Cecilia Mellado and Mustafa Sahin
ATP7A-RELATED COPPER TRANSPORT DISORDERS (MENKES DISEASE AND OCCIPITAL HORN SYNDROME)
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.3The 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 copper and ceruloplasmin after 2 to 3 weeks of age, when these levels normally rise. Brain MRI shows severe cerebral and cerebellar atrophy with tortuous vessels seen on the magnetic resonance angiography. Subdural hematomas may form following the severe atrophy. Copper-transport studies in cultured fibroblasts show impaired cellular copper exodus, and plasma and cerebral spinal fluid catecholamine analysis shows abnormal catechol concentrations at all ages. Molecular testing for MD and OHS is clinically available, and it is useful as confirmatory diagnostic testing, for carrier testing, or in prenatal diagnosis. The ATP7A gene is the only gene known to be associated with these disorders. The molecular test detects more than 95% of affected individuals.
Management for MD/OHS includes periodic developmental, feeding, nutrition and bladder function evaluations; gastrostomy to manage caloric intake; surgery for bladder diverticula; and developmental intervention. Specific treatment for classic MD patients to correct the copper deficiency has been attempted with early copper-histidine or copper chloride subcutaneous injections. This treatment may improve the outcome of MD if begun before 10 days of age.4 However, unfortunately, no newborn screening is available, and presymptomatic detection is difficult.
ACERULOPLASMINEMIA
Aceruloplasminemia is a disorder of iron metabolism, characterized by iron accumulation in the brain and in the visceral organs associated with undetectable levels of ceruloplasmin. It is a rare autosomal recessive disease described for first time in 1987. It has been reported mainly in Japanese patients, but it has been described in other populations as well; its overall prevalence is unknown.
Aceruloplasminemia is caused by mutations in the CP gene, located at chromosome 3q21–24.5 The CP gene encodes the ceruloplasmin protein, a copper oxidase that carries more than 95% of the plasma copper, and it is also known as ferroxidase and Fe(II) oxygen oxidoreductase. Ceruloplasmin is essential in iron hemostasis, catalyzing the oxidation of ferrous to ferric iron, a change required for the release of iron to plasma transferrin. Ceruloplasmin has two forms: (1) the plasma α-2-glycoprotein form, mainly synthesized in hepatocytes and widely expressed, but unable to enter the brain, and (2) the glycosylphosphatidylinositol–anchored form, generated by a brain-specific alternative splicing expressed mainly in astrocytes but also in visceral organs. Mutations in the CP gene lead to an unstable or nonfunctional ceruloplasmin protein or to retention of ceruloplasmin at the endoplasmic reticulum. As a consequence of absence of ceruloplasmin, cells are unable to oxidize and excrete iron to the extracellular space to be bound by transferrin, and iron accumulates in hepatocytes, astrocytes, retinal neurons, and pancreas, among other sites.
Clinically, aceruloplasminemia is characterized by the triad of diabetes, neurologic disease, and retinal degeneration. This disease usually begins in adults. One of the first manifestations is diabetes mellitus due to the pancreas involvement. Progressive neurologic manifestations consist of ataxia, cognitive dysfunction, dementia, and a complex of extrapyramidal signs including blepharospasm, dystonia, rigidity, tremor, and chorea. Iron accumulation in the retina can cause visual loss. Affected individuals often have a mild to moderate degree of anemia with iron deficiency and elevated serum ferritin.6
Differential diagnosis should be made with other diseases with low serum ceruloplasmin concentrations, such as Wilson disease and Menkes disease, which are disorders of copper metabolism. Wilson disease is characterized by the inability to transfer copper into the ceruloplasmin precursor protein, apoceruloplasmin, resulting in a decreased biliary copper excretion, serum ceruloplasmin deficiency, and excess copper accumulation. In Menkes disease there is a decreased copper absorption from the intestine, resulting in copper and ceruloplasmin deficiencies.
Aceruloplasminemia is suspected in individuals with the characteristic triad, and the diagnosis relies on the demonstration of the absence of serum ceruloplasmin and some combination of low serum copper, low serum iron, high serum ferritin, and high hepatic iron concentrations. There is nondetectable plasma ceruloplasmin ferroxidase activity. The diagnosis is supported by characteristic MRI findings at T1- and T2-weighted images that show abnormal low intensities in liver and in the striatum, thalamus, and dentate nucleus in the brain, reflecting iron accumulation (eFig. 573.1 ).6 Molecular testing of the CPgene is available on a research basis only.
The management in symptomatic individuals with hemoglobin concentrations higher than 9 g/dL can be done with chelating agents such as desferrioxamine. This treatment can decrease serum ferritin concentration, and brain and liver iron deposits, and can prevent neurologic progression. However, the use of desferrioxamine in combination with fresh-frozen plasma has demonstrated a better outcome, with persistent increase of serum iron concentration, a bigger decrease in liver iron concentration, and can improve the neurologic symptoms. Vitamin E and zinc, along with chelator agents, can prevent tissue damage. Periodically, tests looking for diabetes mellitus are recommended in individuals at risk.
PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION (HALLERVORDEN-SPATZ DISEASE)
Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz disease (HSD), is a disorder of iron metabolism and consists of neurodegeneration with brain iron accumulation. It is a rare autosomal recessive disorder; the estimated prevalence in the general population is around 1 to 3 in 1,000,000.
PKAN is caused by mutations in the PANK2 gene,7 which is the only gene currently known to be associated with this disorder. The PANK2 gene is located at chromosome 20p13 and encodes the protein pantothenate kinase 2. The deficiency of this protein is hypothesized to cause accumulation of N-pantothenol-cysteine and pantetheine, leading to cell toxicity directly or via free radical damage as chelators of iron, and also results in coenzyme A depletion and defective membrane biosynthesis. Until now, there has been no clear genotype-phenotype correlation; however, individuals with mutations predicted to have no protein have classic PKAN8 Mutations in PANK2 have been reported in families with HARP syndrome (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration), which now is considered part of the PKAN spectrum.
The pathologic findings in PKAN include deposition of iron within astrocytes, microglia, and neurons, which is specific to the globus pallidus and the pars reticulata of the substantia nigra. Focal swelling within axons that are called spheroids is also seen and are not limited just to the areas with iron accumulation. No systemic or global brain increase of iron is seen.
FIGURE 573-1. “Eye-of-the-tiger” sign (arrows). MRI T2-weighted images showing high signal intensity in the globus pallidus with hypointensity at the periphery. (Hayflick SJ, Hartman M, Coryell J, Gitschier J, Rowley H. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol. 2006;27(6):1230-1233.)
Clinically, PKAN has been classified in 2 forms: the classic form and the atypical form. In the classic form, the onset is usually before age 10 years; the patients present with a rapidly progressive disease with loss of ambulation, often occurring 10 or 15 years after the onset of the disease. The atypical form presents onset during the second decade of life, the progression is slow, and the loss of ambulation is after 15 years of onset.
Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by extrapyramidal dysfunction, with dystonia, rigidity, or choreoathetosis.8 Other neurologic findings are spasticity and extensor toe signs, suggesting corticospinal tract dysfunction. In classic PKAN, 75% of patients develop pigmentary retinopathy that includes flecked retina, bone spicule formation, conspicuous choroidal vasculature, and bull’s-eye annular maculopathy. In atypical PKAN, ocular anomalies are rare, but these patients may have sub-clinical retinal changes. Mental deterioration indicative of dementia, epilepsy, and acanthocytosis occur in some of these patients. The course is relentless and progressive, extending over several years; death usually occurs in early adulthood.
Differential diagnosis includes other neurodegenerative syndromes with brain iron accumulation, such as infantile neuroaxonal dystrophy associated with mutations in the PLA2G6 gene, neuroferritinopathy associated with mutations in the FTL gene, and aceruloplasminemia associated with mutations in the gene encoding ceruloplasmin. Other disorders to consider are α-fucosidosis, X-linked mental retardation with Dandy Walker malformation, early-onset Parkinson disease, some childhood-onset ataxias and dystonias, among others.
The diagnosis of PKAN often arises in individuals with the suspected clinical features and with characteristic MRI findings. MRI shows iron deposits associated with decreased intensity of the T2-weighted image and a central region of hyperintensity within the globus pallidus that has been called as the “eye of the tiger” sign. This sign is present in all individuals with PANK2 mutations (Fig. 573-1).9 Brain MRI is one of the most helpful tests in determining the diagnosis of PKAN, and it is standard in the evaluation of these patients. Molecular testing is available clinically, and it is useful as a confirmatory diagnostic testing, as a carrier testing or in prenatal diagnosis. Mutations in PANK2 are detected in more than 99% of individuals with PKAN and the “eye of tiger” sign on MRI, and in 50% of individuals with clinical diagnosis of PKAN. Duplications and deletions have been reported in around 3% to 5 % of patients.
The management consists of periodic evaluations by neurology; ophthalmology; physical, occupational, and speech therapy; and developmental assessment. Treatment of manifestations is focused on palliation of symptoms; extrapyramidal movements with oral trihexyphenidyl may be helpful. Treatment for dystonia has been attempted with baclofen, including intrathecal baclofen infusions, intramuscular botulinum toxin, ablative pallidotomy or thalamotomy, and deep brain stimulation. Individuals with some residual enzyme activity have been reported to have improvement in their symptoms while using high doses of pantothenate; however, the efficacy of pantothenate is currently unknown. Docosahexanoic acid may have a role in preventing retinal degeneration, but as yet no studies have been performed. Treatment with chelating agents such as desferrioxamine has not proved effective in reducing the iron load or improving the clinical symptoms.