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author:("Tang, vingron")
1.  Neonatal Diagnosis and Treatment of Menkes Disease 
The New England journal of medicine  2008;358(6):605-614.
BACKGROUND
Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but presymptomatic detection is hindered by the inadequate sensitivity and specificity of diagnostic tests. Exploiting the deficiency of a copper enzyme, dopamine-β-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes.
METHODS
Between May 1997 and July 2005, we measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in 81 infants at risk. In 12 newborns who met the eligibility criteria and began copper-replacement therapy within 22 days after birth, we tracked survival and neurodevelopment longitudinally for 1.5 to 8 years. We characterized ATP7A mutations using yeast complementation, reverse-transcriptase–polymerase-chain-reaction analysis, and immunohistochemical analysis.
RESULTS
Of 81 infants at risk, 46 had abnormal neurochemical findings indicating low dopamine-β-hydroxylase activity. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting disease. Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination; 1 of these patients had a mutation that complemented a Saccharomyces cerevisiae copper-transport mutation, indicating partial ATPase activity, and the other had a mutation that allowed some correct ATP7A splicing.
CONCLUSIONS
Neonatal diagnosis of Menkes disease by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment.
doi:10.1056/NEJMoa070613
PMCID: PMC3477514  PMID: 18256395
2.  Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease 
Annals of neurology  2009;65(1):108-113.
Protein translation ends when a stop codon in a gene’s messenger RNA transcript enters the ribosomal A site. Mutations that create premature stop codons (nonsense mutations) typically cause premature translation termination. An alternative outcome, read-through translation (or nonsense suppression), is well known in prokaryotic, viral, and yeast genes but has not been clearly documented in humans except in the context of pharmacological manipulations. Here, we identify and characterize native read-through of a nonsense mutation (R201X) in the human copper transport gene, ATP7A. Western blotting, in vitro expression analyses, immunohistochemistry, and yeast complementation assays using cultured fibroblasts from a classical Menkes disease patient all indicated small amounts of native ATP7AR201X read-through and were associated with a dramatic clinical response to early copper treatment.
doi:10.1002/ana.21576
PMCID: PMC2917729  PMID: 19194885
3.  Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome 
Journal of Medical Genetics  2007;44(8):492-497.
Background
Pronounced intrafamilial variability is unusual in Menkes disease and its variants. We report two unrelated families featuring affected members with unusually disparate clinical and biochemical phenotypes and explore the underlying molecular mechanisms.
Methods
We measured biochemical markers of impaired copper transport in five patients from two unrelated families and used RNase protection, quantitative reverse transcription (RT)‐PCR, Western blot analysis and yeast complementation studies to characterise two ATP7A missense mutations, A1362D and S637L.
Results
In two brothers (family A) with A1362D, RNase protection and Western blot analyses revealed higher amounts of ATP7A transcript and protein in the older, mildly affected patient, who also had a higher plasma copper level and lower cerebrospinal fluid dihydroxyphenylalanine : dihydroxyphenylglycol ratio. These findings indicate greater gastrointestinal absorption of copper and higher activity of dopamine‐β‐hydroxylase, a copper‐dependent enzyme, respectively. In family B, three males with a missense mutation (S637L) in an exon 8 splicing enhancer showed equally reduced amounts of ATP7A transcript and protein by quantitative RT‐PCR and western blot analysis, respectively, despite a more severe phenotype in the youngest. This patient's medical history was notable for cardiac arrest as a neonate, to which we attribute his more severe neurodevelopmental outcome.
Conclusions
These families illustrate that genetic and non‐genetic mechanisms may underlie intrafamilial variability in Menkes disease and its variants.
doi:10.1136/jmg.2007.050013
PMCID: PMC2597922  PMID: 17496194
Menkes disease; intrafamilial variation; gene expression, ATP7A; residual copper transport
4.  Clinical Outcomes in Menkes Disease Patients with a Copper-Responsive ATP7A Mutation, G727R 
Molecular genetics and metabolism  2008;95(3):174-181.
Menkes disease is a fatal neurodegenerative disorder of infancy caused by defects in an X-linked copper transport gene, ATP7A. Evidence from a recent clinical trial indicates that favorable response to early treatment of this disorder with copper injections involves mutations that retain some copper transport capacity. In three unrelated infants, we identified the same mutation, G727R, in the second transmembrane segment of the ATP7A gene product that complemented a S. cerevisiae copper transport mutant, consistent with partial copper transport activity. Quantitative reverse transcription-polymerase chain reaction studies showed approximately normal levels of ATP7AG727R transcript in two patients’ fibroblasts compared to wild type controls, but Western blot analyses showed markedly reduced quantities of ATP7A protein, suggesting post-translational degradation. We confirmed the latter by comparing degradation rates of mutant and wild type ATP7A via cyclohexamide treatment of cultured fibroblasts; half-life of the G727R mutant was 2.9 hr and for the wild-type, 11.4 hr. We also documented a X-box binding protein 1 splice variant in G727R cells - known to be associated with the cellular misfolded protein response. Patient A, diagnosed 6 months of age, began treatment at 228 days (7.6 mos) of age. At his current age (2 years), his overall neurodevelopment remains at a 2 to 4 month level. In contrast, patients B and C were diagnosed in the neonatal period, began treatment within 25 days of age, and show near normal neurodevelopment at their current ages, 3 years (B), and 7 months (C). The poor clinical outcome in patient A with the same missense mutation as patients A and B with near normal oucomes, confirms the importance of early medical intervention in Menkes disease and highlights the critical potential benefit of newborn screening for this disorder.
doi:10.1016/j.ymgme.2008.06.015
PMCID: PMC2654537  PMID: 18752978

Results 1-4 (4)