Menkes Disease
Definition/Description
Menkes disease (MD), also known as Menkes syndrome, Steely hair disease, and Copper transport disease is a disorder that affects copper levels in the body. It is characterized by sparse, kinky hair; failure to thrive, and progressive deterioration of the nervous system (De Bie et al., 2007). There are multiple clinical versions of MD: classical MD (90-95% of patients), mild MD, occipital horn syndrome (OHS), and a new syndrome characterized by isolated distal motor neuropathy, no signs of copper deficiency, and adult onset (León-García et al., 2012). The diagnosis of Menkes disease is confirmed by genetic testing showing a mutation on the ATP7A gene. This specific gene is expressed throughout the body (besides liver cells) and provides instruction for making a protein that is crucial to regulating copper levels in the body. Copper is necessary for cellular functions, but is considered toxic in excessive amounts. Menkes disease is a copper deficiency, while a similar disorder, Wilson disease, is a copper overload. Because MD is an X-linked recessive disorder, males are more commonly affected than females. It is estimated that roughly 1 in 100,000 newborns have Menkes disease (Smpokou et al., 2015). The life expectancy of individuals with this disease is ten years—if detected and treated early. Most individuals die around age 3.
History of the Disease
Menkes disease was first described by John Hans Menkes in 1962. Menkes reported the clinical and biochemical phenotype underlying this X-linked recessive disorder of growth retardation, neurodegeneration, and peculiar hair. The discovery relied heavily on the correlation of the unusual hair of affected infants to the texture of the brittle wool of sheep raised on copper-deficient soil in Australia (Kaler, 2014). In one specific case, Menkes and colleagues had described five male infants of an Irish American family with the classic Menkes disease phenotypes. The infants appeared normal at birth and during the first few months after birth, but had thereafter experienced seizures and developmental regression. The infants died between the ages of seven months and three-and-a-half years. At the time, both the copper transport protein and its role in mammalian copper metabolism were unknown. Menkes attended Johns Hopkins University in Baltimore, Maryland, and eventually returned as faculty as the head of Pediatric Neurology. Menkes worked with David Danks, an Australian physician who had come to work with medical geneticist Victor McKusick between October of 1961 and June of 1962. It was not until ten years later that Danks made the initial connection between Menkes disease and copper deficiency. In light of further research, cloning of the gene responsible for this condition and the allelic disorder, occipital horn syndrome (OHS), was achieved in 1993, revealing the importance of ATP7A, a highly conserved ion-motive ATPase (Kaler, 2014).
Signs and Symptoms
The typical clinical features of classic Menkes disease comprise neurological defects (severe mental retardation, neurodegeneration, seizures), growth retardation, hypothermia, laxity of skin and joints, hypopigmentation, and peculiar “kinky” or “steely” hair (de Bie et al., 2007). Preterm or term delivered babies commonly exhibit hypothermia, hypoglycemia, and jaundice in the perinatal period (Kaler, 2014). Babies that survive past birth express a development of progressive hypotonia, loss of previously obtained developmental milestones, seizures, myoclonic jerks, failure to thrive, poor weight gain, loose skin, pectus excavatum, urinary bladder diverticula, and short, sparse, wiry hair. These symptoms begin to appear by four-five months of age. On radiographs, long bones exhibit osteoporosis, metaphyseal spurring, periosteal reaction, and scalloping of the posterior aspects of vertebral bodies. Brain matter atrophy greatly affects the cerebellum. Subdural hemorrhages of different stages and sizes are commonly seen (Gandhi et al., 2012). Death usually occurs by age three due to respiratory failure. Patients with mild MD, however, have less significant defects and tend to have a longer lifespan.
Menkes disease is similar to other diseases such as Leigh’s disease, shaken baby syndrome, and phenylketonuria (PKU). The differentiation comes from the low concentrations of copper and ceruloplasmin, which are only typical of Menkes. Ceruloplasmin is a protein made by the liver that carries the mineral copper around the body (Ramos et al., 2016). When there is a decrease in the concentration of this crucial protein, the body cannot develop and function properly, ultimately resulting in Menkes disease.
Diagnosis, Treatment, and Management
While treatment is not fully effective in every case, early diagnosis is essential. The documentation of low serum copper and ceruloplasmin concentrations in patients with MD recreated interest in the disorder, which had been defined ten years earlier. Diagnosis is confirmed by finding low levels of serum copper and ceruloplasmin with increased copper uptake in cultured fibroblasts. Carrier status can usually be determined by examination of multiple hairs from scattered scalp sites for pili torti. Pili torti is a rare hair condition characterized by fragile hair. Hair appears to have a flattened shaft with clusters of narrow twists at irregular intervals (“Pili torti,” 2015). Intravenous copper and copper histidine therapy has been tried, but not yet proven fully effective. There are currently four issues with therapy that should be taken into consideration. In order to perform this treatment option, the block in intestinal absorption of copper must be bypassed. Likewise with detection, patients must be identified and treatment must be started in life as early as possible. The circulating copper must be delivered to the brain and must be available within cells for cuproenzyme biosynthesis (de Bie et al., 2007). The only currently available treatment option consists of administration of copper-histidine, a naturally occurring copper-amino acid complex in serum. Although copper replacement therapy with copper histidine results in significant improvement in some patients, leading to an increased lifespan by a few years, it has not been uniformly beneficial and the prognosis of patients with classic Menkes disease remains inevitably poor (de Bie et. al, 2007).
Inheritance
The inheritance of Menkes disease follows an X-linked recessive pattern, as shown in Figure 1. This pattern is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are hemizygous for the gene mutation because they have one X and one Y chromosome) and in females who are homozygous for the gene mutation. There are several hallmarks of an X-linked recessive mode of inheritance, and they are as follows: An affected male must have a mother who is either affected or a carrier. Often affected males will be born to two unaffected parents. An affected female must have an affected father and a mother who is either affected or a carrier. For females, one dominant (normal) allele is enough to mask the mutation. Males have a greater chance of inheriting the mutant allele since only one mutant X chromosome is enough to cause the mutant phenotype. In about one-third of cases, Menkes disease is caused by new mutations in the ATP7A gene; these are also referred to as de novo mutations (de Bie et al., 2007). People with a new mutation do not have a history of the disease in their family.