What are the other Names for this Condition? (Also known as/Synonyms)

• Copper Transport Disease
• Menkes Syndrome
• Steely Hair Disease

What is Menkes Disease? (Definition/Background Information)

• Menkes Disease (MNK) is a rare genetic disorder of copper deficiency that is mostly observed in males. In this disorder, due to the disruption of certain body processes, the levels of copper remain deficient leading to bone and joint, skin, and central nervous system abnormalities
• The signs and symptoms of Menkes Disease may be noted during infancy or in early childhood. These may include developmental delays, hair and skin abnormalities, decreased or increased muscle tone, loose joints, malnutrition, failure to thrive, and intellectual disabilities
• The condition is inherited in an X-linked recessive manner, and a family history of the condition is a key risk factor. Mutations in the ATP7A gene results in the development of Menkes Disease. This may be confirmed by the healthcare provider via molecular genetic testing
• A prompt recognition of the condition followed by effective management, which typically involves copper supplementation and supportive treatment, is key to improved outcomes. However, in a majority of cases, the overall prognosis of individuals with Menkes Disease is poor

Who gets Menkes Disease? (Age and Sex Distribution)

• Menkes Disease (MNK) is a very rare congenital disorder. The incidence of the disorder is reportedly 1 case per 100,000 to 250,000 newborn babies. However, the estimated prevalence rate is much higher - ranging from 1 in 34,810 to 1 in 8,664 live male births
• The presentation of symptoms may occur at or following the birth of the child, or even during early childhood
• Predominantly males are affected, since MNK is an X-linked recessive disorder
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Menkes Disease? (Predisposing Factors)

• Menkes Disease is an X-linked disorder; and so, being born to a mother who is a carrier of the disorder is a major risk factor for the condition
• Currently, no other risk factors have been clearly identified for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Menkes Disease? (Etiology)

Menkes Disease is a rare genetic disorder that is inherited in an X-linked recessive manner.

• It is caused by mutations in the ATP7A gene that is located on the female sex chromosome (at specific location Xq21.1). The gene is responsible for the regulation of copper in the body; mutations on the gene causes impaired copper absorption in the body, due to disruption in copper transport to different organs of the body
• Copper is an important metal that the body requires. It incorporates into enzymes that play a vital role in body's regulation of iron, ATP production, melanin pigment formation, connective tissue formation, and brain and nervous system function
• Menkes Disease predominantly affects males. Typically, the mother is the “carrier” of the defective gene and does not develop the disorder
• For a female to get the disease, a mutated gene should be present in both the X chromosomes. This would mean that the father should be diagnosed with Menkes Disease and the mother should be a carrier of the condition. The incidence of such a scenario is extremely low

X-linked recessive: X-linked recessive conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on the two X sex chromosomes that a female has or is present on the single X chromosome of a male (the other sex chromosome is a Y chromosome, which carries many genes distinctly different from X chromosomes). All X-linked recessive traits are fully evident in males because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that the female children of an affected male will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that they inherit two mutated copies of the gene, one from each parent, they will inherit the condition.

What are the Signs and Symptoms of Menkes Disease?

The signs and symptoms associated with Menkes Disease may be mild or severe; progressively worsening signs and symptoms are often noted. Infants may appear normal and healthy at birth. The presentations may develop very early during infancy (after 6-8 weeks) or sometimes later into one’s childhood. It can vary from one individual to another. Menkes Disease is a multisystem disorder involving several organs including the skin, brain, heart, lungs, stomach and intestines, urinary bladder, and musculoskeletal systems.

The general signs and symptoms of Menkes Disease may include:

• Fatigue
• Increased irritability in children
• Poor feeding in infants
• Malabsorption
• Nausea and vomiting

Facial abnormalities may include:

• Broad and short skull (brachycephaly)
• Abnormality of the mouth/palate
• Puffy cheeks
• Expressionless face with open mouth and staring eyes (mask-like facies)

Bone, muscle, and joint anomalies may include:

• Increased or decreased muscle tone (hypertonia or hypotonia)
• Bony outgrowths (metaphyseal spurs and exostoses)
• Marked widening of the metaphysis
• Excessive flexibility of the joints
• Bending of the long bones (such as bowed legs)
• Wormian bones (in the cranium)
• Prominent back of the head (prominent occiput)

Skin-related signs and symptoms:

• Thickened skin
• Loose sagging skin (cutis laxa)
• Stretchy skin (hyperextensibility)
• Sparse/thin hair; wooly hair
• Hypopigmented skin and hair
• Dryness of skin
• Scarring of skin
• Spontaneous hematomas

Digestive system and urinary bladder abnormalities that include:

• Abdominal wall abnormalities or underdevelopment
• Inguinal and umbilical hernia
• Bladder wall outpouching (bladder diverticulum)
• Internal gastrointestinal bleeding

Neurological abnormalities may include:

• Seizures
• Behavioral abnormality
• Intellectual disability that may be mild or severe
• Carotid artery anomalies
• Movement disorder (chorea)

Other signs and symptoms may include:

• Narrowing of the arteries
• Malfunctioning venous walls (venous wall insufficiency)

A milder form of Menkes Disease that manifests during early-to-mid-childhood is known as occipital horn syndrome, predominantly a connective tissue disorder.

How is Menkes Disease Diagnosed?

An early diagnosis of Menkes Disease is crucial to start immediate treatment of the condition and improve the overall outcomes. The healthcare provider may suspect the condition based on the presenting signs and symptoms of the child and their family medical history. However, a diagnosis of Menkes Disease is often challenging due to the range of non-specific symptoms manifested in the child. Also, presently, there is no early screening tools available for diagnosing Menkes Disease.

The diagnosis of Menkes Disease may involve the following tests and exams:

• Complete physical examination and family/medical history evaluation (including cognitive disorders)
• Blood tests that may include:
  • Complete blood count (CBC) test
  • Serum ceruloplasmin levels test
  • Serum copper levels test
  • Catecholamine test - it is an effective test for diagnosing Menkes Disease
  • 3,4-Dihydroxyphenylacetic acid (DOPAC) test
• Comprehensive neurometabolic panel tests
• Radiological imaging studies that may include:
  • X-ray of the affected regions such as the chest and joints
  • CT and MRI scan of the affected body region such as the abdomen, head and neck region, etc.
• Prenatal ultrasound scans of the abdomen
• Molecular genetic testing including gene sequencing, as available

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Menkes Disease?

The complications of Menkes Disease may include:

• Severe emotional stress for parents and caregivers
• Prolonged jaundice in the infants
• Severe malnutrition
• Failure to thrive
• Intrauterine growth retardation (IUGR)
• Low blood sugar or hypoglycemia
• Low body temperature (hypothermia)
• Breastbone is sunken into the chest (pectus excavatum) resulting in heart and lung anomalies
• Weak and deformed bones leading to easy and recurrent fractures
• Excess calcium deposition in the joints (called chondrocalcinosis)
• Walking difficulties
• Respiratory distress
• Bleeding inside the brain (Intracranial hemorrhage)
• Infection in the bone (osteomyelitis)
• Sepsis
• Pneumonia, can result in respiratory failure, which can be fatal

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Menkes Disease Treated?

There is no cure available presently for Menkes Disease. A multidisciplinary team of specialists may be involved in the care of the child and may include pediatricians, internists, neurologists, gastroenterologists, geneticists, pulmonologists, urologists, and other medical professionals such as dietitians, occupational therapists, speech pathologists, and social workers.

Typically, symptomatic and supportive treatment is considered for the patient, which may include:

• Administration of copper supplements intravenously or subcutaneously: This is commenced as early as possible (a few days following birth of the child) and helps in prolonging the child’s life
• A specific copper compound has been tested in a phase 2/3 FDA study and has been presented to the FDA. Their approval is pending. In the interim, copper preparations are already in use, off-label, as no other treatment has been FDA- approved at this time
• Surgery may be considered for children with bladder diverticulum and hernias
• Insertion of a gastrostomy tube (G-tube) may be necessary for feeding sufficient nutrition to the child
• Vitamins C and E supplementation
• Use of medications, such as penicillamine (to prevent excess copper buildup in the body) and L-threo-dihydroxyphenylserine or L-DOPS (to address impairment of the dopamine deficiency beta-hydroxylase enzyme)
• Ongoing research therapies includes viral gene therapy - to insert viral genetic material directly into the brain

How can Menkes Disease be Prevented?

Currently, Menkes Disease may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Menkes Disease? (Outcomes/Resolutions)

• The prognosis of Menkes Disease is dependent upon an early diagnosis and immediate effective treatment of the disorder via copper supplements.
• If treatment is started by the first few weeks following childbirth (within 10 days or less), then the outcomes can be improved. Also, it is observed that an early administration of copper can prolong the life of the affected individual (some children may live up to 12-13 years). It is reported that neurological impairment associated with Menkes Disease may be mitigated (seen in 30% of the cases); there are also fewer seizure episodes
• In general, however, many children succumb to Menkes Disease within the first 3 years of life (a majority by the time they reach age 10). Since several body systems are involved and severe symptoms and complications are noted, presently, the prognosis is largely poor

Newer procedures and treatments are being developed to diagnose the condition earlier and provider prompt treatments.

Additional and Relevant Useful Information for Menkes Disease:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/