Search

This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.

Background: Menkes disease is a disorder of copper transportation that results in multi-systems involvement including neurological deterioration, seizure, dysmorphic facies and kinky hair. The authors report a case of Menkes disease that was complicated with bilateral iliac artery aneurysms., Case Report: A 6-month-old Thai male infant presented with seizure, global delayed development, hypotonia and sparse, short, lightly pigmented and kinky hair. Light microscopic hair analysis showed pili torti. His serum copper and ceruloplasmin levels were low and were compatible with Menkes disease. Radiological finding from magnetic resonance angiography (MRA) revealed irregular tortuosity of abdominal aorta, a large right internal iliac artery aneurysm and a small left common iliac artery aneurysm. Genetic counseling and supportive treatment were provided for this patient., Conclusion: Iliac aneurysms are a serious complication of patients with Menkes disease. Careful investigation with computed tomographic angiography (CTA) or MRA is helpful in those patients.

Mutations in ATP7A lead to at least three allelic disorders: Menkes disease (MD), Occipital horn syndrome and X-linked distal motor neuropathy. These disorders are mainly seen in male individuals, but a few affected females have been described. More than 400 different mutations have been identified in the ATP7A gene. We have conducted several studies in the hope of uncovering the relationship between genotype and phenotype. We have examined the X-inactivation pattern in affected females, the effect of exon-deletions and--duplications, and splice-site mutations on the composition and amount of ATP7A transcript, and we have examined the structural location of missense mutations. The X-inactivation pattern did not fully explain the manifestation of MD in a small fraction of carriers. Most of the affected females had preferential inactivation of the X-chromosome with the normal ATP7A gene, but a few individuals exhibited preferential inactivation of the X-chromosome with the mutated ATP7A gene. The observed mild phenotype in some patients with mutations that effect the composition of the ATP7A transcript, seems to be explained by the presence of a small amount of normal ATP7A transcript. The location of missense mutations on structural models of the ATP7A protein suggests that affected conserved residues generally lead to a severe phenotype. The ATP7A protein traffics within the cells. At low copper levels, ATP7A locates to the Trans-Golgi Network (TGN) to load cuproenzymes with copper, whereas at higher concentrations, ATP7A shifts to the post-Golgi compartments or to the plasma membrane to export copper out of the cell. Impaired copper-regulation trafficking has been observed for ATP7A mutants, but its impact on the clinical outcome is not clear. The major problem in patients with MD seems to be insufficient amounts of copper in the brain. In fact, prenatal treatment of mottled mice as a model for human MD with a combination of chelator and copper, produces a slight increase in copper levels in the brain which perhaps leads to longer survival and more active behavior. In conclusion, small amounts of copper at the right location seem to relieve the symptoms., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Menkes disease is a lethal X-linked recessive disorder of copper metabolism caused by mutations in ATP7A, a copper-transporting ATPase with diverse and important biological functions. Partial deficiency of dopamine-beta-hydroxylase is a biochemical hallmark of this illness due to the normal role of ATP7A in delivery of copper as an enzymatic cofactor. We exploited this fact to develop a diagnostic test for Menkes disease, which proved highly sensitive and specific. The assay has enabled early identification of affected patients, leading to enhanced survival and improved neurodevelopment after early copper treatment, including some completely normal outcomes. In preclinical efforts to develop improved therapies for patients with non-copper-responsive ATP7A mutations, we used brain-directed adeno-associated viral gene therapy to rescue a murine model of the disease. Statistically significant improvement in brain catechol ratios correlated with enhanced survival, and cerebrospinal fluid catechols represent candidate surrogate markers of treatment effect in a future gene therapy clinical trial., (© 2013 Elsevier Inc. All rights reserved.)

Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.

Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-β-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease.

Genetic disorders of copper metabolism, including Menkes kinky hair disease (MD), occipital horn syndrome (OHS) and Wilson's disease (WD) are reviewed with a focus on the neurological aspects. MD and OHS are X-linked recessive disorders characterized by a copper deficiency. Typical features of MD, such as neurologic disturbances, connective tissue disorders and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care for treatment of MD is parenteral administration of copper-histidine. When the treatment is initiated in newborn babies, neurologic degeneration can be prevented, but delayed treatment is considerably less effective. Moreover, copper-histidine treatment does not improve connective tissue disorders. Novel treatments targeting neurologic and connective tissue disorders need to be developed. OHS is the mildest form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. Although the hepatic and nervous systems are typically most severely affected, initial symptoms are variable, making an early diagnosis difficult. Because early treatments are often critical, especially in patients with neurologic disorders, medical education efforts for an early diagnosis should target primary care physicians. Chelating agents and zinc are effective for the treatment of WD, but neurologic symptoms become temporarily worse just after treatment with chelating agents. Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower than rates of neurologic worsening when treating with other chelating agents., (Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.

Epilepsy is a major feature of Menkes disease, an X-linked recessive infantile neurodegenerative disorder caused by mutations in ATP7A, which produces a copper-transporting ATPase. Three prior surveys indicated clinical seizures and electroencephalographic (EEG) abnormalities in a combined 27 of 29 (93%) symptomatic Menkes disease patients diagnosed at 2 months of age or older. To assess the influence of earlier, presymptomatic diagnosis and treatment on seizure semiology and brain electrical activity, we evaluated 71 EEGs in 24 Menkes disease patients who were diagnosed and treated with copper injections in early infancy (≤6 weeks of age), and whose ATP7A mutations we determined. Clinical seizures were observed in only 12.5% (3/24) of these patients, although 46% (11/24) had at least one abnormal EEG tracing, including 50% of patients with large deletions in ATP7A, 50% of those with small deletions, 60% of those with nonsense mutations, and 57% of those with canonical splice junction mutations. In contrast, five patients with mutations shown to retain partial function, either via some correct RNA splicing or residual copper transport capacity, had neither clinical seizures nor EEG abnormalities. Our findings suggest that early diagnosis and treatment improve brain electrical activity and decrease seizure occurrence in classical Menkes disease irrespective of the precise molecular defect. Subjects with ATP7A mutations that retain some function seem particularly well protected by early intervention against the possibility of epilepsy.

Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms.

Protein translation ends when a stop codon in a gene's messenger RNA transcript enters the ribosomal A site. Mutations that create premature stop codons (nonsense mutations) typically cause premature translation termination. An alternative outcome, read-through translation (or nonsense suppression), is well known in prokaryotic, viral, and yeast genes but has not been clearly documented in humans except in the context of pharmacological manipulations. Here, we identify and characterize native read-through of a nonsense mutation (R201X) in the human copper transport gene, ATP7A. Western blotting, in vitro expression analyses, immunohistochemistry, and yeast complementation assays using cultured fibroblasts from a classic Menkes disease patient all indicated small amounts of native ATP7A(R201X) read-through and were associated with a dramatic clinical response to early copper treatment.

Menkes disease is a fatal neurodegenerative disorder of infancy caused by defects in an X-linked copper transport gene, ATP7A. Evidence from a recent clinical trial indicates that favorable response to early treatment of this disorder with copper injections involves mutations that retain some copper transport capacity. In three unrelated infants, we identified the same mutation, G727R, in the second transmembrane segment of ATP7A that complemented a Saccharomyces cerevisiae copper transport mutant, consistent with partial copper transport activity. Quantitative reverse transcription-polymerase chain reaction studies showed approximately normal levels of ATP7A(G727R) transcript in two patients' fibroblasts compared to wild-type controls, but Western blot analyses showed markedly reduced quantities of ATP7A, suggesting post-translational degradation. We confirmed the latter by comparing degradation rates of mutant and wild-type ATP7A via cyclohexamide treatment of cultured fibroblasts; half-life of the G727R mutant was 2.9h and for the wild-type, 11.4h. We also documented a X-box binding protein 1 splice variant in G727R cells-known to be associated with the cellular misfolded protein response. Patient A, diagnosed 6 months of age, began treatment at 228days (7.6 months) of age. At his current age (2.5 years), his overall neurodevelopment remains at a 2- to 4-month level. In contrast, patient B and patient C were diagnosed in the neonatal period, began treatment within 25 days of age, and show near normal neurodevelopment at their current ages, 3years (patient B), and 7 months (patient C). The poor clinical outcome in patient A with the same missense mutation as patient A and patient B with near normal oucomes, confirms the importance of early medical intervention in Menkes disease and highlights the critical potential benefit of newborn screening for this disorder.

Although the molecular basis of many inherited metabolic diseases has been defined, the availability of effective therapies in such disorders remains problematic. Menkes disease is a fatal neurodegenerative disorder due to loss-of-function mutations in the ATP7A gene encoding a copper-transporting P-type Atpase. To develop therapeutic approaches in affected patients, we have identified a zebrafish model of Menkes disease termed calamity that results from splicing defects in the zebrafish orthologue of the ATP7A gene. Embryonic-recessive lethal mutants have impaired copper homeostasis that results in absent melanin pigmentation, impaired notochord formation, and hindbrain neurodegeneration. In this current study, we have attempted to rescue these striking phenotypic alterations by using a series of antisense morpholino oligonucleotides directed against the splice-site junctions of two mutant calamity alleles. Our findings reveal a robust and complete correction of the copper-deficient defects of calamity in association with the generation of the WT Menkes protein in all rescued mutants. Interestingly, a quantitative analysis of atp7a-specific transcripts suggests that competitive translational regulation may account for the synthesis of WT protein in these embryos. This in vivo correction of Menkes disease through the rescue of aberrant splicing may provide therapeutic options in this fatal disease and illustrates the potential for zebrafish models of human genetic disease in the development of treatments based on the principles of interactions of synthetic oligonucleotide analogues with mRNA.

Menkes' disease is a rare X-linked multisystemic lethal disorder of copper transport metabolism. Failure of synthesis of several copper enzymes explains most of the clinical features, which were characterised by neurodegenerative symptoms and connective tissue manifestations. Most cases are still prone to rapidly progressive cerebral degeneration and early death in the first few years. Since CNS-dysfunction usually preceeds development of the pathognomonic "steely" hair, delay of clinical diagnosis and onset of therapeutic intervention precludes longlasting neurological benefit. This is particularly true for patients with large deletions or severe truncations of the responsible ATP7A gene. We report on our own experience with a patient, who was diagnosed to be affected by Menkes' syndrome at the age of one year, due to the specific hair texture and biochemical abnormalities. Molecular investigation revealed a total deletion of exon 15 of the ATP7A gene. Heterozygosity was confirmed by means of real-time PCR in the child's mother, but could be excluded in the grandmother and other female relatives at risk. Therapeutic support with subcutaneous injection of copper-histidinate normalised diminished copper and coeruloplasmin serum levels, but was unable to influence the clinical course and to prevent the fatal outcome at the age of two years. This observation is in line with the experience of the literature claiming that currently available medication will hardly be able to normalise brain copper levels. However, observations of clinical variants of Menkes' disease with quite a different outcome and, more importantly, emerging of alternative copper transport pathways might still justify this time-limited therapeutic intervention.

The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinical manifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seen in the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult disorders in the context of a developing country.

The isolation and the X-ray crystal structure of physiological copper(II)-L-histidine complex are reported. The neutral five-coordinate complex shows distorted square pyramidal geometry with bidentate and tridentate L-histidine ligands. The basic character of the pendent imidazole group and H-bonding interactions of bidentate L-histidine ligand are important for copper transport. The unique structural features help explain the origin of its thermodynamic stability and kinetic reactivity in human blood along with the ternary copper(II)-amino acid complexes. The role of L-histidine in interaction with copper(II)-albumin, in cellular uptake of copper, and in treatment of Menkes disease can be studied using these results.

The clinical manifestations of classical Menkes disease, mild Menkes disease and occipital horn syndrome are reviewed. Menkes disease is a neurodegenerative disease with X-linked recessive inheritance. Orally administered copper accumulates in the intestine, resulting in the failure of copper absorption. The primary metabolic defect that causes copper accumulation in the intestine is present in almost all extrahepatic tissues. The blood, liver and brain are in a state of copper deficiency, which is due to defective copper absorption. The characteristic features, including neurological disturbances, arterial degeneration and hair abnormalities, can be explained by the decrease in cuproenzyme activities. DNA-based diagnosis is now possible. Mild Menkes disease and occipital horn syndrome, which show milder forms than Menkes disease, have been identified as genetic disorders resulting from mutations in the Menkes disease gene. Because the clinical spectrum of Menkes disease is wide, males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport. The treatment accepted currently is parenteral administration of copper. When treatment is started in patients with classical Menkes disease above the age of 2 months, it does not improve the neurological degeneration. When the treatment is initiated in newborn babies affected with this disease, the neurological degeneration can be prevented in some, but not all, cases. Moreover, early treatment cannot improve non-neurological problems, such as connective tissue laxity. Therefore, alternative therapies for Menkes disease and occipital horn syndrome should be studied.

The molecular genetics and pathophysiology of Menkes disease and an animal model for this disease are reviewed. The Menkes gene, located on chromosome X13.3, encodes a copper-transporting ATPase, as shown by the sequencing of a cDNA of 4500 bp. Mutations in the Menkes gene in patients with Menkes disease show great variety, including missense, nonsense, deletion and insertion mutations. Mutations in the Menkes gene have also been identified in patients with mild Menkes disease or occipital horn syndrome, showing that these diseases are allelic variants of Menkes disease. Mutations in the mottled gene, the murine homolog of the Menkes gene, have been demonstrated in mottled mutant mice that display biochemical and phenotypic abnormalities similar to those observed in patients with Menkes disease. In affected cells, copper significantly accumulates as metallothionein-bound copper in the cytosol and copper transport to the organelles, as well as copper efflux, is disturbed. As a result, cuproenzymes cannot receive the copper necessary for their normal function. Thus, the objective in treatment of Menkes disease and occipital horn syndrome is to deliver copper to the intracellular compartments where cuproenzymes are synthesized.

Copper is an essential component of a number of important enzymes. Efficient systems have developed for providing sufficient copper for essential functions, while eliminating excess to avoid tissue toxicity. Copper transport is disrupted in two human diseases: Wilson disease and Menkes disease. Both have defects in copper transporting membrane proteins. Many other proteins are involved in copper transport. Some of these proteins have been identified through a study of the similar copper pathway in yeast. This suggests other copper transport diseases are yet to be discovered. Molecular diagnosis holds promise for reliable diagnosis of patients. Testing of flanking markers is a reliable way to detect presymptomatic sibs of a definite patient.

In the 25 y since copper deficiency was first delineated in persons with Menkes syndrome, advances in our understanding of the clinical, biochemical, and molecular aspects of this rare disorder have surpassed progress in the design of effective therapies. In contrast with purely nutritional copper deficiency, in which copper replacement can be curative, the nature of the basic defect in Menkes syndrome suggests that corrective efforts are likely to be more complicated, a point supported by the cumulative literature on this topic as well as by emerging molecular data. In this paper, certain clinical, biochemical, and molecular aspects of copper histidine treatment in 25 Menkes syndrome patients at the National Institutes of Health are reviewed. The delineation of a distinctive neurochemical pattern in plasma and cerebrospinal fluid, reflecting deficiency of the copper enzyme dopamine beta-monooxygenase, is arguably the most important finding in the study of Menkes syndrome. This abnormal pattern has proven extremely reliable as a rapid diagnostic test, enabling early identification of affected infants--a fundamental requirement for improving clinical outcomes. Of 11 patients identified by prenatal or prompt postnatal testing and treated within the first 10 d of age, one walked at 14 mo of age and has normal neurodevelopment at age 3 y and another infant's early progress appears promising. However, five patients died in infancy and neurodevelopmental outcome was suboptimal in four others. Consideration of additional therapeutic strategies seems necessary, therefore, for most patients and families facing this troublesome form of copper deficiency.

Menkes disease and occipital horn syndrome (OHS) are related disorders of copper transport that involve abnormal neurodevelopment, connective tissue problems, and often premature death. Location of the gene responsible for these conditions on the X chromosome was indicated by pedigree analysis from the time of these syndromes' earliest descriptions. Characterization of an affected female with an X-autosomal translocation was used to identify the Menkes/OHS gene, which encodes a highly evolutionarily conserved, copper-transporting P-type ATPase. The gene normally is expressed in nearly all human tissues, and it localizes to the trans-Golgi network of cells. However, in over 70% of Menkes and OHS patients studied, expression of this gene has been demonstrated to be abnormal. Major gene deletions detectable by Southern blotting account for 15-20% of patients, and an interesting spectrum of other mutations is evident among 58 families whose precise molecular defects have been reported as of this writing. The center region of the gene seems particularly prone to mutation, and those that influence mRNA processing and splicing appear to be relatively common. Further advances in understanding the molecular and cell biological mechanisms involved in normal copper transport may ultimately yield new and better approaches to the management of these disorders.

Copper is a trace element necessary for the normal function of several important enzymes but copper homeostasis is still poorly understood. In recent years remarkable progress has been made in this field following the isolation of the gene defective in Menkes disease. Menkes disease and occipital horn syndrome are X-linked recessive disorders, demonstrating the vital importance of copper, which is also highly toxic in excessive amounts. Its destructive effects are reflected in the autosomal recessive Wilson's disease. Progressive neurodegeneration and connective tissue disturbances are the main manifestations of Menkes disease. Although many patients present a severe clinical course, variable forms can be distinguished, and the occipital horn syndrome has been suggested to be a mild allelic form. The Menkes locus is mapped to Xq13.3 and the gene defective in Menkes disease has been isolated by positional cloning. The gene is predicted to encode an energy-dependent copper-binding protein, the first intracellular copper transporter described in eukaryotes. Isolation of the gene and subsequent characterization of the exon-intron organization now enables the establishment of DNA-based diagnostic methods. Furthermore, identification of the Menkes disease gene led to other important findings, such as isolation of its mouse homologue, confirming the allelic relationship between Menkes disease and occipital horn syndrome, and isolation of the defective genes in Wilson's disease and its rat homologue.

Copper is an essential trace element with a well established mechanism for maintaining balance of the metal in the body, which is controlled by at least two genes. Disruption of one gene on the X chromosome determines a defect in the process of copper absorption, with consequent deficiency of available copper at the cellular level. This results in abnormalities of collagen formation and brain maturation, leading to early death. As yet there is no effective treatment. Disruption of the other copper controlling gene, located on chromosome 13, is associated with accumulation of excess copper in the body, first in the liver leading to cirrhosis, and then in the brain giving rise to destruction of the centre of motor control and, frequently, changes in personality. Copper excess can also cause renal damage, osteoarticular changes and joint pains. If the renal lesion leads to calcium loss in the urine and other tubular defects, there may be osteoporosis or, occasionally, osteomalacia with pathological fractures. In this disease, the abnormal stores of copper can be mobilised with chelating agents or depleted by the administration of zinc salts or thiomolybdate. This usually, but not invariably, leads to improvement or even complete reversal of symptoms. Brain lesions, as demonstrated by computed tomography or magnetic resonance imaging, may also resolve. The mechanism of this phenomenon is obscure but suggests that the long held doctrine that there is no recovery in the central nervous system may have to be reviewed.

We herein describe a case of Menkes' Syndrome in a Jamaican infant. The diagnosis was confirmed by low serum copper and ceruloplasmin levels.

Genetic disorders of trace element transport are now known in humans, mice, dogs and cattle. Those involving copper have been known longest and are best known clinically. Effects due to copper deficiency are seen in Menkes' disease, in X-linked cutis laxa and in the X-linked series of mottled mutants in the mouse. Copper accumulation is also harmful, causing damage initially to the liver and later to the kidneys and brain in Wilson's disease, in some Bedlington terriers and in toxic milk mice. Zinc deficiency is seen in acrodermatitis enteropathica and in premature babies born to women who seem to secrete milk that is zinc-deficient, as is seen in lethal milk mice. Study of animal mutants, especially mutant mice, is helpful in understanding the human diseases and identification of the basic defects in trace element transport in these diseases is improving knowledge relevant to trace element nutrition.

Menkes' syndrome is an X-linked recessive multisystem disease which is usually fatal prior to 5 years of age. Though originally felt to be a disorder of copper deficiency, it now appears to be a copper storage disease, with the observed defects resulting from inappropriate systemic copper distribution. Disorders in the metabolism of metallothionein, a metalloprotein involved in cellular copper transport, may be the primary defect in this syndrome. This review summarizes the relevant clinical and pathologic findings seen in this condition to date. It also describes some of the abnormalities in the metabolism of copper and metallothionein in these infants.