Overview 

Have you ever wondered what the severity of a single gene mutation can do to the growth and development of infants? That is the case of Menkes disease, a rare hereditary disorder that is caused by copper deficiency. Despite being seemingly healthy at birth, symptoms of Menkes disease can manifest months after the child is born and can be fatal if not treated promptly. The impact of Menkes disease is detrimental to the patient's growth, slowing their development in various areas, including physical, neurological and also appearance-wise. 

What is menkes disease?

Menke disease is an X-linked recessive disorder that is caused by copper deficiency. This condition impacts the growth and development of the affected infant. The affected babies often appear healthy at birth and symptoms manifest 6 to 8 weeks after birth.¹ 

Menkes disease was first discovered in 1962 by John Hans Menkes, a paediatric neurologist, who noticed odd characteristics of brittle hair in a seemingly healthy child. In 1972, a physician, David Miles Danks, associated the clinical manifestation with copper metabolism and discovered that copper deficiency has led to abnormal development of the infant. 

The disease results from a problem in the  ATP7A gene, located on chromosome Xq13.3. This gene is responsible for the production of \ ATP7A protein. The protein is found in the cell membrane of cells in the intestine, brain and other parts of the nervous system.^3,4 

This protein is responsible for the absorption of copper, copper transport and maintaining copper levels in the blood.^5,6 With its defective form, the protein is no longer able to bring the copper to the relevant enzymes, resulting in low levels of copper in these parts of the body, in particular the brain, liver and blood,  This reduces the activity of copper-dependent enzymes.⁷

Simultaneously, due to the absence of ATP7A, copper absorption is lessened, resulting in the accumulation of copper at abnormally high levels in the kidney and intestinal lining.⁷

Menkes disease is fatal, and most patients live between 6 months to 3 years, in its severity depends on the scale of gene deletion and the presence of functioning ATP7A.¹ The disorder is more commonly found in people assigned male at birth (AMAB), where the rate of occurrence is around 1 in 35,000 births.⁸

Clinical features and their impact on growth and development

The symptoms of Menkes disease are widespread, affecting numerous organs. This leads to a wide range of clinical features, each impacting different aspects of an infant's growth and development. Overall, infants with Menkes disease have stunted growth, with a much slower and abnormal development.

One of the major areas that is significantly impacted by Menkes disease is the neurological and cognitive development of the infant. The copper deficiency in the brain leads to a reduction in the activity of copper-dependent enzymes, such as cytochrome C oxidase, an enzyme involved in oxidative phosphorylation in the mitochondria,⁹ which the brain relies heavily on for the production of cellular energy to transmit and process electric signals and survive.⁹ This reduces the function of the brain.

Copper is also involved in the myelination of the nerves, in which myelin sheaths are needed to allow for saltatory conduction, so under reduced copper level conditions, nerve impulse transmission will be hindered.¹⁰ In addition, low levels of copper are associated with the gradual degeneration of the neurons.¹¹ All of these lead to progressive brain damage, intellectual disabilities and seizures. 

Physical impairment is another major consequence of Menkes disease. Similar to the brain, muscles require a large amount of energy to function, so the decrease in copper-dependent enzyme activity, like cytochrome C oxidase, would lead to impaired muscle development and hypotonia(loss of tone).⁹ Decreased muscle tone occurs in combination with other clinical symptoms of Menkes disease, such as degeneration of nerves, especially in some parts of the brain like the cerebellum and cerebral cortex. This in addition to poor myelination, can lead to reduced coordination and difficulty in movement and balance.¹² 

A distinct feature that allows physicians to identify and diagnose infants is the abnormal appearance of their hair. Patients with Menkes disease have kinky and sparse hai. This is one of the first noticeable symptoms. The hair abnormality is caused by the reduced activity of the copper-dependent enzymes that are involved in hair formation, including sulfhydryl oxidase.¹ 

The inactivity of lysyl oxidase is also associated with degraded connective tissue formation, resulting in joints and bones being unable to develop properly.¹

Transmission and risk factors 

Menkes disease is a hereditary disorder, which is passed onto offspring through the X-linked recessive pattern. It means that the abnormal gene is on the X chromosome. Since the ATP7A gene is located on the X chromosome, infants AMAB are more likely to inherit the defective gene allele if the mother has it on one or both X chromosomes in comparison with comparison to people assigned female at birth (AFAB). Menke disease occurs in males almost exclusively due to the X-linked recessive trait. Females are carriers and usually do not manifest symptoms unless there are unusual genetic circumstances. This is due to male offspring always receiving their X chromosome from the mother and only requiring one altered allele to cause Menkes disease.¹³ When affected by the disease, the clinical features are usually milder in people with AFAB.¹⁴

Prevention, treatment and management

Since Menkes disease is a genetic disorder, it is not possible to prevent offspring or future generations from getting Menkes disease. However, patients with the disorder can reach out to healthcare providers and arrange genetic counselling and testing. 

Genetic counselling involves patients talking to counsellors who can help them raise awareness of the risks of genetic disorders and how future generations might be affected, educating the patients and their families with useful and helpful information regarding the disorders and providing support. 

Genetic testing for Menkes disease involves using next-generation sequencing (NGS) techniques to detect any defects or variations within the ATP7A gene sequence. It is useful for carrying diagnostic tests, especially for those who have a family history of Menkes disease. 

There is currently no definitive cure for Menkes disease due to the rare occurrence of the disorder, making the research for a treatment challenging and difficult. However, gene therapy shows a promising solution in the future, where it can alter the genetic makeup of the patient to help treat disease by replacing the mutated gene or silencing the gene that causes the specific disorder.

 A current example is the AAV-ATP7A gene therapy, which is currently undergoing preclinical development and has demonstrated success in increasing the survival chances in experimental mouse models.¹⁵ This gene therapy involves administering working ATP7A proteins, combined with copper histidine, to the patients using adenosine-associated viruses as the delivery vectors.

As of now, the typical method for managing Menkes disease once diagnosed is with copper supplements. Patients will be administered daily subcutaneous injections of copper histidine to restore the amount of copper in the blood, allowing copper to be transported around the body and resuming the activity of copper-dependent enzymes.¹⁶ It is a long-term treatment that has shown effectiveness at managing Menkes disease when used at an early stage of the disorder, around the first 28 days. It has shown positive effects in managing the disorder, such as mitigating brain damage, ameliorating neurological symptoms, reducing the frequency and severity of seizures and increasing life expectancy.

Conclusion

Menkes disease can significantly impact the growth of a child and impair physical and neurological development, such as learning disabilities, poor coordination, and nerve and progressive brain damage. It also leads to abnormal growth and appearance of hair and stunted growth. The severity of its impact can even become fatal if it is not diagnosed and treated at an early stage of life. Thankfully, technology and research have slowly been developed to treat these rare disorders. Techniques like gene therapy have undergone clinical trials and testing and have shown success in potentially restoring normal ATP7A genes in patients.