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Prevalence at birth is estimated at 1/300,000 and 1/360,000 in Europe and Japan, respectivley. In Australia, the birth prevalence is much higher (1/50,000-100,000), likely due to a founder effect. The disorder is X-linked and thus primarily affects males.

Menkes disease (MD) manifests 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. Unusual sparse and dull scalp hair is often the initial observation at the age of 1-2 months. Characteristically, the hair appears hypopigmented/depigmented, resembles steel wool and is friable, especially in the areas of the scalp subjected to friction. Additional symptoms are failure to thrive, poor eating, vomiting, and diarrhea. The appearance of pale skin, frontal or occipital bossing, micrognathia and pudgy cheeks may be observed. Patients develop gradual motor dysfunction and seizures. Muscular hypotonia in early life is replaced later-on 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, which further presents with prominent bony exostoses and bladder diverticula.

MD is caused by pathogenic variants in ATP7A (Xq21.1) encoding a membrane bound copper-transport protein (Cu2+-transporting ATPase-alpha polypeptide). To date, about 300 different variants in this gene have been reported. There is no obvious correlation between the variants and the clinical course.

Initial diagnosis is based on clinical features (typical hair changes associated with hypotonia and delayed neuromotor development) 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 used as a diagnostic test when the clinical diagnosis suggests MD. Although not specific, other laboratory investigations are useful to complete the clinical work up, these include light microscopy (for hair), radiological imaging (for generalized osteoporosis, metaphyseal flaring and spurs in the long bones, diaphyseal periosteal reaction and thickening, and Wormian bones in the cranial sutures), and arteriography (arterial tortuosity, especially of the intracranial arteries). Definitive diagnosis is based on molecular genetic testing.

Differential diagnosis includes Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa syndromes, mitochondrial disorders, osteogenesis imperfecta and child abuse.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member and the preferred situation is to determine the carrier status of the mother prior to pregnancy and prenatal diagnosis.

Transmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. In rare cases, a female fetus may be affected (manifesting heterozygote) and this possibility should also be considered during genetic counselling. Similarly, germ-line mosaicism has been described and, although probably infrequent, it should also be discussed when counselling non-carrier mothers of singleton cases.

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.