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.