Introduction

Menkes disease is a rare condition that affects the body’s copper levels, characterised by reduced copper levels in the brain and serum of affected individuals. This is caused by a mutation in the ATP7A (copper-transporting ATPase) gene, which is responsible for transporting and maintaining copper levels in the body.¹

Menkes disease is an inherited X-linked chromosome disorder that mostly affects infants assigned males at birth. A common physical sign is a steely or kinky hair, which develops within a few months of age. Menkes disease is also associated with seizures, poor growth, and impaired neurological development.²

Although there is currently no complete cure for Menkes disease, there have been positive outcomes in treatment with copper-histidine (CuHis) injections that aim to restore copper levels in the body. This treatment has helped to increase survival and improve neurological symptoms, especially when started within 28 days of birth.

Pathophysiology

Role of copper in the body

Copper is one of the essential metals required to maintain many body functions, but it is used in small amounts. For example, copper helps to develop brain function, the formation of blood vessels, and the conversion of iron into a usable form in the body. It is also a part of the immune system, particularly in wound healing.¹

According to the World Health Organisation (WHO), the recommended intake of copper is about 30 micrograms per kilogram of body weight per day, this approximates to about 2mg daily for an average adult. Copper is naturally available in most diets and can be taken as a supplement.¹

Copper also plays an important role in enzyme function by coupling with enzymes responsible for metabolism, which protects cells and organs involved in the development of the nervous system from damage. Therefore, a reduced level of copper–either caused by a gene disorder due to mutations or low dietary copper intake–can lead to low levels of iron, mental retardation, weak immune function, delayed wound healing, and impaired nervous system development.¹

Mechanism of ATP7A mutation

Studies suggest that when copper is taken through the diet, only a small percentage is absorbed in the stomach, where the acidic environment turns it into free copper ions. However, a larger portion of ingested copper is absorbed into the intestinal tract by a simple diffusion process and is transported through a specialised transporter called the copper-transporting adenosine triphosphatase (ATPase) found on the mucosal cell membrane. The type of enzyme that produces the ATPase, is the copper-transporting P-type ATPase gene (ATP7A).¹

When there is a dysfunction of the ATP7A gene, it disrupts the transportation of copper, which affects the body’s ability to maintain proper copper distribution. Menkes disease, also known as Menkes syndrome, is a rare neurodegenerative disorder caused by a mutation of the ATP7A gene, leading to a deficiency in copper levels in the body.²

Some studies suggest that Menkes disease is linked to the X chromosome, making it more common in individuals assigned male at birth (AMAB), who have only one X chromosome compared to individuals assigned female at birth (AFAB), who have two X chromosomes. Therefore, an individual AFAB carrying only one defective copy of ATP7A may not develop the disease if the second X chromosome is normal. This explains why Menkes disease is almost exclusively seen in individuals AMAB and is estimated to occur in about 1 in 35,000 infants assigned male at birth.²

Clinical presentation

Menkes disease is caused by low copper levels in the brain, which reduces the function of copper-dependent enzymes throughout the body. This can also lead to an accumulation of copper in other parts of the body, such as the kidneys, resulting in severe damage to the brain and nervous system, ultimately affecting an infant’s development.²

Early signs and symptoms

• Sparse, kinky hair (pili torti) - Appears colourless or steel-coloured and breaks easily
• Hypotonia (weak muscle tone) - Often associated with feeding difficulties 
• Developmental delays - This may be less severe if it develops later in childhood³

Neurological symptoms

• Seizures
• Deterioration of nervous system function - Typically begins during early infancy, at around 6 - 10 weeks³

Systemic symptoms

The early signs and symptoms of Menkes disease arise from the dysfunction of the important enzymes necessary for brain growth and body function. As ATP7A is essential to numerous neurological functions, its absence or dysfunction may result in impaired neurodevelopment and extensive neurodegeneration in infants and may lead to:³ 

• Growth failure
• Hypothermia (low body temperature)
• Distinctive facial features

Diagnostic methods

There are various ways of diagnosing Menkes disease, but it is primarily characterised by clinical features that often suggest the diagnosis.

Clinical evaluation

Family history, physical examination, and observation of symptoms are usually the first steps in diagnosing Menkes disease. This involves looking for the most common signs and symptoms, such as poor growth or thin, steely-coloured, kinky hair. Hair samples are examined under light microscopy, with as many strands as possible, because one hair may not show typical features.⁴

Biochemical testing

This is mostly performed by a paediatrician or any health care practitioner, and blood tests may be ordered to make an accurate diagnosis. In Menkes disease, serum copper and ceruloplasmin levels are typically low, in the range of 0-55 microgram/dl and 10-160 mg/dl, respectively (normal levels: 70 to 150 micrograms/dl and 200-450 mg/dl). However, as these levels are typically low in babies, biochemical tests should not be used as the only diagnosis testing. In newborns, plasma catecholamine analysis, which measures certain natural neurochemicals, helps identify the disorder, as a rapid diagnostic test.⁴

Molecular genetic testing

Genetic testing can detect ATP7A mutations, which may involve:⁵

• Identification of ATP7A gene mutation
• Carrier testing for family members

Neuroimaging and other diagnostic tools

• MRI/CT scans to check for brain abnormalities
• X-rays to check for bone changes⁶

Treatment strategies

Copper replacement therapy

This involves copper supplements delivered by daily subcutaneous injections, with dosage monitoring and adjustments, based on the type of copper complex used and the severity of the ATP7A mutation.⁷

For example, patients who can still transport a small amount of copper in their system are most responsive to copper-histidine (CuHis) injection treatment. This helps to improve growth, neurological development, and reduces the occurrence of seizures.⁷

It is recommended that treatment is started as soon as possible, ideally within the first 4 weeks after birth. Since copper is vital for a developing nervous system, the copper complex used must be able to cross the blood-brain barrier.⁷

Symptomatic treatment

Menkes disease affects many areas of the body, so a multidisciplinary approach involving different specialities may be required for the best patient outcomes. 

This may include:⁸

• Management of seizures with the neurology team
• Nutritional support with the gastroenterology and nutrition team
• Physical and occupational therapy

Experimental and emerging therapies

With Menkes Disease being a rare condition caused by the mutation of the ATP7A gene, more research needs to be done into gene therapy approaches through clinical trials and research developments.⁹

If left untreated, most patients do not survive past the age of three. Therefore, early diagnosis and treatment are important for the child’s survival and to improve symptoms.⁹

Management

Long-term management

This includes regular follow-up and monitoring with a cross-functional team of healthcare providers, along with supportive care and developmental support.¹⁰

Psychosocial and support considerations

Family counselling and support, such as genetic counselling, are available for families who may be struggling with a Menkes disease diagnosis. Your GP may be able to provide a referral.

Support groups and resources, such as the UK Mendes Foundation website, offer lots of useful information, and guidance that are readily available.

Summary

Copper is an essential metal for body and brain function development. The WHO recommends a daily intake of about 2 mg per day, which can be obtained from most food.

Menkes disease is the depletion of copper levels in the body caused by a mutation in the ATP7A gene. This gene is responsible for the movement of copper throughout the body.

Menkes disease has been linked with a disorder of the X chromosome and almost exclusively affects individuals assigned male at birth. Affected newborns are often born prematurely and may exhibit symptoms such as hypothermia, kinky hair, seizures, poor brain function, and growth failure.

Although there is no cure for Menkes disease, early treatment with parenteral copper-histidine (CuHis) has been shown to improve survival and neurological outcomes.