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Science (New York, N.Y.) May 2020Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is...
Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.
Topics: Animals; Biological Transport; Brain; Cell Line; Copper; Copper Transporter 1; Disease Models, Animal; Electron Transport Complex IV; Hydrazines; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Knockout; Mitochondria; Neurodegenerative Diseases; Rats
PubMed: 32381719
DOI: 10.1126/science.aaz8899 -
Archives of Iranian Medicine Dec 2021
Topics: Copper; Humans; Menkes Kinky Hair Syndrome
PubMed: 35014241
DOI: 10.34172/aim.2021.138 -
Indian Pediatrics Jan 2016
Topics: Cerebral Veins; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 26840692
DOI: No ID Found -
Arquivos de Neuro-psiquiatria May 2024
Topics: Humans; Menkes Kinky Hair Syndrome; Male
PubMed: 38740034
DOI: 10.1055/s-0044-1786761 -
Journal of Multidisciplinary Healthcare 2016Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with... (Review)
Review
Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of "kinky hair disease"). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype-phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions.
PubMed: 27574440
DOI: 10.2147/JMDH.S93454 -
AJNR. American Journal of Neuroradiology Oct 2017This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter... (Review)
Review
This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.
Topics: Brain; Child; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging; Retrospective Studies
PubMed: 28495940
DOI: 10.3174/ajnr.A5192 -
AJNR. American Journal of Neuroradiology Oct 2017Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain... (Review)
Review
Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.
Topics: Brain; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging; Retrospective Studies; White Matter
PubMed: 28495946
DOI: 10.3174/ajnr.A5186 -
The Turkish Journal of Pediatrics 2022Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in...
BACKGROUND
Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice.
METHODS
Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated.
RESULTS
In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis.
CONCLUSIONS
Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.
Topics: Humans; Child; Menkes Kinky Hair Syndrome; Giant Axonal Neuropathy; Hair; Hair Diseases; Nervous System Diseases; Primary Immunodeficiency Diseases; Amino Acid Metabolism, Inborn Errors
PubMed: 36583891
DOI: 10.24953/turkjped.2022.221 -
Neurobiology of Disease Sep 2015ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging... (Review)
Review
ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Computational Biology; Copper-Transporting ATPases; Humans; Menkes Kinky Hair Syndrome; Mice; Mutation; Neurodegenerative Diseases; Neurodevelopmental Disorders
PubMed: 25583185
DOI: 10.1016/j.nbd.2014.12.024 -
Neurology. Genetics Dec 2016Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter . Other mutations have...
Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter . Other mutations have been linked to juvenile occipital horn syndrome and adult-onset hereditary motor neuropathy. About 5%-10% of the patients present with "atypical Menkes disease" characterized by longer survival, cerebellar ataxia, and developmental delay. The intracellular copper transport is regulated by 2 P type ATPase copper transporters ATP7A and ATP7B. These proteins are expressed in the trans-Golgi network that guides copper to intracellular compartments, and in copper excess, it relocates copper to the plasma membrane to pump it out from the cells. mutations cause Wilson disease with dystonia, ataxia, tremor, and abnormal copper accumulation in the brain, liver, and other organs..
PubMed: 27878136
DOI: 10.1212/NXG.0000000000000119