Ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis.

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.

Small amounts of functional ATP7A protein permit mild phenotype.

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.

Catecholamine metabolites affected by the copper-dependent enzyme dopamine-beta-hydroxylase provide sensitive biomarkers for early diagnosis of menkes disease and viral-mediated ATP7A gene therapy.

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.

Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment.

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.

ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model.

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-ß-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.

ATP7A-related copper transport diseases-emerging concepts and future trends.

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.

Molecular correlates of epilepsy in early diagnosed and treated Menkes disease.

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.

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.

Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease.

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.

Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R.

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.

[Menkes' disease: heterozygosity testing by quantitative real-time PCR and the dilemma of therapeutic support]. / Quantitative Heterozygotentestung und das therapeutische Dilemma bei Menkes-Syndrom.

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.

Copper: not too little, not too much, but just right. Based on the triennial Pewterers Lecture delivered at the National Hospital for Neurology, London, on 23 March 1995.

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.

Síndrome de los cabellos impeinables (a propósito de 4 observaciones) / Uncombable hair syndrome ( for the purpose of four observations)

Se presentan 4 pacientes con síndrome de los cabellos impeinables. En 3 de ellos se pudieron detectar antecedentes familiares de esta displacia pilosa. Ninguno de los casos se asoció a alteraciones sistémicas ni a otra patología del pelo. La biopsia de cuero cabelludo efectuada a uno de los enfermos evidenció que algunos tallos pilosos presentaban una sección triangular, mientras que la microscopía electrónica de barrido demostró en todos los pacientes la presencia de un surco longitudinal a lo largo del tallo del pelo

Enfermedad de Menkes: presentación de un caso y revisión bibliográfica / Menkes´s disease: report of a case and review of the literature

Se presenta un niño de 2 meses de edad que comenzó su enfermedad con convulsiones focales y prolongadas. La primera descripción fue efectuada por Menkes en 1962 en 5 miembros de una familia. Los hallazgos típicos consistían de niños varones con facies características, pelo ensortijado, convulsiones. hiportermia, retardo madurativo y pondoestatural severo que llevan a un estado vegetativo. El curso de esta enfermedad es uniformemente progresivo culminando con la muerte antes de 1 a 3 años de edad. El estudio microscópico de pelo comprueba pili torti, moniletrix y tricorresis nudosa. Estudios radiológicos muestran cambios en los huesos largos consistentes en espolones simétricos metafisarios y reaccion periotal diafisiaria. Estudios angiográficos cerebrales permiten apreciar una anormal tortuosidad de los vasos y variaciones en su calibre. La tomografía computada revela importantes hallazgos patológicos, pricipalmente colecciones subdurales probablemente secuandarias a la atrofia cerebral. El descubrimiento por Danks en 1972 del trastorno en el metabolismo del cobre fue un importante paso en la comprensión de la patología y cuyo defecto básico está en la absorción intestinal. El diagnóstico se efectúa por los niveles bajos de ceruloplasmina y cobre en suero. Esta enfermedad está ligada a la herencia recesiva por el cromosoma X, no existe tratamiento específico pero es posible hoy hacer el diagnóstico prenatal.