A severe case of Menkes disease with repeated bone fracture during the neonatal period, followed by multiple arterial occlusion.

Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A. Early diagnosis and treatment are important, although the diagnosis is difficult prior to 2 months of age. We present an unusually severe case of MD with skull fractures at the birth and repeated fractures during the neonatal period, with further examinations leading to diagnosis. The patient died due to hemorrhagic shock, due to multiple arterial occlusion despite initiation of copper-histidine therapy in early infancy. Bone fracture at birth and multiple arterial occlusion are very rare findings in MD. This unusual and severe presentation emphasizes the importance of early diagnosis and treatment. A congenital bone fracture should be considered as a possible presentation of MD, especially in cases without birth complications.

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.

The role of copper ions in pathophysiology and fluorescent sensors for the detection thereof.

Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale, are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address these diseases.

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.

Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment.

Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. Death by age three years is typical. While provision of working copies of ATP7A to the brain by viral vectors is a promising strategy under development, the only treatment currently available is subcutaneous copper injections. These can normalize circulating blood levels and may replete brain copper depending on the molecular context, e.g., the severity of ATP7A mutation and potential presence of mosaicism. In this paper, we summarize somatic growth and neurodevelopmental outcomes for 60 subjects enrolled in a recently concluded phase I/II clinical trial of copper histidine for Menkes disease (ClinicalTrials.gov Identifier: NCT00001262). Primary outcomes indicate highly statistically significant improvements in gross motor, fine motor/adaptive, personal-social, and language neurodevelopment in the cohort of subjects who received early treatment prior to onset of symptoms (n=35). Correlating with these findings, quantitative parameters of somatic growth indicated statistically significant greater growth in head circumference for the initially asymptomatic group, whereas weight and height/length at age three years (or at time of death) did not differ significantly. Mortality at age 3 was higher (50%) in subjects older and symptomatic when treatment commenced compared to the asymptomatic group (28.6%). We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation.

Changes in body weight and height in survivors of Menkes disease.

OBJECTIVE: To explore the changes in the body weight and height of Menkes disease (MNK) patients treated with long-term copper-histidine. METHODS: A survey involving a retrospective review of medical records or summaries of MNK patients was conducted. Patients were 44 males born after 1994, and their feeding method and genetic analysis of the ATP7A gene were reviewed. We compared the data of body weight and height from birth until 6 years between classical MNK patients and the general population obtained from national data and between patients who received early treatment and patients who received late treatment. RESULTS: Although five patients who received early treatment reached some developmental milestones, the body weight and height did not differ from patients who received late treatment in the mode of oral nutrition, and were lower in comparison to the national data (<3 percentile). CONCLUSION: We reported changes in the body weight and height of MNK patients who received early and late treatment. Although early treatment with copper-histidine had favorable effects on neurological development, it did not result in improvements in body weight and height. We suggest that the establishment of sufficient nutritional support is necessary along with early parenteral copper treatment to improve whole body condition in MNK patients.

Modeling of Menkes disease via human induced pluripotent stem cells.

Menkes disease (MD) is a copper-deficient neurodegenerative disorder that manifests severe neurologic symptoms such as seizures, lethargic states, and hypotonia. Menkes disease is due to a dysfunction of ATP7A, but the pathophysiology of neurologic manifestation is poorly understood during embryonic development. To understand the pathophysiology of neurologic symptoms, molecular and cellular phenotypes were investigated in Menkes disease-derived induced pluripotent stem cells (MD-iPSCs). MD-iPSCs were generated from fibroblasts of a Menkes disease patient. Abnormal reticular distribution of ATP7A was observed in MD-fibroblasts and MD-iPSCs, respectively. MD-iPSCs showed abnormal morphology in appearance during embryoid body (EB) formation as compared with wild type (WT)-iPSCs. Intriguingly, aberrant switch of E-cadherin (E-cad) to N-cadherin (N-cad) and impaired neural rosette formation were shown in MD-iPSCs during early differentiation. When extracellular copper was chelated in WT-iPSCs by treatment with bathocuprione sulfate, aberrant switch of E-cad to N-cad and impaired neuronal differentiation were observed, like in MD-iPSCs. Our results suggest that neurological defects in Menkes disease patients may be responsible for aberrant cadherin transition and impaired neuronal differentiation during early developmental stage.

Menkes syndrome presenting as possible child abuse.

Menkes syndrome, also known as kinky-hair disease, is a rare X-linked recessive, lethal, neurodegenerative disorder of impaired copper transport. The disorder typically is characterized by fine, hypopigmented, wiry hair; doughy skin; bone and connective-tissue disturbances; vascular abnormalities that can result in spontaneous hemorrhaging; and progressive neurologic deterioration. These early findings often are easily confused with child abuse. We report a case of a 6-month-old boy with Menkes syndrome whose symptoms originally were thought to be from child abuse.

Prenatal treatment of mosaic mice (Atp7a mo-ms) mouse model for Menkes disease, with copper combined by dimethyldithiocarbamate (DMDTC).

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a (mo-ms) recapitulates the Menkes phenotype and die about 15.75±1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl(2) (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76±25.3 days, whereas treatment with CuCl(2) alone (50 mg/kg) only leads to survival for about 21 days ±5 days. These copper-DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl(2) alone, a significant increase in the amount of copper was observed in the brain after prenatal copper-DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper-DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans.

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.

Audiological profile of children and young adults with syndromic and complex craniosynostosis.

OBJECTIVES: To determine syndrome-specific type, severity, and prevalence of hearing loss to facilitate follow-up and treatment. DESIGN: Tertiary pediatric hospital craniofacial clinic survey study. If insufficient or no data were available for a child, he or she was referred to an audiologist for pure-tone audiometry. SETTING: Academic research facility. PATIENTS: Information was gathered regarding 132 children and young adults with craniosynostosis. MAIN OUTCOME MEASURES: The primary outcome was hearing assessment of children and young adults with various types of craniosynostosis. A secondary outcome was inference regarding the incidence of otitis media among children and young adults with craniosynostosis. RESULTS: We found mild or moderate hearing loss in 44.0% of patients with Apert syndrome, in 28.5% with Crouzon syndrome, in 62.1% with Muenke syndrome, in 28.6% with Saethre-Chotzen syndrome, and in 6.7% with complex craniosynostosis. Hearing loss was conductive in most patients with Apert, Crouzon, and Saethre-Chotzen syndromes and it was predominantly sensorineural in patients with Muenke syndrome. Sensorineural hearing loss at lower frequencies was found only in patients with Muenke syndrome. CONCLUSIONS: Most patients with syndromic and complex craniosynostosis have recurrent otitis media with effusion, causing episodes of conductive hearing loss throughout their lives. Sensorineural hearing loss can occur in all 4 syndromes studied but is the primary cause of hearing loss in children and young adults with Muenke syndrome. For patients with these syndromes, we recommend routine visits to the general practitioner or otolaryngologist, depending on national standards of care, to screen for otitis media with effusion throughout life. We also advise early screening for sensorineural hearing loss among children and young adults with these syndromes.

Transient left temporal lobe lesion in Menkes disease may influence the generation of tonic spasms.

We report a 7-month-old boy with Menkes disease who presented West syndrome. Magnetic resonance imaging (MRI) revealed atrophy of the frontal and parietal lobes, subdural hematoma on the right side, and left temporal lobe lesion (low intensity in T1-weighted imaging (T1-WI), high intensity in T2-weighted imaging (T2-WI) and low intensity in diffusion-weighted imaging (DW-I)) at 7 months of age. The apparent diffusion coefficient (ADC) was 1.68×10(-3)mm(2)/s in the left temporal lobe lesion and 1.15×10(-3)mm(2)/s on the contralateral side. (1)H-magnetic resonance spectroscopy ((1)H-MRS) revealed a decrease in N-acetylaspartate/(creatine+phosphocreatine) (NAA/Cr) (0.71) and a lactate peak in the left temporal lobe lesion. At 8 months of age, the left temporal lobe lesion disappeared, the ADC of this lesion was within the normal range (1.10×10(-3)mm(2)/s), and (1)H-MRS revealed a slight increase in NAA/Cr (1.12) and disappearance of the lactate peak. We suspected that the transient temporal lobe lesion in Menkes disease was mainly vasogenic edema. Electroencephalography (EEG) revealed left hemisphere dominant hypsarrhythmia and slowing in the left hemisphere. Ictal EEG revealed generalized slow wave burst with P3, T3 spike antecedence and the antecedent spike was consistent with left temporal lobe lesion. After disappearance of the left temporal lobe lesion, tonic spasms disappeared and EEG findings improved. In this case, the clinical course and ictal EEG suggested that epileptic activity from the left temporal lobe lesion may have given rise to tonic spasms.

Pathology, clinical features and treatments of congenital copper metabolic disorders--focus on neurologic aspects.

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.

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.