Introduction

Menkes disease is a devastating diagnosis affecting infants and young children. With a markedly shortened lifespan and a poor prognosis, there needs to be an increased focus on educating and preparing the family for the inevitable death of their child. 

Overview of Menkes disease

Menkes disease is a genetic disorder that alters the body’s ability to use copper normally. This defect leads to a build-up of copper in the tissues, especially in the brain and nerves. The following symptoms can be specifically linked to damage to the nervous system: 

• Floppy muscle tone (hypotonia)
• Saggy facial features
• Seizures

Menkes disease is very rare and only occurs in about one of 34,810 births although the incidence could be as high as one in 8,664 males. Diagnosing Menkes disease can be quite challenging at birth and early recognition is key. It is important to know that about 33% of Menkes cases are caused by a new gene mutation and may be more difficult to detect.²

Importance of prognosis and life expectancy

Having a tentative prognosis and an estimated life expectancy is crucial to providing patient-centric care, education, and support to the family. While the expected time of death is based on previous evidence and is more of a best guess, having an estimate can provide a general timeframe so that necessary planning can occur. This may include advanced care planning, funeral planning, or even planning out experiences to remember later.

Causes and pathophysiology

Genetic mutation (ATP7A gene)

Menkes disease is a progressive genetic disorder resulting from a mutation in the “X” chromosome which is one of the sex chromosomes.¹ This disorder is recessive which means that it takes two faulty copies to cause the disorder in the case of a biological female. However, in the case of a biological male, it only takes one faulty copy which is why the disease is much more common.²

This mutation causes a defect in the ATP7A gene which makes an improperly formed copper transport protein. This leads to a malfunction in the pump that moves copper within the cells causing a build-up of copper in the intestinal cells and a deficiency throughout the body. Several important enzymes cannot function in a copper-deficient state and this causes the tissues in the nervous system to shrink and degenerate.¹

Impaired copper absorption and metabolism

As mentioned earlier, because the copper pump malfunctions, the copper becomes trapped in the blood-brain barrier and cannot enter the brain and other nervous system cells.¹ Due to this copper deficiency, and a build-up of other toxic waste products such as free radicals, the nervous system cells become damaged.

Clinical features

Early signs and symptoms

There are several signs in a newborn baby which could indicate Menkes disease; however, the diagnosis is usually not made right after delivery. Many of the symptoms are nonspecific and may include:

• Prolonged jaundice (yellowing of the skin)
• White, silver, or grey hair colour
• Thin hair with a “kinky” or “wiry” texture
• Poor muscle tone
• Seizures
• Poor growth
• Low body temperature (hypothermia)

While some of these signs can be seen within the initial newborn period, others take days to months to notice. Also, some of these symptoms can occur without a diagnosis of Menkes. Developmentally, the infant will typically not hit their milestones after about two months.² Neurologically, seizures will likely begin at about two months and will change throughout the lifetime. Most infants die by their third birthday and some die as early as six months.² 

Diagnostic approaches

Genetic testing is the best confirmatory test for Menkes disease. However, it may not be ordered right after birth due to the non-specific signs mentioned above.² Family history can be useful in identifying a potential case of Menkes when an evaluation is started. The most definitive and rapid test to diagnose Menkes is a blood test measuring the levels of plasma catecholamines (hormones made by the adrenal glands- epinephrine, norepinephrine, and dopamine). A low level of plasma dopamine beta-hydroxylase, which turns dopamine into norepinephrine, indicates Menkes disease.²

Prognostic factors

Age at diagnosis

An early diagnosis is critical. Since most children will not live past the age of three, early identification, treatment, and life-planning are important. Being involved with the appropriate medical teams can help provide the best child and family support available. These medical teams include the following:

• Neonatologists or paediatricians care for newborns and children
• Neurologists facilitate the best care for neurological problems which are especially prevalent in Menkes disease
• Geneticists help determine the risk of having another child with Menkes disease
• Gastroenterologists and Nutritionists manage the symptoms of copper build-up in the intestines and provide optimal nutrition (likely through a surgically implanted feeding tube)¹
• Urologists manage recurrent urinary tract infections which are likely because of bladder deformities which occur frequently in Menkes disease
• Physical and occupational therapists help older children move and function as normally as possible
• Psychologists and social workers help parents move through the phases of devastation and grief¹

Early initiation of treatment

The earlier treatment is started, the better. Ideally, treatment should be started within the first four weeks of life; however, the diagnosis is often not made within that time frame. The defectiveness of the ATP7 gene will likely affect how effectively the treatment works. Typically, if treatment is not started in the first month of life, the outlook includes death within the first three years.

Management and Treatment

The current treatment for Menkes is an injection of copper under the skin. This helps to replace the blood copper which can slow down the damage to the nervous system cells, lessen or delay symptoms, and possibly prolong the child’s life.

Life expectancy

As mentioned above, life expectancy is about six months to three years in  66% of cases which are genetically inherited. In rare cases, if treatment was given in time, the child may live for several more years and possibly up to ten. Several factors can influence life expectancy and these include:

• The severity of the defect in the copper transport proteins
• The age at diagnosis
• If treatment was initiated within the first four weeks of life
• If the child received appropriate supportive services to prevent and manage life-threatening complications

Long-term prognosis

The long-term prognosis is not good. As mentioned earlier, the child will likely die by the age of three. After the first few months, they will start to regress developmentally and develop neurological symptoms such as seizures. They are also prone to bladder infections, bleeding in the brain, poor growth, and bone fractures.

According to a study by Rozensztrauch’s team, children who experience more physical effects of the disease will likely show a steeper decline in their mental and emotional health.³ Overall, Menkes disease is linked to a low quality of life when viewed in terms of health-related factors. It does not appear, based on the quality of life questionnaire, that the age, number of seizures, use of a feeding tube, or early treatment with copper change the perceived quality of life.

On the other hand, the quality of life experienced by the parents or caregivers of children with Menkes disease is generally low. Parents or caregivers tend to have more difficulty with concentration and memory. This is similar to concerns voiced by parents of children with other chronic, life-limiting diseases.³ The emotional burden on the parent is usually manifested in physical symptoms as well. 

Prognosis is useful in providing guidance when making care decisions. Having a general estimate of life expectancy can help the family determine what medical avenues they would like to pursue to relieve symptoms and enhance the quality of life. This can also help guide the family in planning for palliative care or hospice if that is felt to be the best option. 

Quality of life considerations

Supportive care needs

As mentioned earlier, children with Menkes disease require many different healthcare teams. These include physicians, therapists, and genetic counsellors. Additional care is required compared to their healthy peer age group. 

• A neurologist will help to manage their seizures and other neurologic symptoms 
• Special tools and therapy can help them to move and eat safely 
• Gastroenterologists and nutritionists can help optimise nutrition and growth with a feeding tube and special formula if required.
• It is important to remain in close contact with a urologist because of the likelihood of frequent bladder infections 
• Finally, a geneticist can help the family determine if there is a risk of having more children with Menkes disease

Family and social impact

There are several organisations which serve families of children with Menkes disease. The most specific support group in this case though is The Menkes Foundation. Caring for a child with a terminal diagnosis is very stressful for a caregiver and can cause a decline in their physical, mental, spiritual, and family health.³

Summary

Menkes disease is a lethal genetic disease that affects children. Due to a disorder in the metabolism of copper, this mineral builds up in the nervous system tissues and causes seizures and the other symptoms associated with this disease. Children rarely live past three years old without treatment and ten years old if they have received treatment. An honest prognosis at the time of diagnosis is important to ensure that appropriate measures are put in place to support the family and promote a high quality of life.