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Menke disease (occipital horn variant)
This condition is caused by alterations in the ATP7A gene, which is essential for proper copper distribution in the body. It generally presents with milder symptoms than classic Menkes disease, often affecting bones and connective tissues.
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Overview
Menkes disease (occipital horn variant) is a rare inherited disorder that affects how the body processes and distributes copper. Copper is a vital trace element needed for many bodily functions, including the development of strong connective tissue, healthy bones, and a functioning nervous system. In this variant, problems with copper transport lead to its accumulation in some tissues and deficiency in others [PMID:20301323].
This condition is often considered a milder form of classical Menkes disease. It is sometimes referred to as 'occipital horn syndrome' because of characteristic horn-like bone growths that can develop at the back of the skull. The impact on individuals can vary, but generally, neurological symptoms are less severe compared to the classic form.
Symptoms & clinical features
Symptoms of Menkes disease (occipital horn variant) typically appear during infancy or early childhood. Skeletal issues are common, including soft bones (osteopenia), which can lead to fractures, and loose joints. The distinctive 'occipital horns' - bony projections at the base of the skull - are a key feature and can sometimes be seen on X-rays.
Connective tissue problems can result in stretchy skin, bladder diverticula (pouches in the bladder wall), and vascular abnormalities. Hair may be sparse, wiry, or abnormally coloured. While neurological problems are generally less pronounced than in classic Menkes disease, some individuals may experience developmental delays or intellectual disability [PMID:20301323].
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Affected organs
This condition primarily affects organs and systems that rely heavily on copper for proper function. The skeletal system is notably impacted, leading to fragile bones and characteristic occipital horns. Connective tissues throughout the body can be weakened, affecting skin, blood vessels, and internal organs like the bladder.
The nervous system can also be affected, though typically to a lesser extent than in classical Menkes disease. Hair follicles are also impacted, resulting in distinctive hair characteristics.
Risks & severity
Menkes disease (occipital horn variant) is considered rare, and its exact prevalence is not well established. The severity of symptoms can vary significantly among affected individuals, even within the same family. While it is generally a milder form of Menkes disease, complications can still arise from the skeletal, vascular, and connective tissue issues.
Long-term health concerns often involve managing bone health, addressing potential bladder issues, and monitoring for any developmental progress. Early diagnosis and management can be important in addressing some of these aspects. The condition is progressive, meaning symptoms can change over time, and ongoing medical care is typically needed [PMID:33678036].
Genetic causes
Menkes disease (occipital horn variant) is caused by pathogenic variants in the ATP7A gene. This gene provides instructions for making a protein called a copper-transporting ATPase. This protein plays a crucial role in moving copper around the body's cells and tissues.
Normally, the ATP7A protein ensures that copper is absorbed from the diet and transported to where it's needed for various enzymes to function correctly. Pathogenic variants in ATP7A disrupt this process, leading to a functional copper deficiency in some tissues, such as the brain, while copper can accumulate in others, such as the kidneys and intestines [PMID:20301323]. This imbalance of copper distribution leads to the wide range of symptoms seen in the condition.
- ATP7A ATPase copper transporting alphaThe ATP7A gene provides instructions for producing a protein vital for regulating copper levels within the body, ensuring proper cellular function and preventing toxicity.
Inheritance pattern
Menkes disease (occipital horn variant) has an X-linked recessive inheritance pattern. This means the ATP7A gene is located on the X chromosome, one of the two sex chromosomes. Females have two X chromosomes, while males have one X and one Y chromosome.
Typically, males are more severely affected because they only have one X chromosome. If their single X chromosome carries a pathogenic variant in ATP7A, they will develop the condition. Females with one altered ATP7A gene on one X chromosome and a normal gene on the other X chromosome are usually carriers and often do not show symptoms, or have very mild ones. If a mother is a carrier, there is a 50% chance with each pregnancy that her son will inherit the altered gene and develop the condition, and a 50% chance that her daughter will be a carrier.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosis of Menkes disease (occipital horn variant) is often suspected based on an individual's clinical signs and symptoms, such as the characteristic skeletal changes or connective tissue issues. Blood tests can measure copper and ceruloplasmin levels, which are often low in affected individuals. However, these tests alone may not be conclusive due to the variable nature of copper distribution in this specific variant.
A definitive diagnosis is confirmed through genetic testing, which looks for pathogenic variants in the ATP7A gene. Referral to a clinical genetics service is usually made by a paediatrician or other specialist when Menkes disease is suspected. Genetic testing for ATP7A variants falls under specific NHS Genomic Medicine Service (GMS) pathways, often initiated via a Genomic Laboratory requesting an R-code, such as R365 Menkes disease, which covers testing for ATP7A.
Management & lifestyle
Management of Menkes disease (occipital horn variant) focuses on alleviating symptoms and addressing specific complications, as there is currently no cure. Care is typically managed by a multidisciplinary team of specialists, which may include paediatricians, orthopaedic surgeons, neurologists, and geneticists.
For some individuals, copper histidine supplementation may be considered, particularly if treatment begins early, as it may help improve some outcomes, especially neurological ones, though its effectiveness varies, especially for this milder variant. Regular monitoring of bone health and addressing any fractures is important. Bladder issues and vascular abnormalities also require appropriate medical attention and surveillance within the NHS framework. Genetic counselling is an important part of the care pathway to discuss the inheritance pattern and implications for family members.
UK care pathway
In the UK, individuals suspected of having Menkes disease (occipital horn variant) would typically be referred by their GP or another specialist to a clinical genetics service. This service can provide expert diagnosis, counselling, and access to the NHS Genomic Medicine Service (GMS) testing. Genetic testing for ATP7A variants is available through the GMS, often using specific R-codes like R365 for Menkes disease.
A genetic counsellor within the clinical genetics team can offer support and information regarding the condition's inheritance, potential impact on the family, and available resources. Management is then coordinated by various specialist teams, ensuring a holistic approach to care within the NHS.
Frequently asked questions
What is the difference between Menkes disease (occipital horn variant) and classical Menkes disease?
The occipital horn variant is generally considered a milder form of Menkes disease. While both are caused by changes in the ATP7A gene and affect copper transport, the occipital horn variant typically has less severe neurological involvement and distinctive skeletal features like 'occipital horns'.
Can females be affected by Menkes disease (occipital horn variant)?
Because it is an X-linked recessive condition, males are typically more severely affected. Females are usually carriers and may show no symptoms, or sometimes very mild features, due to having a second functional copy of the ATP7A gene on their other X chromosome.
Are there treatments available for this condition?
There is no cure for Menkes disease (occipital horn variant). Management focuses on addressing specific symptoms and complications. In some cases, copper histidine supplementation, especially if started early, may be considered, but its effectiveness can vary.
How is this condition inherited?
The condition is inherited in an X-linked recessive pattern. This means that a pathogenic variant on the X chromosome causes the condition. Males, with one X chromosome, are usually affected, while females with two X chromosomes can be carriers and typically have milder or no symptoms.
Where can I find support in the UK for Menkes disease?
You can seek support through your NHS clinical genetics team, who can provide information and connect you with patient support groups. Rare disease organisations in the UK may also offer resources and communities for affected families.