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Menkes disease (MD) is a usually severe multisystemic disorder of copper metabolism, characterized by progressive neurodegeneration and marked connective tissue anomalies as well as typical sparse abnormal steely hair.
ORPHA:565Classification level: Disorder
- Kinky hair disease
- Kinky hair syndrome
- Menkes syndrome
- Steely hair disease
- Steely hair syndrome
- X-linked copper deficiency
- Prevalence: Unknown
- Inheritance: X-linked recessive
- Age of onset: Neonatal
- ICD-10: E83.0
- OMIM: 309400
- UMLS: C0022716
- MeSH: -
- GARD: 1521
- MedDRA: 10027294
Prevalence data are not available. The birth incidence is 1/300,000 in Europe and 1/360,000 in Japan. In Australia, the birth incidence is reported to be much higher (1/50,000-100,000), which may be due to a founder effect. MD is an X-linked disease primarily affecting males while females are usually unaffected carriers.
Onset occurs in the neonatal period. Most patients are born at term with appropriate birth measurements. Cephalohematomas and spontaneous fractures are occasionally observed at birth. In the early neonatal period, patients may present with prolonged jaundice, hypothermia, hypoglycemia and feeding difficulties. Pectus excavatum and umbilical and inguinal hernias have also been reported. The first sign may be unusual sparse and dull scalp hair at the age of 1-2 months. The characteristic abnormal hair is hypopigmented or depigmented and resembles and feels like steel wool. It is dull and friable, especially in the areas of the scalp subjected to friction. Additional symptoms are failure to thrive, poor eating, vomiting, and diarrhea. An odd appearance, with pale skin, frontal or occipital bossing, micrognathia and pudgy cheeks may be observed. Patients develop gradual motor dysfunction and seizures. Muscular tone is often decreased in early life, but is later replaced by spasticity and weakness of the extremities. The clinical course is usually severe. Variable forms exist with occipital horn syndrome (OHS) being the mildest recognized form (see this term).
MD is caused by mutations in the ATP7A gene (Xq21.1) encoding a copper-transport protein, Cu2+-transporting ATPase-alpha polypeptide. To date, about 200 different mutations in this gene have been reported. There is no obvious correlation between the mutations and the clinical course.
Initial diagnosis is based on clinical features (especially typical hair changes) and supported by demonstration of reduced levels of serum copper and ceruloplasmin. However, in the neonatal period these markers should be interpreted with caution, as their levels are also low in healthy newborns. In this period, plasma catecholamine analysis (ratio of DOPA to dihydroxyphenylglycol), indicative of dopamine beta-hydroxylase deficiency, may be the best rapid diagnostic test. Radiographs show generalized osteoporosis, metaphyseal flaring and spurs in the long bones, diaphyseal periosteal reaction and thickening, and Wormian bones in the cranial sutures. Definitive diagnosis is based on molecular genetic testing.
Differential diagnosis includes Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa, mitochondrial disorders, osteogenesis imperfecta (see these terms) and child abuse.
Due to the large size of the gene and the variety of the mutations observed in different families, detection of the defect in a given family may take time. Therefore in at-risk families it is very important to define the ATP7A mutation in due time and identify heterozygous females prior to possible pregnancy and prenatal diagnosis.
Transmission is X-linked recessive.
Management and treatment
Treatment is mainly symptomatic. Early parenteral copper-histidine supplementation may modify disease progression and some symptoms by providing extra copper to tissue and to copper-dependent enzymes. Oral administration of copper is ineffective as it is trapped in the intestines.
Prognosis is poor and patients usually die in early childhood. However, careful medical care, and possibly copper administration, may extend life span.