Menkes Disease Treatment Approved, After Three Decades of Testing

One of my greatest joys in revising my human genetics textbook is adding treatments for genetic diseases that have been FDA-approved since the last edition. The list has grown quite a lot since I finished the last revision as the pandemic finally faded away, and certainly since my gene therapy book was published in 2013. And so I was thrilled a few days ago when the father of a boy who had Menkes disease reposted my DNA Science blog from 2021, which described the rare disease, the clinical trial, and the family’s participation.

The “new” treatment – many kids with Menkes have been part of the clinical trial for years – is a simple injection administered daily under the skin that delivers copper, which the body cannot process from food. It’s not gene therapy, nor gene editing, nor magic – it is a sensible, decades-old strategy of finding a way around a biochemical glitch. Specifically, the drug Zycubo, aka copper histidinate, is a copper replacement therapy. Cyprium Therapeutics developed the long-awaited treatment.

My congratulations to the families that made this stride possible! Below is an updated version of my 2021 post.

Copper Deficiency

Menkes disease results from a mutation in a gene (ATP7A) on the X chromosome, so its affects boys. About 70% of patients inherit the mutation from their mothers, who are carriers. The rest have a new mutation that arises in an X chromosome in an egg or sperm.

The healthy version of the gene encodes a protein that controls enzymes that shuttle copper from food through the lining of the small intestine into the bloodstream, and into the brain, where copper is vital for neural connectivity. Copper is also essential for hair growth and pigmentation, which is why Menkes is also called kinky hair disease. Boys have sparse, pale, and twisty hairs. (When my textbook was reviewed for DEI violations, “kinky hair” was pulled for demonizing certain racial groups. However, hair texture variations occur in several genetic diseases, and are part of a diagnostic work-up.)

It takes about three months for the symptoms of Menkes disease to unfurl after birth. Then parents may notice poor growth, developmental delay, seizures, weak muscles, and low body temperature. Many boys die before their third birthdays.

Different mutations in the gene cause milder conditions (occipital horn syndrome and ATP7A-related distal motor neuropathy). But none of the clinical variations have approved treatments.

Menkes disease was thought to affect only 1 in 34,810 newborn boys, but a recent recalculation based on genome sequencing data indicates prevalence could be as high as 1 in 8,664. That’s still pretty rare.

Daniel DeFabio, whose son Lucas lost his battle with Menkes in 2020, talked to me about how the family coped with COVID restrictions here and tells the family’s story in “We’re All Rare Disease Families Now“. Also see The Menkes Foundation.

Long-Term Clinical Trials

Giving boys copper is a logical treatment approach. The challenge isn’t in delivering copper – it can be injected and make its way to the bloodstream, circumventing the intestines – but in recognizing the condition soon enough after birth for supplementation to stave off symptoms.

Newborn screening for Menkes has been lacking, but may soon join test panels. A project called Baby Detect from University Hospital in Liege, Belgium, has developed such a test based on genomics, while an NIH-funded project in the US has added Menkes to some traditional biochemical screening panels, which use the older technology of mass spectrometry to detect unusual metabolites.

Developing copper treatment for Menkes has taken many years. Clinicaltrials.gov has only a handful of entries for the disease. Compare that to the hundreds to thousands of listings for more prevalent single-gene conditions.

Entries at ClinicalTrials.gov for Menkes disease lead to Stephen G. Kaler, MD, at Nationwide Children’s Hospital, and colleagues. Dr. Kaler’s papers, assembled chronologically, trace the treatment’s development, going back to 1993. The case reports and clinical trials indicate that the copper treatment works to varying degrees, depending on how early a boy can be treated and how severe his mutation. Many boys in the US with Menkes disease have participated in the clinical trials. Lucas DeFabio began too late.

Mutations and Timing Matter

Development of the treatment for Menkes disease offers a compelling example of the process of clinical science – and starkly illustrates the danger of interrupting clinical trials, especially the many that have been ongoing, accruing data, for years.

For Menkes disease, the first step was finding a way to identify boys before symptoms appear. It wasn’t straightforward. Blood levels of copper at birth overlap with normal, so the researchers used altered ratios of the levels of key neurochemicals in umbilical cord blood to identify affected newborns. (The test, developed in 1993, assesses levels of dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol.)

The clinical trials listings describe the experiments that built toward the drug approval and expanded the science. A few highlights:

1995 Two related boys with a severe mutation began receiving the copper treatment, one a few weeks before birth and the other at age 10 days. Their mutation changed just one amino acid in the protein, but at a position critical enough to block production of the associated functional protein. Despite the early treatment, both boys had severe neurological impairment, suggesting that copper replacement may only work for mild mutations. The gene is huge, so many mutations are possible. These findings led to the next step: testing copper replacement in boys with milder mutations.

1996 A boy missing a bit of DNA in a non-critical part of the gene began receiving copper injections when he was 8 days old. His head grew to a normal size, as his brain neurons became ensheathed in their essential fatty coverings. He walked at 14 months, with normal brain development. Tellingly, his half-brother and first cousin, who’d inherited the same mutation but weren’t diagnosed and treated early enough, had small heads, brain degeneration, and abnormal development. So timing as well as mutation matter.

2008 Twelve newborns with Menkes disease were diagnosed with neurochemical tests and treated early. Their survival at median follow-up of 4.6 years was 92%, compared to 13% by 1.8 years for 15 boys diagnosed after symptoms began and treated later. Two of the 12 patients with mild mutations that allowed partial enzyme activity had normal neurodevelopment and brain myelination, confirming the 1996 findings.

2014 Ten boys treated early showed large improvements in both small and large movements, in personal and social behavior, and in language acquisition. Death rate by age 3 was 28.6% among boys treated early, so it isn’t perfect, but among controls, it was 50%.

2021 Cyprium Therapeutic’s data were striking. Participants born after 1999 with severe mutations received the drug twice daily until a year old, and daily after that, for up to 3 years. Sixty-six boys began treatment before 4 weeks of age and 35 after 4 weeks. Patients treated early survived on average just under 15 years, compared to slightly more than a year for boys treated after the age of 4 weeks. Still, the patients treated later lived considerably longer than 18 boys not treated at all.

So kudos to the researchers, the health care providers, and especially to the families who have allowed their sons to participate in the quest to conquer Menkes disease.

Photo credit Daniel DeFabio