Menkes disease

Overview

Menkes disease, also known as Menkes syndrome or kinky hair disease, is a rare, X-linked recessive neurodegenerative disorder of copper metabolism. It is caused by defective absorption and transport of copper in the body, leading to systemic copper deficiency. This disrupts the function of several copper-dependent enzymes, affecting the brain, connective tissue, hair, blood vessels, and other organs.

The disease is named after pediatric neurologist Dr. John Hans Menkes, who first described the condition in the early 1960s. It primarily affects males and typically presents in infancy with neurological deterioration, failure to thrive, hypotonia, seizures, and characteristic brittle, twisted hair. Without early intervention, the disease progresses rapidly and is usually fatal by early childhood.

Causes

Menkes disease is caused by mutations in the ATP7A gene located on the X chromosome. This gene encodes a copper-transporting ATPase enzyme that is essential for:

• Absorption of dietary copper in the intestines

• Transport of copper to various organs and tissues

In individuals with Menkes disease, the mutated ATP7A gene results in impaired copper transport from the intestinal lining into the bloodstream. This leads to systemic copper deficiency despite normal or elevated copper levels in the intestines. As a result, copper-dependent enzymes such as cytochrome c oxidase, lysyl oxidase, dopamine β-hydroxylase, and superoxide dismutase are unable to function properly.

Because the condition is X-linked recessive, it primarily affects males. Females can be carriers and may have mild or no symptoms due to random X-chromosome inactivation.

Symptoms

Symptoms of Menkes disease usually begin within the first 2 to 3 months of life. The clinical manifestations are multisystemic and result from copper deficiency in the central nervous system, skin, hair, and connective tissue.

Neurological Symptoms

• Progressive neurodegeneration

• Seizures (often difficult to control)

• Hypotonia (low muscle tone)

• Developmental delay or loss of milestones

• Irritability and poor feeding

• Hypothermia (low body temperature)

Hair and Skin Features

• Scalp hair that is sparse, brittle, and colorless or lightly pigmented

• Pili torti: Twisted, kinky, or corkscrew-like hair visible under a microscope

• Loose skin (cutis laxa), especially on the face and trunk

Facial and Skeletal Features

• Elfin or cherubic facial appearance

• Frontal bossing (prominent forehead)

• High-arched palate and wide-set eyes (hypertelorism)

• Micrognathia (small chin)

• Delayed bone age and metaphyseal widening

Vascular and Connective Tissue Complications

• Tortuosity and elongation of cerebral blood vessels (visible on imaging)

• Subdural hematomas or hemorrhages (due to vessel fragility)

• Bladder diverticula and hernias (due to weak connective tissue)

Other Symptoms

• Failure to thrive and poor weight gain

• Recurrent infections

• Gastrointestinal problems such as vomiting and diarrhea

Diagnosis

Early diagnosis of Menkes disease is critical for initiating timely treatment. Diagnosis is based on clinical presentation, biochemical tests, imaging, hair analysis, and genetic testing.

1. Clinical Examination

• Observation of characteristic hair and facial features

• Neurological signs such as hypotonia and seizures

2. Laboratory Tests

• Low serum copper and ceruloplasmin levels: Despite copper accumulation in the intestines

3. Hair Microscopy

• Reveals twisted, kinky hair (pili torti)

4. Neuroimaging (MRI)

• Shows brain atrophy, subdural hematomas, and vascular tortuosity

5. Genetic Testing

• Confirms mutations in the ATP7A gene

• Also used for carrier testing and prenatal diagnosis in at-risk families

Treatment

There is no cure for Menkes disease, but early treatment can slow disease progression and improve outcomes in some patients. Treatment primarily involves parenteral copper supplementation and supportive care.

1. Copper Histidinate Injections

• Subcutaneous or intravenous copper histidinate (Cu-His) is the most effective form of copper supplementation

• Most beneficial if started within the first few weeks of life, ideally before the onset of neurological symptoms

• Less effective in advanced cases where brain damage has already occurred

2. Symptomatic and Supportive Care

• Anticonvulsants for seizure management

• Physical and occupational therapy for motor development

• Feeding support, including gastrostomy if needed

• Management of bladder and gastrointestinal complications

3. Genetic Counseling

• Essential for families with a history of Menkes disease

• Prenatal genetic testing and carrier screening can help in family planning

Prognosis

The prognosis for Menkes disease is generally poor, especially if not treated in the early neonatal period. Most affected males do not survive beyond the age of 3 to 5 years. Key prognostic factors include:

• Age at diagnosis: Earlier diagnosis and treatment are associated with better neurological outcomes

• Severity of mutations: Some mutations may result in milder or variant forms of the disease (e.g., Occipital Horn Syndrome)

• Response to copper therapy: Only a subset of patients benefit significantly, particularly those with residual ATP7A function

While ongoing research continues to explore gene therapy and novel treatments, current management remains primarily supportive. With early intervention, some children with milder variants may live longer with improved quality of life.