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Journal Der Deutschen Dermatologischen... Mar 2018
Topics: Cerebral Arteries; Copper-Transporting ATPases; Craniofacial Abnormalities; Early Diagnosis; Epilepsies, Partial; Exons; Growth Disorders; Hair; Hair Diseases; Humans; Infant; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Point Mutation; Skull
PubMed: 29288599
DOI: 10.1111/ddg.13407 -
JPMA. the Journal of the Pakistan... Oct 2017Menkes disease (MD) (OMIM: 309400) is also known as kinky hair disease, trichopoliodystrophy, and steely hair. A 7-months-old, male infant presented to our outpatient...
Menkes disease (MD) (OMIM: 309400) is also known as kinky hair disease, trichopoliodystrophy, and steely hair. A 7-months-old, male infant presented to our outpatient department in June 2016 with history of developmental delay and seizures. Seizures started at 3 months of age and worsened progressively to clusters of extensor spasms. Physical examination showed sparse and kinky hair. Neurological examination revealed a central hypotonia with marked decrease in muscle power with normal deep tendon reflexes. The serum ceruloplasmin level and serum copper level were decreased. Ultrasound KUB showed Hutch diverticulum along left ureteric orifice. Magnetic resonance imaging (MRI) carried out at five months of age showed frontal cortical atrophy. His EEG was consistent with hypsarrythmia pattern. Patients with classic MD usually exhibit a severe neurodegenerative course, with poor long term outcome and death before the third year of life.
Topics: Developmental Disabilities; Hair; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Muscle Hypotonia; Rare Diseases; Spasms, Infantile
PubMed: 28955085
DOI: No ID Found -
Archives of Disease in Childhood.... Dec 2017In paediatrics, one of our main aims in the diagnostic process is to identify any treatable conditions. The copper metabolism disorder Wilson's disease (WD) is one such...
In paediatrics, one of our main aims in the diagnostic process is to identify any treatable conditions. The copper metabolism disorder Wilson's disease (WD) is one such condition that is caused by mutations in the gene. Delay in treatment could result in irreversible disability or even death. Although liver disease is the most common presenting feature in children, some children may initially present with a subtle neurological presentation only. In patients presenting with dystonia, tremor, dysarthria or with a deterioration in school performance, there should be a high index of suspicion for WD. However, the differential of these clinical presentations is wide and exclusion of WD is difficult. No single diagnostic test can exclude WD and each of the biochemical tests has limitations. In this article, we discuss copper metabolism disorders including WD and Menke's disease. We then discuss the available diagnostic tests and how to investigate children for these rare disorders.
Topics: Adolescent; Algorithms; C-Reactive Protein; Ceruloplasmin; Child; Child, Preschool; Copper; Female; Genetic Testing; Hepatolenticular Degeneration; Humans; Infant; Liver Function Tests; Male; Menkes Kinky Hair Syndrome; Young Adult
PubMed: 28751535
DOI: 10.1136/archdischild-2016-310960 -
Clinical Genetics Nov 2017Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of...
Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving MD patient (37 years) receiving early-onset and long-term copper treatment. He has few neurological symptoms without connective tissue disturbances; and a missense ATP7A variant, p.(Pro852Leu), which results in impaired protein trafficking while the copper transport function is spared. These findings suggest that some cuproenzymes maintain their function when sufficient copper is provided to the cells; and underline the importance of early initiated copper treatment, efficiency of which is likely to be dependent on the mutant ATP7A function.
Topics: Adolescent; Adult; Child, Preschool; Copper; Copper-Transporting ATPases; Humans; Infant; Infant, Newborn; Male; Menkes Kinky Hair Syndrome; Protein Transport
PubMed: 28657131
DOI: 10.1111/cge.13083 -
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 -
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 -
Metabolic Brain Disease Aug 2017ATP7A is a copper-transporting P-type adenosine triphosphatase whose loss of function leads to the Menkes disease, an X-linked copper metabolism multi-organ disorder (1...
ATP7A is a copper-transporting P-type adenosine triphosphatase whose loss of function leads to the Menkes disease, an X-linked copper metabolism multi-organ disorder (1 in 100.000 births). Here we document our experience with the ATP7A linked diseases in Italy. We analyzed the exonic structure of the ATP7A gene in 25 unrelated Italian families and studied the variants of unknown significance. We identified 22 different DNA alterations, 13 of which first reported in this study. The classical Menkes phenotype was present in 21 of the 25 families and was linked with highly damaging mutations (7 nonsense; 4 frame-shift; 2 small in-frame deletions, 2 splice site alterations, 2 gross deletions, and 1 gross duplication). Of the 4 cases with milder variants of the Menkes disease two had a missense mutation, one a leaky splice site alteration and one a nonsense mutation in exon 22. We determined in silico that all the mutations leading to the classical Menkes disease leave no residual activity of ATP7A including the apparently less severe in-frame deletions. Whereas milder forms of the disease are characterized by mutations that allow a limited residual activity of ATP7A, including the nonsense mutation observed.
Topics: Codon, Nonsense; Computer Simulation; Copper-Transporting ATPases; DNA Mutational Analysis; Humans; Italy; Menkes Kinky Hair Syndrome; Mutation; Mutation, Missense; Phenotype
PubMed: 28451781
DOI: 10.1007/s11011-017-0010-8 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Apr 2017To delineate the clinical features and potential mutation of the ATP7A gene in a family affected with Menkes disease.
OBJECTIVE
To delineate the clinical features and potential mutation of the ATP7A gene in a family affected with Menkes disease.
METHODS
Clinical data of a patient and his family members were analyzed. Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assays were performed to detect the mutation of the ATP7A gene.
RESULTS
The patient was admitted at the age of 5 months due to severe epilepsy and marked delayed psychomotor development. Significantly light complexion, pudgy cheeks and sparse fuzzy wooly hair were noted. Cranial magnetic resonance imaging and angiography revealed cortical atrophy, leukoencephalopathy and circuitous of intracranial vessels. The plasma ceruloplasmin was decreased. MLPA has identified a deletion spanning exons 8 to 12 of the ATP7A gene. His mother was found to be a heterozygous carrier of the same mutation.
CONCLUSION
The clinical features and a novel mutation of the ATP7A gene of the family have been delineated.
Topics: Adenosine Triphosphatases; Adult; Asian People; Cation Transport Proteins; China; Copper-Transporting ATPases; DNA Mutational Analysis; Exons; Female; Heterozygote; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Mutation; Pedigree
PubMed: 28397223
DOI: 10.3760/cma.j.issn.1003-9406.2017.02.015 -
Metabolic Brain Disease Aug 2017Menkes disease (MD) is a fatal X-linked multisystem disease caused by mutations in ATP7A. In this study, clinical and genetic analysis was performed in 24 male MD...
Menkes disease (MD) is a fatal X-linked multisystem disease caused by mutations in ATP7A. In this study, clinical and genetic analysis was performed in 24 male MD patients. Development delay, seizures, kinky coarse hair, and dystonia were found in 24, 22, 24, and 24 patients, respectively. Serum ceruloplasmin/copper tested in 19 patients was low. Abnormal classic features of MD presented in the MRI/MRA of 19 patients. Seventeen mutations of ATP7A were identified in 22 patients. Twelve were novel mutations including three small deletion/insertion, one missense mutation, two nonsense mutations, three splicing-site mutations, and three gross deletions. Twenty-two patients were genetically diagnosed; neither point mutation nor deletion/duplication was found in two of them. c.2179G > A found in five patients might be a hot-spot mutation. Prenatal molecular diagnosis was performed for five unrelated fetuses (1 female and 4 male), which found four fetuses to be wild type and one male carried the same mutation as the proband. This study of the largest sample of Chinese MD patients examined to date discovered the unique phenotype and genotype spectrum in Chinese patients with 12 novel mutations of ATP7A, and that c.2179G > A might be a hot-spot mutation in MD patients. Five successful prenatal diagnosis contributed important information for MD families.
Topics: China; Copper-Transporting ATPases; Female; Genetic Testing; Humans; Male; Menkes Kinky Hair Syndrome; Mutation; Pregnancy; Prenatal Diagnosis
PubMed: 28397151
DOI: 10.1007/s11011-017-9985-4 -
Scientific Reports Apr 2017Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the...
Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit the catalytic phosphorylation of the protein. Four mutants showed diffuse post-TGN localization, while two displayed copper dependent trafficking. These six variants were identified in patients with mild MD and typically displayed activity in the yeast assay. The four post-TGN located mutants were presumably affected in the catalytic dephosphorylation of the protein. Together these results indicate that the severity of MD correlate with cellular localization of ATP7A and support previous studies indicating that phosphorylation is crucial for the exit of ATP7A from TGN, while dephosphorylation is crucial for recycling back to TGN.
Topics: Alleles; Alternative Splicing; Amino Acid Substitution; Biomarkers; Copper; Copper-Transporting ATPases; Fibroblasts; Fluorescent Antibody Technique; Humans; Intracellular Space; Menkes Kinky Hair Syndrome; Models, Biological; Mutation, Missense; Phenotype; Phosphorylation; Proteasome Endopeptidase Complex; Protein Transport; Proteolysis; Severity of Illness Index
PubMed: 28389643
DOI: 10.1038/s41598-017-00618-6