In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.
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 (Q724H), 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.
Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892‐1853, USA.
Marie Reine
MR
Haddad
Charles J
CJ
Macri
Courtney S
CS
Holmes
David S
DS
Goldstein
Beryl E
BE
Jacobson
Jose A
JA
Centeno
Edwina J
EJ
Popek
Willam A
WA
Gahl
Stephen G
SG
Kaler
D000251:Adenosine Triphosphatases / Q000235:genetics*; D002396:Catechols / Q000097:blood; D027682:Cation Transport Proteins / Q000235:genetics*; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood; D000073840:Copper-Transporting ATPases; D005260:Female; D005313:Fetal Death / Q000473:pathology; D005333:Fetus / Q000187:drug effects*; D006639:Histidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D050497:Stillbirth
D002396:Catechols; D027682:Cation Transport Proteins; D009942:Organometallic Compounds; D006639:Histidine; D003300:Copper; C098468:copper histidine; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; C034221:catechol