In utero copper treatment for Menkes disease associated with a severe ATP7A mutation

Abstract

Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 μg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 μg/dL prior to treatment to 45 μg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 μg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient’s ATP7A mutation, which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

A Novel Two-Nucleotide Deletion in the ATP7A Gene Associated With Delayed Infantile Onset of Menkes Disease

“…Another MD patient with a mutation that resulted in no ATP7A protein on Western blotting died at 5.5 months despite very early copper treatment [10]. Although our patient’s current medical problems appear consistent with classic MD, his progressive development up until 8 months old, when he could control his head and sit with minimal assistance, in the absence of copper treatment, was atypical [7].…”

L‐Threo‐Dihydroxyphenylserine corrects neurochemical abnormalities in a menkes disease mouse model

“…Other ATP7A functions include removal of copper from cells across the plasma membrane in response to increases in its concentration, pumping copper into melanosomes for metalation of tyrosinase, contribution to axonal and synaptic development, and involvement in neuronal activation . Mutations in ATP7A , or its murine homolog, Atp7a , impair all these processes, with the defect in copper transfer to DBH resulting in distinctively abnormal neurochemical patterns, including markedly elevated ratios of non–beta‐hydroxylated to beta‐hydroxylated metabolites in the catecholamine biosynthetic pathway …”

Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model

“…The molecular characterization of Mo-dp null mutation and establishment of a genotyping assay for the Mo-dp allele facilitate these efforts. We previously showed that prenatal copper replacement alone in a human fetus with a severe loss of function mutation in ATP7A gene failed to rescue the phenotype [14]; thus we speculate that neonatal ATP7A gene addition plus subcutaneous copper injections represents a reasonable approach in such circumstances. Given the complete loss-of-function mutation in Atp7a , rescue of affected male Mo-dp mice by viral gene therapy would provide further proof of concept for this therapeutic approach in human patients.…”

“…Copper levels in fresh frozen brains were determined by graphite furnace atomic absorption and confirmed by inductively coupled plasma mass spectrometry, as previously described [14, 15]. …”