title: Novel mutations and clinical outcomes of copper-histidine therapy in Menkes disease patients.
abstract: Menkes disease is a very rare X-linked copper metabolism disorder that results from an ATP7A gene mutation. With the advent of subcutaneous copper-histidine therapy, the early diagnosis of Menkes disease becomes of utmost importance for patients' prognosis. In the present study, the clinical characteristics of 12 Korean patients with Menkes disease (11 males and 1 female from 11 unrelated families) were described along with the mutation spectrum. Only 2 male patients were diagnosed in the neonatal period, and the other male patients were diagnosed at age 4.3 ± 1.9 months. The presenting signs included depigmented kinky hair, neurologic deficits, and hypotonia. Serum copper and ceruloplasmin levels were markedly decreased. Intracranial vessels were dilated with tortuosity and accompanied by regional cerebral infarctions, even at an early age. Of note, the female patient was diagnosed at age 18 months, during the evaluation for developmental delay, by characteristic MRA findings, biochemical profiles, and genetic evaluation. A total of 11 ATP7A mutations were identified, including five previously unreported mutations. Most mutations were truncated (except 1 missense mutation), including 3 frameshift, 2 nonsense, 3 large deletion, and 2 splice-site variants. The age at commencement of copper-histidine treatment was variable among patients age 7.3 ± 7.5 (0.5-27) months. Despite the treatment, seven patients died before age 5 years, and the remaining patients were severely retarded in neurodevelopment. The poor outcomes of our patients might be related to delayed therapy, but severe ATP7A mutations should be noted as well.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Ja Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Yoo-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Chong Kun
authors.initials: CK
authors.lastname: Cheon
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002544:Cerebral Infarction / Q000209:etiology; D002570:Ceruloplasmin / Q000032:analysis; D041321:Chromosomes, Human, X / Q000235:genetics; D018389:Codon, Nonsense; D003300:Copper / Q000097:blood / Q000627:therapeutic use*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D061345:Early Medical Intervention; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006639:Histidine / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007279:Injections, Subcutaneous; D007723:Korea; D018810:Magnetic Resonance Angiography; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000188:drug therapy* / Q000235:genetics; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion; D017211:Treatment Failure; D049951:X Chromosome Inactivation
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; D022821:RNA Splice Sites; D006639:Histidine; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases