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-β-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-β-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.

Epilepsy is a major feature of Menkes disease, an X-linked recessive infantile neurodegenerative disorder caused by mutations in ATP7A, which produces a copper-transporting ATPase. Three prior surveys indicated clinical seizures and electroencephalographic (EEG) abnormalities in a combined 27 of 29 (93%) symptomatic Menkes disease patients diagnosed at 2 months of age or older. To assess the influence of earlier, presymptomatic diagnosis and treatment on seizure semiology and brain electrical activity, we evaluated 71 EEGs in 24 Menkes disease patients who were diagnosed and treated with copper injections in early infancy (≤6 weeks of age), and whose ATP7A mutations we determined. Clinical seizures were observed in only 12.5% (3/24) of these patients, although 46% (11/24) had at least one abnormal EEG tracing, including 50% of patients with large deletions in ATP7A, 50% of those with small deletions, 60% of those with nonsense mutations, and 57% of those with canonical splice junction mutations. In contrast, five patients with mutations shown to retain partial function, either via some correct RNA splicing or residual copper transport capacity, had neither clinical seizures nor EEG abnormalities. Our findings suggest that early diagnosis and treatment improve brain electrical activity and decrease seizure occurrence in classical Menkes disease irrespective of the precise molecular defect. Subjects with ATP7A mutations that retain some function seem particularly well protected by early intervention against the possibility of epilepsy.

Background

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) PET may show more specific 5-HT1A receptor binding reduction in seizure initiation than propagation regions. 18FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI negative TLE patients.

Methods

We performed 18F-FCWAY-PET and 18F-FDG-PET in 12 MRI negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction-corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared 18F-FCWAY-PET and 18F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG and surgical outcome.

Results

Mean 18F-FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus and parahippocampus ipsilateral to epileptic foci, and AIs significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two non-lateralized, 18F-FCWAY PET. One patient with bitemporal seizure onset had non-lateralized 18F-FCWAY-PET. 18FFDG-PET showed congruent hypometabolism in 7/11 EEG-lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and mid temporal 18F-FCWAY V/f1 binding AI than those with lateral or diffuse foci.

Conclusion

18F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than 18F-FDG-PET.