Document Detail

Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small In-frame deletion.
MedLine Citation:
PMID:  8812725     Owner:  NLM     Status:  MEDLINE    
Classical Menkes disease is a fatal X-linked neurodegenerative disorder caused by defects in a gene (MNK) that encodes a copper-transporting ATPase. Treatment with parenteral copper has been proposed for patients identified before symptoms develop. We recently described suboptimal outcomes despite early copper replacement in two classical Menkes patients whose mutation predicts little if any functional copper transporter. Here, we describe successful copper replacement therapy in a patient with Menkes disease with a splice acceptor site mutation (IVS8,AS,dup5) that causes exon-skipping and generates a mutant transcript with a small in-frame deletion in a noncritical region. The patient was diagnosed by analysis of neurochemical levels in cord blood, and parenteral copper replacement was begun at 8 days of life. Throughout infancy, he showed normal head growth, brain myelination, and age-appropriate neurodevelopment, including independent walking at 14 months of age. In contrast, his affected half-brother and first cousin with the same mutation, but who were not diagnosed and treated from an early age, showed arrested head growth, cerebral atrophy, delayed myelination, and abnormal neurodevelopment. We propose that the successful neurological outcome in this patient was related to early repletion of circulating copper levels, in combination with residual copper transport by a partially functional MNK ATPase containing the small deletion. We hypothesize that raising plasma copper concentrations in patients with Menkes disease with some residual functional gene product can increase the ligand: transporter ratio and thus alter favorably the kinetics of copper transport into and within the brain.
S G Kaler; S Das; B Levinson; D S Goldstein; C S Holmes; N J Patronas; S Packman; W A Gahl
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical and molecular medicine     Volume:  57     ISSN:  1077-3150     ISO Abbreviation:  Biochem. Mol. Med.     Publication Date:  1996 Feb 
Date Detail:
Created Date:  1997-01-24     Completed Date:  1997-01-24     Revised Date:  2008-02-12    
Medline Journal Info:
Nlm Unique ID:  9508702     Medline TA:  Biochem Mol Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  37-46     Citation Subset:  IM    
Section on Human Biochemical Genetics, NICHD, Bethesda, Maryland, 20892, USA.
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MeSH Terms
Adenosine Triphosphatases / genetics*
Base Sequence
Carrier Proteins / genetics*
Cation Transport Proteins*
Cells, Cultured
Child, Preschool
Copper / therapeutic use*
Fibroblasts / metabolism
Gene Expression
Infant, Newborn
Menkes Kinky Hair Syndrome / drug therapy*,  genetics*
Molecular Sequence Data
Polymerase Chain Reaction
Recombinant Fusion Proteins*
Sequence Deletion*
Reg. No./Substance:
0/Carrier Proteins; 0/Cation Transport Proteins; 0/Recombinant Fusion Proteins; 7440-50-8/Copper; EC 3.6.1.-/Adenosine Triphosphatases; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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