidinate: Pediatric First Approval. Paediatr Drugs. 2026;28(4):441-445. PubMed PMID: 42018271
2. Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358(6):605-14. PubMed PMID: 18256395
3. Kaler SG. Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. J Trace Elem Med Biol. 2014;28(4):427-30. PubMed PMID: 25281031
4. Vairo FPE, Chwal BC, Perini S, Ferreira MAP, de Freitas Lopes AC, Saute JAM. A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease. Mol Genet Metab. 2019;126(1):6-13. PubMed PMID: 30594472
5. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet. 2010;18(5):511-8. PubMed PMID: 19888294
6. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet. 1993;3(1):7-13. PubMed PMID: 8490659
7. Chelly J, Tümer Z, Tønnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet. 1993;3(1):14-9. PubMed PMID: 8490646
8. Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S, Lockhart P, Grimes A, Bhave M, Siemieniak D, et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet. 1993;3(1):20-5. PubMed PMID: 8490647
9. Kaler SG. ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol. 2011;7(1):15-29. PubMed PMID: 21221114
10. Kaler SG, Ferreira CR, Yam LS. Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD). Mol Genet Metab Rep. 2020;24:100602. PubMed PMID: 32528851
11. Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG. Clinical expression of Menkes disease in females with normal karyotype. Orphanet J Rare Dis. 2012;7:6. PubMed PMID: 22264391
12. Fujisawa C, Kodama H, Sato Y, Mimaki M, Yagi M, Awano H, Matsuo M, Shintaku H, Yoshida S, Takayanagi M, Kubota M, Takahashi A, Akasaka Y. Early clinical signs and treatment of Menkes disease. Mol Genet Metab Rep. 2022;31:100849. PubMed PMID: 35242581
13. Parad RB, Kaler SG, Mauceli E, Sokolsky T, Yi L, Bhattacharjee A. Targeted next generation sequencing for newborn screening of Menkes disease. Mol Genet Metab Rep. 2020;24:100625. PubMed PMID: 32714836
14. Kaler SG, Venkataraman L, Pham MT, Kennedy BJ, Marhabaie M, Koboldt DC. Whole genome sequencing from dried blood spots for newborn screening of Menkes disease and 36 other actionable inherited neurometabolic disorders. Mol Genet Metab. 2026;147(3):109763. PubMed PMID: 41687279
15. Haddad MR, Macri CJ, Holmes CS, Goldstein DS, Jacobson BE, Centeno JA, Popek EJ, Gahl WA, Kaler SG. In utero copper treatment for Menkes disease associated with a severe ATP7A mutation. Mol Genet Metab. 2012;107(1-2):222-8. PubMed PMID: 22695177
16. Kaler SG, Tang J, Donsante A, Kaneski CR. Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol. 2009;65(1):108-13. PubMed PMID: 19194885
17. Tümer Z, Petris M, Zhu S, Mercer J, Bukrinski J, Bilz S, Baerlocher K, Horn N, Møller LB. A 37-year-old Menkes disease patient-Residual ATP7A activity and early copper administration as key factors in beneficial treatment. Clin Genet. 2017;92(5):548-553. PubMed PMID: 28657131
18. Christodoulou J, Danks DM, Sarkar B, Baerlocher KE, Casey R, Horn N, Tümer Z, Clarke JT. Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. Am J Med Genet. 1998;76(2):154-64. PubMed PMID: 9511979
19. George DH, Casey RE. Menkes disease after copper histidine replacement therapy: case report. Pediatr Dev Pathol. 2001;4(3):281-8. PubMed PMID: 11370266
20. Kim JH, Lee BH, Kim YM, Choi JH, Kim GH, Cheon CK, Yoo HW. Novel mutations and clinical outcomes of copper-histidine therapy in Menkes disease patients. Metab Brain Dis. 2015;30(1):75-81. PubMed PMID: 24919650
21. Sheela SR, Latha M, Liu P, Lem K, Kaler SG. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Clin Genet. 2005;68(3):278-83. PubMed PMID: 16098018
22. Panichsillaphakit E, Kwanbunbumpen T, Chomtho S, Visuthranukul C. Copper-histidine therapy in an infant with novel splice-site variant in the ATP7A gene of Menkes disease: the first experience in South East Asia and literature review. BMJ Case Rep. 2022;15(4):e247937. PubMed PMID: 35393273
23. Yoganathan S, Sudhakar SV, Arunachal G, Thomas M, Subramanian A, George R, Danda S. Menkes disease and response to copper histidine: An Indian case series. Ann Indian Acad Neurol. 2017;20(1):62-68. PubMed PMID: 28298846
24. Flores-Pulido AA, Jiménez-Pérez VM, García-Chong NR. Síntesis y uso de histidinato de cobre en niños con enfermedad de Menkes en México. Gac Med Mex. 2019;155(2):191-195. PubMed PMID: 31056589
25. Guzman ML, Barbieri F, Luciani-Giacobbe LC, Inga CM, Bustos-Fierro C, Gavelli ME, Apas AL, Alovero FDL, Gasparotto AM, Olivera ME. Overcoming barriers in Menkes disease: A standardized high quality and stable injectable copper histidinate. J Pharm Sci. 2025;114(6):103722. PubMed PMID: 40081494
26. Kroepfl T, Mair E, Deutsch J, Brunner-Krainz M, Paschke E, Plecko B. Copper concentration of liver tissue under long-term copper-histidine therapy in a patient with Menkes disease. J Inherit Metab Dis. 2006;29(4):593. PubMed PMID: 16786254
27. Natera-de Benito D, Sola A, Sousa PR, Boronat S, Expósito-Escudero J, Carrera-García L, Ortez C, Jou C, Muchart J, Rebollo M, Armstrong J, Colomer J, Garcia-Cazorla À, Hoenicka J, Palau F, Nascimento A. Copper Toxicity Associated With an ATP7A-Related Complex Phenotype. Pediatr Neurol. 2021;119:40-44. PubMed PMID: 33894639
28. Hui WF, Hon KL, Leung AKC, Pang KKY, Leung MWY. Tubular Dysfunction and Ruptured Ureter in a Child with Menkes Syndrome. Case Rep Pediatr. 2021;2021:4398456. PubMed PMID: 34457367
29. Rozensztrauch A, Dzien I, Śmigiel R. Health-Related Quality of Life and Family Functioning of Primary Caregivers of Children with Menkes Disease. J Clin Med. 2023;12(5):1769. PubMed PMID: 36902556
30. Kaler MM, Brock G, Jeanty CJ, Iammarino MA, Hampton KA, Pham MT, Sabo BT, Lowes LP, Sullivan P, Goldstein DS, Kaler SG. Safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease and occipital horn syndrome in the USA: a randomised phase 1/2a crossover trial. EClinicalMedicine. 2026;94:103898. PubMed PMID: 42016919
31. Haddad MR, Choi EY, Zerfas PM, Yi L, Martinelli D, Sullivan P, Goldstein DS, Centeno JA, Brinster LR, Ralle M, Kaler SG. Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev. 2018;10:165-178. PubMed PMID: 30090842
32. Venkataraman L, Jeanty CJ, Kaniganti T, Kennedy BJ, Sullivan P, Goldstein DS, Kaler SG. Intravenous AAV9-ATP7A plus subcutaneous copper histidinate optimizes outcomes in a lethal Menkes disease mouse model. Sci Adv. 2025;11(35):eadw5612. PubMed PMID: 40880469

PubMed Topic Searches

1. PubMed: copper histidinate and Menkes disease
2. PubMed: Menkes disease newborn screening
3. PubMed: ATP7A gene therapy

Food and Drug Administration Documents

1. Prescribing label, application 211241, January 2026
2. Approval letter, application 211241, January 2026
3. Integrated review, application 211241

Connections

• Drugs — every drug page on the site
• Copper — the mineral and how the body uses it
• Copper Deficiency — symptoms, causes and recovery
• Copper Deficiency: Hair and Skin Pigment — why hair and skin change
• Copper for Connective Tissue — the enzyme behind collagen strength
• Copper Test — serum copper and ceruloplasmin
• Ceruloplasmin Test — the main copper-carrying protein
• Histidine — the amino acid in the drug
• Wilson's Disease — the opposite copper disorder, from the sister gene ATP7B

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