Menkes disease (MD) and occipital horn syndrome (OHS) are X-linked
recessive disorders that affect young infants. They are caused by
a defect in copper transportation across the intestinal mucosa,
resulting in a copper deficiency and dysfunction of copper-dependent
enzymes. The incidence is estimated at 1 in 50,000 to 1 in 250,000
live births; one third of cases result from new mutations. MD usually
affects males; however, a few affected females with unfavorable
X-lyonization or X chromosome anomalies have been reported.
The genetic defect of MD and OHS is related to ATP7A gene
mutations.1 This gene mapped to Xq13.3 and encodes
for a P1B-type ATPase, a ubiquitously expressed protein
that transports copper across cellular membranes and is critical
for copper homeostasis. This protein serves to incorporate copper
into copper-dependent enzymes and to remove the excess of copper
from the cytosol maintaining the intracellular copper levels. Defects
in this P-type ATPase lead to a reduced transport of copper from
the intestine into the circulation and central nervous system and
to a reduced transport of copper into the Golgi apparatus for incorporation
into various copper-dependent enzymes.2 The result
is a systemic copper deficiency and a reduced activity of various
copper-dependent enzymes, which finally account for the characteristic
features of the disease. Deficiencies of enzymes such as cytochrome c-oxidase,
superoxide dismutase, and lysyl oxidase may explain the severe neurologic
deterioration. Other enzymes implicated are: tyrosinase for the
hypopigmentation, lysyl oxidase for defects in connective tissue,
ascorbate oxidase for the osteoporosis, dopamine β-hydroxylase
for faulty catecholamine production, and sulfhydryl oxidase for
the steely hair.
The ATP7A gene is very similar to the gene responsible
for Wilson disease, the ATP7B gene, which encodes
for another copper-transporting protein. The differential expression
of these 2 genes explains the difference in the clinical phenotype.
The ATP7A gene is expressed in the intestinal mucosa
and other tissues but not liver, whereas the ATP7B gene
is expressed in liver and brain.
In classic Menkes disease,2 the neurologic features
may begin in utero or shortly after birth (6 to
10 weeks of age) and consist of developmental regression, seizures,
retinal degeneration, and later spasticity. Systemic features consist
of failure to thrive; hypothermia; osteoporosis; bladder diverticula; sparse,
thin hair that is twisted at the shaft (pili torti) and often lightly
pigmented (white, silver, or gray); lax skin; tortuous and elongated
arterial vessels; distinctive facial features; pectus excavatum;
and hernias. Death by 3 years of age is typical.
Occipital horn syndrome (OHS), an allelic
variant of Menkes disease (MD), has only minimal neurologic features
consisting of mild developmental delay and autonomic instability.3 The
systemic features consist of inguinal hernias, bladder diverticula,
lax skin and joints, vascular tortuosity and a characteristic calcified
occipital horn in the skull.
Differential diagnosis includes infantile-onset neurodegenerative
disorders such as biotinidase deficiency, organic acidurias, aminoacidurias, and
mitochondrial myopathies. Diagnostic confirmation consists of finding
a low serum ...