-
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 -
Journal of Assisted Reproduction and... Apr 2023Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in...
Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.
Topics: Menkes Kinky Hair Syndrome; Chromosomes, Human, X; Reproductive Techniques, Assisted; Humans; Male; Female; Pregnancy; Middle Aged; Pregnancy Outcome
PubMed: 36995557
DOI: 10.1007/s10815-023-02778-z -
Neuromuscular Disorders : NMD Oct 2019We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation...
We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients' blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.
Topics: Adenosine Triphosphatases; Aged; Copper-Transporting ATPases; Cutis Laxa; Ehlers-Danlos Syndrome; Genetic Association Studies; Humans; Male; Menkes Kinky Hair Syndrome; Middle Aged; Motor Neuron Disease; Muscular Atrophy, Spinal; Mutation
PubMed: 31558336
DOI: 10.1016/j.nmd.2019.08.008 -
Pharmaceutical Research Aug 2021Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The...
PURPOSE
Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated.
METHODS
CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated.
RESULTS
When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the C was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered.
CONCLUSION
Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
Topics: Administration, Oral; Animals; Coordination Complexes; Disease Models, Animal; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C3H; Particle Size; Thiosemicarbazones
PubMed: 34403032
DOI: 10.1007/s11095-021-03090-0 -
Urology Feb 2020Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results... (Review)
Review
Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results from mutations in the ATP7A gene. Along with neurological decline, characteristic coarse appearance of the hair is seen. Urological issues are prevalent in this patient population, with bladder diverticula being the most common. Herein, we describe a unique male patient with genetic mosaicism and osseous metaplasia found in a ruptured bladder diverticulum.
Topics: Bone Diseases; Bone and Bones; Child; Diverticulum; Humans; Male; Menkes Kinky Hair Syndrome; Metaplasia; Mosaicism; Urinary Bladder
PubMed: 31758979
DOI: 10.1016/j.urology.2019.10.024 -
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 -
Current Journal of Neurology Oct 2020Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN...
Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN (gigaxonin) gene. Herein, we reported the clinical presentations and results of genetic analysis of the first Iranian GAN case. Phenotypic data were obtained by neurologic examination, brain magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), and sonography from the proband. Deoxyribonucleic acid (DNA) was isolated from peripheral blood leucocytes and whole exome sequencing (WES) was performed. The candidate variant was screened by Sanger sequencing in the proband and her family members. The proband was a 7-year-old girl who was admitted with a chief complaint of ataxia, muscle weakness, delayed developmental milestones, and history of psychiatric disorders. She was very moody and had clumsy gait, decreased deep tendon reflexes (DTRs) of lower limbs, and kinky hair. The brain MRI revealed white matter abnormality. The EMG revealed that her disease was compatible with the chronic axonal type of sensorimotor polyneuropathy; however, her EEG was normal. Results of the WES revealed a homozygous variant; c.G778T:p.E260 in the GAN gene, indicating the GAN disorder. The present study affirmed GAN allelic heterogeneity and resulted in the expansion of the phenotypic spectrum of GAN pathogenic variants. Identification of more families with mutations in GAN gene helps to further understand the molecular basis of the disease and provides an opportunity for genetic counseling especially in the populations with a high degree of consanguineous marriage such as the Iranian population.
PubMed: 38011432
DOI: 10.18502/cjn.v19i4.5548 -
Genes May 2021Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to...
Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α () gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins ( = 9.44 × 10). Additional studies are necessary to validate these findings as hallmarks of MD.
Topics: Adolescent; Adult; Cell Movement; Copper-Transporting ATPases; Down-Regulation; Female; Humans; Immune System Phenomena; Infant; Male; Menkes Kinky Hair Syndrome; Mutation; Proteome; Proteomics; Up-Regulation; Exome Sequencing; Young Adult
PubMed: 34069220
DOI: 10.3390/genes12050744 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Feb 2021To explore the genetic basis for three children with Menkes disease.
OBJECTIVE
To explore the genetic basis for three children with Menkes disease.
METHODS
The patients were subjected to next-generation sequencing (NGS) to detect potential variants of the ATP7A gene. Suspected variants were verified by Sanger sequencing of their family members and 200 healthy individuals. Multiplex ligation-dependent probe amplification (MLPA) was also carried out to detect potential deletions in their family members and 20 healthy individuals.
RESULTS
Variants of the ATP7A gene were detected in all of the three families, including a novel c.1465A>T nonsense variant in family 1, a novel c.3039_3043del frame-shifting variant in family 2, and deletion of exons 3 to 23 in family 3, which was reported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.1465A>T and c.3039_3043del variants of ATP7A gene were predicted to be likely pathogenic (PVS1+PM2).
CONCLUSION
Variants of the ATP7A gene may underlay the Menkes disease in the three children. Above findings have facilitated clinical diagnosis and enriched the spectrum of genetic variants of Menkes disease.
Topics: Case-Control Studies; Child; Copper-Transporting ATPases; Exons; Family Health; High-Throughput Nucleotide Sequencing; Humans; Menkes Kinky Hair Syndrome; Mutation; Pedigree
PubMed: 33565059
DOI: 10.3760/cma.j.cn511374-20200216-00083 -
Clinical Genetics May 2023Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal...
Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.
Topics: Humans; Infant; Infant, Newborn; Ceruloplasmin; Copper; Copper Transporter 1; Copper-Transporting ATPases; Hepatolenticular Degeneration; Menkes Kinky Hair Syndrome; Mutation, Missense
PubMed: 36562171
DOI: 10.1111/cge.14289