Menkes Disease

Menkes Disease is a rare genetic condition that affects copper levels throughout the body. Copper has many roles in the body, including helping to make red blood cells, bone, and connective tissue, and is involved in the nervous and immune systems. Menkes Disease is caused by changes in the ATP7A gene. Changes in ATP7A cause an uneven distribution of copper in the body, with lower levels of copper in the brain and liver and higher levels of copper in the kidneys and intestines. Menkes Disease usually onsets in infancy and most individuals do not survive past three years old without treatment.

Clinical Features

Sparse, steely/kinky hair is a characteristic of Menkes Disease.

Menkes Disease affects many body systems. Some features of Menkes Disease include:

Prenatal:

• Generally normal pregnancy and birth
• May be born prematurely

Infancy:

• Sparse, steely/kinky hair
• Low muscle tone (hypotonia)
• Low weight (failure to thrive)
• Seizures
• Sagging cheeks
• Unstable body temperature
• Prolonged jaundice
• Poor eating/feeding difficulties
• Skeletal differences (eg. pectus excavatum)
• Loss of nerve cell function in the brain over time (neurodegeneration)
• Developmental delay
• Intellectual disability

Late Manifestations:

• Blindness
• Respiratory failure
• Osteoporosis, leading to broken bones
• Bleeding in the brain

Genetics and Prevalence

Menkes Disease is inherited in an X-linked recessive pattern.

Menkes Disease is a genetic condition, meaning it can run in families. Menkes Disease affects about 1 in 35,000 live male births. Menkes Disease usually affects males, but can be seen in females in rare situations.

Genetic information that provides the instructions for growth and development is stored in genes. Changes or mutations in genes can prevent their function in the body. Menkes Disease is caused by changes in one gene called ATP7A. ATP7A transports copper throughout the body, and disruptions to this function can cause the clinical features of Menkes Disease.

Inheritance

Menkes Disease is inherited in an X-linked recessive pattern.

The ATP7A gene is found on the X chromosome. Females usually have two X chromosomes (one from their mother and one from their father). Males usually have one X chromosome (from their mother) and one Y chromosome (from their father). Males who inherit a change in ATP7A will develop Menkes Disease since they only have one copy of this gene. Females that inherit a change in ATP7A are called carriers because they have another functional copy of the ATP7A gene on their other X chromosome. Female carriers of ATP7A changes do not usually have symptoms of Menkes Disease.

When a mother is a carrier of an ATP7A change:

• Her sons have a 50% chance of inheriting the change, causing Menkes Disease
• Her daughters have a 50% chance of inheriting the change, being carriers for Menkes Disease

Approximately 2/3 of individuals with Menkes Disease inherit a changes in the ATP7A gene from their mother. About 1/3 of individuals with Menkes Disease have a new (de novo) ATP7A change and are the first person in their family with this condition.

Diagnosis

Menkes Disease can be difficult to diagnose early due to its non-specific features.

Physical Exam

A doctor may examine an infant for Menkes Disease if there are suggestive physical features (specifically sparse, steely/kinky hair).

Blood Tests

A doctor may run blood tests to determine the amount of copper in the blood or by measuring enzymes that use copper.

1. Low levels of copper in the blood
2. Low levels of ceruloplasmin in the blood
3. Plasma catecholamine analysis

Blood Concentration for Copper and Ceruloplasmin in Menkes Disease

Blood concentration	Normal Range	Menkes Disease
Copper	75-150 µg/dL; (birth - 3 mos: 20-70 µg/dL)	<40 µg/dL
Ceruloplasmin	200-450 mg/L; (birth - 3 mos: 50-200 mg/L)	10-100 mg/L

*Low levels of copper and ceruloplasmin are also seen in healthy newborns which can make blood tests for Menkes Disease unreliable.

Genetic Testing

Another blood test, specifically looking for changes in the ATP7A gene, can be done to diagnose Menkes Disease.

Genetic testing may look at just the ATP7A gene (single gene test) or may look at multiple genes for similar conditions (multigene panel).

Management

Currently, there is no cure for Menkes Disease. Individuals with Menkes Disease require a multidisciplinary team.

If Menkes Disease is identified within 28 days after birth, a copper-histidine treatment may be suggested. Copper-histidine can be injected under the skin to provide extra copper to the body systems that require it. Treatments for Menkes Disease aim to deliver copper to the brain to reduce neurodegeneration.

Related Conditions

Changes in ATP7A can also cause Occipital Horn Syndrome (OHS) and ATP7A-Related Distal Motor Neuropathy (DMN).

The severity of Menkes Disease and other related conditions may depend on where the change is found in the ATP7A gene. There may also be variability within a family with Menkes Disease.

Occipital Horn Syndrome (OHS)

OHS is a milder form of Menkes Disease. It is often identified in childhood-adolescence. OHS is also caused by differences in copper levels throughout the body, and results in loose skin and joints and coarse hair. Individuals with OHS have characteristic "occipital horns" which are a buildup of calcium in a wedged shape at the base of the skull.

ATP7A-Related Distal Motor Neuropathy (DMN)

DMN is an adult-onset condition that causes muscle weakness over time. Copper levels are normal in individuals with DMN.

Genetic Counselling

Genetic counsellors are healthcare professionals trained in medical genetics and counselling that may be involved in the care of a family with Menkes Disease. Individuals may choose to speak to a genetic counsellor if they have a personal or family history of Menkes Disease. Topics discussed in a genetic counselling session may include:

• Personal medical history
• Family history
• Providing information about Menkes Disease (eg. inheritance patterns, clinical features)
• Providing risk estimates
• Facilitating genetic testing options
• Providing psychosocial support

Reproductive Options

Preimplantation genetic diagnosis (PGD) may be an option for family planning when there is a known ATP7A gene change. In PGD, embryo's are tested for the ATP7A gene change prior to implantation. PGD requires in-vitro fertilization (IVF) techniques to create an embryo. Genetic testing for the ATP7A gene change is completed on each of the embryos and embryos that do not contain the ATP7A gene change are implanted into the mother's uterus. In British Columbia, PGD can be explored at a private pay clinic.

Psychosocial Implications

It can be very challenging to receive a diagnosis of Menkes Disease in the family. Genetic counsellors can provide patients with more information about Menkes Disease, resources, and psychosocial support. This may help families discuss feelings of anxiety, grief, anger, and guilt.

Patient Resources

Information about Menkes Disease:

• NORD: Menkes Disease

• Mount Sinai: Menkes Disease

• The Menkes Foundation

Information about genetic counselling or finding a genetic counsellor:

• National Society of Genetic Counsellors

• Canadian Association of Genetic Counsellors