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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 -
Arquivos de Neuro-psiquiatria May 2024
Topics: Humans; Menkes Kinky Hair Syndrome; Male
PubMed: 38740034
DOI: 10.1055/s-0044-1786761 -
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 -
Actas Dermo-sifiliograficas Jul 2021
Topics: Hair Diseases; Humans; Infant; Menkes Kinky Hair Syndrome
PubMed: 33905712
DOI: 10.1016/j.ad.2020.08.013 -
Molecular Genetics & Genomic Medicine Sep 2023CREBBP truncating mutations and deletions are responsible for the well-known Rubinstein-Taybi syndrome. Recently, a new, distinct CREBBP-linked syndrome has been... (Review)
Review
INTRODUCTION
CREBBP truncating mutations and deletions are responsible for the well-known Rubinstein-Taybi syndrome. Recently, a new, distinct CREBBP-linked syndrome has been described: missense mutations located at the 3' end of exon 30 and the 5' portion of exon 31 induce Menke-Hennekam syndrome. Patients with this syndrome present a recognizable facial dysmorphism, intellectual disability of variable severity, microcephaly, short stature, autism, epilepsy, visual and hearing impairments, feeding problems, upper airway infections, scoliosis, and/or kyphosis. To date, all diagnoses were made postnatally.
METHOD AND CASE REPORT
Trio-whole exome sequencing (WES) was performed in a fetus showing increased nuchal translucency persistence and aorta abnormalities at 28 weeks of gestation (WG).
RESULTS
WES revealed a CREBBP de novo missense mutation (c.5602C>T; p.Arg1868Trp) in exon 31, previously reported as the cause of Menke-Hennekam syndrome. Termination of pregnancy was performed at 32 WG. We further reviewed the prenatal signs of Menke-Hennekam syndrome already reported. Among the 35 patients reported and diagnosed postnatally up to this day, 15 presented recognizable prenatal signs, the most frequent being intra-uterine growth retardation, brain, and cardiovascular anomalies.
CONCLUSION
Menke-Hennekam is a rare syndrome with unspecific, heterogeneous, and inconstant prenatal symptoms occurring most frequently with the c.5602C>T, p.(Arg1868Trp) mutation. Therefore, the prenatal diagnosis of Menke-Hennekam syndrome is only possible by molecular investigation. Moreover, this case report and review reinforce the importance of performing prenatal WES when unspecific signs are present on imaging.
Topics: Pregnancy; Female; Humans; Phenotype; Exome Sequencing; Mutation; Rubinstein-Taybi Syndrome; Mutation, Missense; Menkes Kinky Hair Syndrome
PubMed: 37353886
DOI: 10.1002/mgg3.2219 -
Expert Opinion on Investigational Drugs Jan 2021
Topics: Animals; Copper; Drug Repositioning; Drugs, Investigational; Humans; Hydrazines; Menkes Kinky Hair Syndrome
PubMed: 33081534
DOI: 10.1080/13543784.2021.1840550 -
PLoS Genetics Jan 2023Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson...
Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.
Topics: Mice; Animals; Copper-Transporting ATPases; Copper; Choroid Plexus; Menkes Kinky Hair Syndrome; Brain
PubMed: 36626371
DOI: 10.1371/journal.pgen.1010558 -
Molecular Genetics & Genomic Medicine Aug 2019Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair...
BACKGROUND
Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair texture. Menkes disease is an X-linked recessive inherited disease caused by pathogenic variants in ATP7A, which leads to profound copper deficiency.
METHOD
We identified an infant male who presented with prematurity, hypotonia, and dysmorphic features for whom a family history of clinical Menkes disease was revealed after discussion with the clinical genetics team.
RESULTS
Although initial first-tier genetic testing identified Kdv syndrome (17q21.31 syndrome), the family history led the team to consider a second diagnostic possibility, and testing of ATP7A revealed a pathogenic variant (c.601C>T, p.R201X).
CONCLUSION
Menkes disease and KdV syndrome may both present with hypotonia and abnormal hair, in addition to seizures and failure to thrive. While these genetic conditions have overlapping clinical features, they have different natural histories and different therapeutic options. Here, we report on a patient affected with both disorders and review the diagnostic and therapeutic difficulties this presented.
Topics: Abnormalities, Multiple; Chromosome Deletion; Chromosomes, Human, Pair 17; Comparative Genomic Hybridization; Copper-Transporting ATPases; DNA Mutational Analysis; Fatal Outcome; Genetic Testing; Histidine; Humans; Hypertension, Pulmonary; Infant, Newborn; Intellectual Disability; Male; Medical History Taking; Menkes Kinky Hair Syndrome; Mutation; Nitric Oxide; Organometallic Compounds; Pedigree; Respiratory Insufficiency
PubMed: 31250568
DOI: 10.1002/mgg3.829 -
BMJ Case Reports Apr 2022Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an gene mutation. We report a male infant aged 4 months who... (Review)
Review
Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an gene mutation. We report a male infant aged 4 months who presented with kinky hair, hypopigmented skin, epilepsy and delayed development. Magnetic resonance imaging (MRI) of brain demonstrated multiple tortuosities of intracranial vessels and brain atrophy. Investigation had showed markedly decreased serum copper and ceruloplasmin. The novel c.2172+1G>T splice-site mutation in the gene confirmed MD. He was treated with subcutaneous administration of locally prepared copper-histidine (Cu-His). Following the therapy, hair manifestation was restored and serum ceruloplasmin was normalised 1 month later. Despite the treatment, epilepsy, neurodevelopment and osteoporosis still progressed. He died from severe respiratory tract infection at the age of 9.5 months. These findings suggest that the benefit of Cu-His in our case is limited which might be related to severe presentations and degree of mutation.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Ceruloplasmin; Copper; Copper-Transporting ATPases; Epilepsy; Asia, Eastern; Histidine; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Mutation; Organometallic Compounds; Peptide Fragments
PubMed: 35393273
DOI: 10.1136/bcr-2021-247937