Menkes Disease

What is Menkes Disease?

Menkes disease is a rare inherited disease that affects how the body processes copper. This condition tends to worsen over time, and it often sadly results in early childhood death. Diagnosing Menkes disease early is difficult due to its minor noticeable signs and unclear lab results. However, an accurate diagnosis is crucial. It allows for appropriate treatment management to lessen complications and early death, as well as providing important information for parents and future pregnancy planning.

Menkes disease was first identified in 1962 by Menkes and colleagues. A decade later, a group of researchers first discovered that the disease was linked to an issue with copper metabolism. They also noticed a connection between the unusual, steel-like hair of patients with Menkes disease and the brittle wool of sheep in areas of Australia known for copper deficiency. Furthermore, they found that these patients had abnormal copper and ceruloplasmin (a protein that carries copper in the bloodstream) levels.

What Causes Menkes Disease?

Menkes disease is a condition associated with changes in the way the body handles copper, a vital nutrient. The root cause of this problem is a mutation in the ATP7A gene. This gene resides on a region of the X chromosome labelled as Xq13.3 and consists of 23 different segments known as exons. It is responsible for creating a protein composed of 1500 amino acids. This protein is extensively found in various parts of the body like the brain, lungs, kidneys, and muscles.

Till now, researchers have identified about 357 different types of mutations in the ATP7A gene. These mutations comprise insertions (where additional DNA is added), deletions (where some DNA is removed), missense mutations (where the original DNA is replaced), partial deletion and splice mutations.

Studies of families affected by Menkes disease reveal that mothers carry the gene mutation in 75% of cases. In the remaining 25% of cases, it is not clear who carries the mutation. Interestingly, there’s no clear connection between specific mutations and the severity or progression of the disease.

Although Menkes disease most often affects males, there are rare instances of females with the disorder. This is likely due to changes involving the X chromosome, such as when the normal X chromosome selectively gets inactivated (a process called X autosome translocation), or due to a single altered DNA building block (point mutation), or due to preferential inactivation of the normal X chromosome.

Risk Factors and Frequency for Menkes Disease

Menkes disease is a rare condition that affects mostly males. Roughly 1 in every 35,000 male babies is born with this disease worldwide. Within the United States, the incidence of Menkes disease ranges from 1 in every 50,000 to 1 in every 250,000. Interestingly, one-third of these cases are the result of new mutations. A study conducted in Japan from 1993 to 2003 found that the rate was 1 in 2.8 million live births there, and only 4.9 in every million male births. Please note that females can also have Menkes disease, but this is usually due to unusual genetic situations.

Menkes disease is more common in Australia, affecting between 1 in 50,000 to 1 in 100,000 people, possibly due to a phenomenon known as the founder effect.

People from all races and ethnic backgrounds can have Menkes disease. It is believed that one-third of the cases of Menkes disease come from new mutations. These mutations can happen anywhere, regardless of a person’s racial or ethnic background.

Going deeper into the genetics, Menkes disease usually affects males due to its X-linked recessive trait. Females are typically just carriers of the disease and don’t show any symptoms unless there are unusual genetic scenarios.

Parents usually notice the signs of Menkes disease in their children between six to eight weeks after birth when they see delayed development or the presence of unusual eye movements or strange limb movements that could suggest seizures.

Signs and Symptoms of Menkes Disease

Menkes disease is a serious condition usually resulting in death during early childhood, often by the age of 3. This condition typically features ongoing deterioration of the nervous system and malfunctions in the body’s connective tissues.

Babies born with Menkes disease are usually healthy at birth, but start showing signs such as prolonged jaundice, hypothermia, muscle weakness, and feeding problems right after birth. In some cases, babies may have spontaneous fractures or blood accumulation beneath the skin of their head.

By the age of two months, signs that are more classic to Menkes disease usually begin. For example, the hair which is normal at birth, is replaced by hair that is thin, sparse, wiry or has a metallic appearance. Other signs can include sagging facial features, smaller jaw, loose skin, arched palate, along with abnormalities in the brain, lungs, heart and other parts of the body.

Babies with this disease may show more nonspecific signs, which often results in the condition being overlooked. Some of these signs include low blood sugar levels, hypothermia, prolonged jaundice, and unusual chest shape. It takes weeks for the definite diagnostic test to yield results, so quicker and reliable tests are needed to diagnose the condition before obvious symptoms appear.

• Distinctive hair changes
• Neurological signs such as developmental regression and seizures
• Abnormalities in the connective tissue and skeletal system
• Eye abnormalities leading to very poor visual acuity, eye misalignment, iris abnormalities
• Problems with the autonomic nervous system, leading to chronic diarrhea and blood pressure issues
• Gastrointestinal manifestations
• Urological complications

Seizures often start around 2 to 3 months, and they evolve through different stages as the condition worsens. The early stage is composed of seizures that are related to a lack of uniform blood flow due to abnormally twisted blood vessels. As the condition progresses, the seizures become more severe and harder to control. By the final stage, around the age of 2 years, seizures are caused by ongoing degeneration of the brain’s cortex.

Other common symptoms include delay in motor skills development, absence of language skills, and there is a link with failure to thrive and growth restriction.

Problems with the body’s connective tissue manifest as loose, wrinkled skin, and issues with motor development due to muscle weakness. Bone deformities may occur, which may sometimes be mistaken for child abuse. Treatments focusing on increasing bone mineral density can be beneficial.

Dysauto has signs such as constant diarrhea, fainting, and low blood pressure when standing up. These symptoms are due to abnormal chemical reactions in the brain. There may also be a wide array of gastrointestinal manifestations, leading to complications such as gastric polyps, acid reflux, and other conditions. There may be growth failure and complications with the digestive system leading to the necessity of a feeding tube.

Urological issues are very common in this disease. The most frequent manifestation is bladder diverticula, which often lead to urinary infections, organ damage, and other complications. Pneumonia is also a frequent occurrence in persons with Menkes disease.

Testing for Menkes Disease

Diagnosing Menkes disease involves paying attention to specific signs and conducting several tests. Menkes disease has certain clinical, biochemical, and radiological features that help doctors identify this condition. However, these features are often not enough to diagnose the disease, that’s why other tests are conducted.

Tests that measure the level of certain chemicals in your body can greatly help in diagnosing Menkes disease. For instance, the levels of substances called serum copper and ceruloplasmin are usually quite low when you have Menkes disease. However, these levels tend to be low in babies who are under six months old too, so this test alone isn’t sufficient to confirm a diagnosis. In such cases, another test that checks for a chemical imbalance characteristic of Menkes disease (low dopamine beta-hydroxylase) can be performed.

Another way to detect Menkes disease is by examining the patient’s hair under a microscope. There are changes to the hair strands in Menkes disease that are usually quite noticeable.

Brain scans like magnetic resonance imaging (MRI) can also provide useful information. Certain features like cerebral atrophy (loss of cells in the brain), delayed development of the insulating layer around nerve fibers, and signs of fluid accumulation or blood clots in certain brain regions are common in Menkes disease. Other changes involve the shape and intensity of certain features in the center of the brain, blood clots blocking blood flow, and narrowing and twisting of blood vessels. The latter is a compelling indication of Menkes disease. A type of scan called magnetic resonance angiography (MRA) is particularly helpful in revealing these blood vessel changes.

An electroencephalogram (EEG), a test that records electrical activity in the brain, can show specific abnormalities at different stages of Menkes disease.

X-ray imaging can reveal bone changes often seen in Menkes disease, such as generalized osteoporosis (a condition that weakens bones and makes them fragile), metaphyseal flaring (widening of the ends of bones), and spurs in long bones. There can also be thickening around the central part of long bones and rib fractures that are commonly mistaken for signs of child abuse.

Lastly, genetic testing can play a significant role in diagnosing Menkes disease. A technique that analyzes a specific gene (ATP7A) involved in Menkes disease can be used. If no changes are found in this gene, other genetic tests can be tailored to check other genes associated with related conditions.

If there’s a history of Menkes disease in a family, prenatal (before birth) tests can be performed on pregnant women to check for the disease’s genetic markers. These tests involve sampling and analyzing cells from the placenta or checking copper intake in cultured cells.

Treatment Options for Menkes Disease

Menkes disease is a serious illness that often leads to death between six months and three years of age. The outcome of any treatment depends largely on the extent of the defect in the ATP7A gene and how much of this gene’s protein is still functional.

The primary goal of treatment is ensuring that the body’s enzymes, which require copper to function, have access to it. This is challenging because the body is not very good at absorbing copper in patients with Menkes disease. Therefore, treatment should focus on:

1. Improving how well the body absorbs copper
2. Making sure copper is available to the enzymes that need it
3. Starting early, as delaying treatment can result in permanent damage to the nervous system

Getting treatment started early – ideally within the first four weeks of life – is crucial. The preferred method of treatment is to administer copper histidine, which seems to be the most effective. This can’t be given orally, as the copper gets trapped in cells in the intestine. It is therefore usually administered either under the skin or directly into a vein. Starting treatment before the infant is three weeks old can significantly reduce nerve damage in some patients. Treatment with copper histidine can reverse changes to the skin and hair, improve muscle tone, promote weight gain, and help children reach normal developmental milestones. Results depend on how early treatment is started and how much ATP7A protein is still functional.

Many skills are required to manage the complications of Menkes disease. For instance, a feeding tube might be needed to make sure the child is getting enough nutrition. A patient who has difficulty swallowing might need a tube inserted directly into their stomach. Surgery might be needed to correct urinary issues, and different types of medication can help manage seizures. Heart complications are also common, as is notable muscle weakness. In addition to medical treatments and surgery, patients may require extensive physical, occupational, and speech therapies. Devices to assist with movement may also be beneficial.

Copper supplementation doesn’t always lead to a significant improvement in neurological function in Menkes disease cases. However, it can lead to modest benefits, such as reducing seizures and decreasing irritability. But the decision to use copper therapy should involve open communication with the parents, as the benefits are usually limited. Copper replacement is particularly indicated if the diagnosis is made before neurological damage begins, as prevention of further damage may be possible in some individuals.

Too much copper can damage the kidney’s filtration system, a condition known as copper overload. Ironically, people with Menkes disease have a natural tendency to store copper in their kidneys. This effect is usually not significant, as the copper losses rarely reach a level requiring replacement therapy.

There are other potential treatments that are still being studied and are not yet commonly used, including:

• Vitamin C – which could help limit the interaction of copper and certain proteins
• Vitamin E
• Carbamic acid derivatives – such as diethyldithiocarbamate
• Gene therapy directed to the brain

Despite having Menkes disease, there’s no increased risk when it comes to anesthesia. Patients with this condition might need surgery to deal with ear infections, feeding problems, or bladder issues.

What else can Menkes Disease be?

Occipital horn syndrome (OHS) is a milder form of a condition called Menkes disease. Children with OHS typically start showing symptoms between 5 to 10 years old. These symptoms are similar to those of classic Menkes disease. Newborns with OHS may experience low body temperature and prolonged yellow skin or eyes (jaundice). Other signs of OHS include issues with the body’s connective tissues, such as belly button and groin hernias. These children may also have bone abnormalities, especially growths (exostoses) at the back of the skull (occiput). While their neurological symptoms are not as severe as in full Menkes disease, children with OHS often exhibit lower intellectual capabilities and developmental delays in motor skills, mainly due to low muscle tone.

Another condition related to ATP7A, the gene responsible for Menkes disease, is adult-onset distal motor neuropathy, which is similar to Charcot Marie Tooth disease. This condition is marked by a gradual deterioration of muscle strength and mass in the limbs (distal muscle weakness and atrophy), which can cause high-arched feet (pes cavus). Unlike Menkes and OHS, tests for copper levels in the body will typically come back normal in this condition.

Biotinidase deficiency is another inherited condition that often becomes apparent within the first few months of life. This deficiency can lead to seizures, low muscle tone, delayed overall development, lack of coordination (ataxia), and vision and hearing problems. Other symptoms may include skin rashes, lighter skin, and hair loss.

Hupke-Brendel syndrome is also a rare genetic condition. Its symptoms include birth defects such as bilateral congenital cataracts, sensorineural hearing loss, and severely delayed development. Sadly, most patients with Hupke-Brendel syndrome pass away between the ages of 9 months and 6 years. The diagnosis is typically based on its characteristic features and confirmed by genetic testing that reveals specific genetic changes (biallelic pathogenic variants) in the SCL33A1 gene.

What to expect with Menkes Disease

It’s hard to say how long a child with Menkes disease might live, but most, sadly, don’t live past their third birthday. A usual cause of passing is pneumonia, which causes breathing problems severe enough that the body can’t function. Sometimes, a person with Menkes disease may pass away suddenly, without any clear immediate medical reason.

The disease tends to cause a lot of illness and is a frequent cause of death because it affects many different parts of the body, including these systems:

• The nervous system, which includes the brain and nerves.
• The gastrointestinal system, which includes the stomach and intestines.
• The connective tissue, which supports, binds, or separates other tissues or organs.
• The vascular system, which includes the heart and blood vessels.

Possible Complications When Diagnosed with Menkes Disease

Late side effects of Menkes disease might include difficult-to-control seizures, a build-up of blood outside the brain, blindness, and recurring infections. In severe cases of Menkes disease, death may occur by the age of three, often due to complications related to blood vessels or infections in the lungs. Kidney complications might also occur as copper becomes trapped in the early part of the kidney tube responsible for filtering waste from the blood. Growth problems might emerge not long after the nervous system begins to degenerate.

Eye-related issues have also been seen, such as less pigment in the retina, partial withering of the optic nerve, a condition affecting the central part of the retina called macular dystrophy, birth defect causing clouding of the eye lens and small cysts in the colored part of the eye.

Possible Late Complications of Menkes Disease:

• Difficult-to-control seizures
• Build-up of blood outside the brain
• Blindness
• Recurring infections
• Death by the age of three, often related to complications with blood vessels or lung infections
• Kidney complications from trapped copper
• Growth problems following the start of nervous system degeneration
• Eye-related issues like less pigment in the retina, partial withering of the optic nerve, macular dystrophy, congenital cataracts and small cysts in the iris

Preventing Menkes Disease

Talking to a genetic counselor and getting prenatal tests are beneficial in stopping Menkes disease, a rare genetic disorder, from occurring. However, brand new genetic changes are responsible for about one-third of all Menkes disease cases. Established advice exists for testing and diagnosing this disease during pregnancy.

Parents may be taught exercises and skills from physical and occupational therapists that can help manage their child’s condition. Menkes disease can be particularly hard on families since it often results in a healthy newborn rapidly declining into a severe, irreversible illness within the first few months. This can place immense emotional and mental strain on the family, making support for their mental health a critical part of the overall care plan.