Introduction

Menkes disease (MD) is a rare, inherited disorder that is caused by a mutation in the ATP7A gene, which is responsible for controlling levels of copper in the body.¹ Copper is an essential mineral required by the body to regulate the normal functioning of the brain and the formation of blood vessels. It is only used in small quantities but is essential.² In MD, copper accumulates to abnormally low levels in the brain and liver, but to unusually high levels in the kidney.³

The ATP7A gene produces the ATPase enzyme, which regulates copper levels in the body.¹ Low copper levels at birth do not necessarily mean the infant has Menkes disease, as many healthy newborns may have temporarily low copper levels.²

Inheritance pattern of Menkes disease

Menkes disease predominantly affects male children³ and occurs in about 1 in 35,000 live male births.² It is considered an X-linked recessive disorder that affects many body systems. An X-linked recessive disorder is a genetic condition caused by a non-functioning gene on the X chromosome that is passed down through the X chromosome.¹ When a disorder is considered ‘X-linked’, it means the faulty gene causing the disorder is located on the X chromosome. MD is mainly seen in male infants as they have an ‘XY’ chromosome pair, whereas females have an ‘XX’ pair. Since males only have one X chromosome, inherited from the mother, if the ATP7A gene is non-functioning, then the male will develop the condition. Females on the other hand, have two X chromosomes, so if one of the X chromosomes is affected, the other X chromosome will compensate for the non-functioning gene on the affected X chromosome, and they will be considered a carrier (i.e., a female with one normal and one mutated X chromosome, who typically won’t show symptoms of the disease).

The majority of diagnosed infants are male, but females may be affected by MD too.¹

The defect in the ATP7A gene results in an inability for copper to be properly distributed throughout the body. Consequently, the brain and other parts of the body do not receive adequate amounts of copper for their normal functioning, while copper accumulates in the kidney and small intestine.⁴

Low copper levels can affect various body systems and manifest as physical symptoms.

Symptoms of Menkes disease

Menkes disease may not become apparent until 2-3 months after birth.² Infants with MD may be born prematurely and present with the following non-specific symptoms:

• Low muscle tone (hypotonia)²
• Seizures²
• Low body temperature (hypothermia)²
• Intellectual disability²
• Rosy cheeks⁴
• Feeding difficulties⁴
• Sagging facial skin⁴

Jaundice (i.e., a yellow appearance of the skin) is another symptom that may occur in the affected infant, caused by excessive bilirubin in the blood.¹

Clinical features of Menkes disease

The clinical features of MD are a combination of symptoms and objective findings observed by the clinician, and include:

• Coarse, sparse, steely hair¹ 
• Failure to thrive (i.e., reduced rate of physical development)²
• Low muscle tone (hypotonia)²
• Seizures²
• Neurodegeneration (e.g., intellectual disability)²
• Bone abnormalities (i.e., osteoporosis [weakened bones; may result in fractures])⁴
• Arterial tortuosity (i.e., twisted arteries that appear abnormal and may become blocked)³

The ‘steely hair’ is a specific feature of MD that appears tangled and light in colour (or is entirely colourless) due to abnormal copper metabolism.

Diagnosis of Menkes disease

Ceruloplasmin blood test

Once MD is suspected, several tests may be conducted to further confirm the diagnosis, such as a ceruloplasmin blood test which measures the level of ceruloplasmin protein in the blood⁵. Ceruloplasmin is a protein produced by the liver and is responsible for binding to copper to help transport it through the bloodstream⁵. The ceruloplasmin test is therefore employed to evaluate disorders related to copper deficiency, such as Menkes disease, and another genetic condition known as Wilson’s disease, a disorder characterised by excessive accumulation of copper in the body.

Copper blood test

Additionally, a copper blood test may be conducted to diagnose Menkes disease.⁴ Blood tests are conducted to identify low copper levels and other chemicals to detect symptoms.⁶

Skin biopsy

A healthcare provider may remove a small sample of the child’s skin to examine it under the microscope and determine how well their body is processing copper.⁷

Gene testing

Gene testing is a method to check for a defect in the ATP7A gene.⁴ It should be noted that Menkes disease is not currently part of the newborn screening program in the United Kingdom.

Treatment of Menkes disease

If an infant presents with signs of Menkes disease in the days following birth, treatment with daily copper injections may help stabilise copper levels in their body.³ The effectiveness of these copper injections depends on whether the child’s ATP7A gene still functions.⁶ The injections will help increase the production of copper in the body, but it cannot replace it completely. Copper may also be obtained naturally from many foods and dietary supplements, however, it is important to seek the guidance of a qualified healthcare professional for an effective health plan.

There is currently no complete cure for Menkes disease, but treatment with copper histidinate (CuHis) may increase survival and reduce the severity of neurological symptoms if administered within one month of birth¹. However, advice should be taken from a healthcare professional.

Physical therapy may be recommended to improve the child’s muscle development, and occupational therapy can assist in their learning needs.⁶

FAQs

What are the common symptoms of copper deficiency?

Potential signs of copper deficiency include low body temperature, bone fractures and abnormal heartbeats. It is important to note that it is rare for someone to be truly deficient in copper. 

Who is most likely to have copper deficiency?

Copper deficiency is uncommon in healthy people, but is more likely to occur among infants who have health problems or inherit a genetic abnormality.

Does my family need to be tested for Menkes disease?

Since Menkes disease is inherited, if your family has a history of the disorder, you may be able to get tested for the faulty ATP7A gene.⁶

Summary

Menkes disease (MD) is a rare, inherited disorder characterised by copper deficiency due to a mutation in the ATP7A gene that is responsible for regulating copper levels in the body. Copper is an essential mineral required for the normal functioning of several body processes. In MD, copper accumulates to abnormally low levels in the brain but to high levels in the kidney. The imbalance of copper levels is associated with various symptoms of the condition. MD follows an X-linked inheritance pattern as it affects the ATP7A gene on the X chromosome. Since males only have one X chromosome in their ‘XY’ pair, they are affected. Females with a fault in this gene are considered as ‘carriers’, and may or may not display symptoms of the disorder. 

Non-specific symptoms of MD include low body temperature, low muscle tone (hypotonia), rosy cheeks and intellectual disability. Specific symptoms of MD include coarse, steely hair that is light or colourless, a failure to thrive, bone abnormalities (e.g., osteoporosis), hypotonia, intellectual disability and arterial tortuosity. Upon suspicion of MD, clinicians may carry out additional tests to confirm the diagnosis, such as conducting a copper blood test or gene testing to confirm the faulty ATP7A gene. A ceruloplasmin blood test may also be done to determine whether the levels of this copper-transporting protein are low or normal. MD is typically treated with daily copper injections, however, there is currently no complete cure for the condition.