Neonatal diagnosis and treatment of Menkes disease.
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-beta-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-beta-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. (ClinicalTrials.gov number, NCT00001262.)
Kaler
Stephen G
SG
Unit on Pediatric Genetics, Program in Molecular Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, Rm. 5-2571, 10 Center Dr., MSC 1832, Bethesda, MD 20892-1832, USA.kalers@mail.nih.gov
Holmes
Courtney S
CS
Goldstein
David S
DS
Tang
Jingrong
J
Godwin
Sarah C
SC
Donsante
Anthony
A
Liew
Clarissa J
CJ
Sato
Susumu
S
Patronas
Nicholas
N
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000251:Adenosine Triphosphatases / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D027682:Cation Transport Proteins / Q000235:genetics*; D003300:Copper / Q000378:metabolism / Q000627:therapeutic use*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000097:blood; D004299:Dopamine beta-Hydroxylase / Q000097:blood / Q000172:deficiency; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D009154:Mutation; D015997:Neonatal Screening; D009638:Norepinephrine / Q000097:blood; D010375:Pedigree; D016364:Reading Frames; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
D015415:Biomarkers; D027682:Cation Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D008734:Methoxyhydroxyphenylglycol; D003300:Copper; D004299:Dopamine beta-Hydroxylase; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; D009638:Norepinephrine