CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.

Determinants of reduced health-related quality of life in pediatric inherited neuropathies.

OBJECTIVE: We have shown that health-related quality of life (QOL) in children with inherited neuropathies (Charcot-Marie-Tooth disease [CMT]) is significantly reduced compared to population norms, thus establishing its utility as an outcome measure in therapeutic trials. However, the Australian ascorbic acid trial in children with CMT type 1A (CMT1A) identified no change in QOL scores despite a trend toward improvement in nerve conduction velocities in the treated group. The objective of this study was to identify clinical, electrophysiologic, and functional correlates of QOL in children with CMT1A, to guide future investigations of strategies to improve QOL and reduce disability in these patients. METHODS: In this cross-sectional study, a series of multivariate regression models were developed to determine whether QOL scores could be explained by demographic and symptom data, standardized measures of gross motor function, foot/ankle and hand/finger involvement, electrophysiology, and gait characteristics in 70 children aged 5-16 years with CMT1A. RESULTS: Independent determinants of reduced QOL in children with CMT1A, from strongest to weakest, were leg cramps, hand tremor, short step length, reduced long jump distance, ankle inflexibility, poor agility and endurance, advancing age, and foot drop. Many of the standardized clinical and electrophysiologic measures used as endpoints in clinical trials of CMT correlated poorly with QOL. CONCLUSION: QOL is negatively affected by CMT1A in children. Multivariate modeling suggests that interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility might have a substantial effect on QOL in children with CMT1A.

Emergent headaches during pregnancy: correlation between neurologic examination and neuroimaging.

BACKGROUND AND PURPOSE: Emergent evaluation of the pregnant headache patient requires rational selection of acute neuroimaging studies, yet guidelines do not exist. We investigated the demographic and clinical features that are predictive of intracranial pathologic lesions on neuroimaging studies in pregnant women with emergent headaches. MATERIALS AND METHODS: We conducted a retrospective review of demographic factors, clinical features, and radiologic findings in a consecutive case series of 63 pregnant women emergently evaluated with a chief complaint of headache, including those with previous headache histories. Clinical data were abstracted from emergency department records, hospital course, and discharge summaries. Multivariate logistic regression analysis examined predictors of intracranial pathologic lesions on emergent neuroimaging studies. RESULTS: Multiparous African American women constituted 63% of the case subjects. Headaches were frequently accompanied by photophobia (59%), nausea (52%), vomiting (37%), and occasionally with fever (11%), meningismus (9%), or seizures (7%). A total of 43% of case subjects had abnormal neurologic examination findings. Emergent neuroimaging, including noncontrast head CT and MR imaging, revealed an underlying headache etiology in 27%, including cerebral venous thrombosis, reversible posterior leukoencephalopathy, pseudotumor, and intracranial hemorrhage. The odds of having intracranial pathologic lesions on neuroimaging were 2.7 times higher in patients with abnormal results on neurologic examination (P=.085). CONCLUSIONS: Emergent neuroimaging studies may reveal an underlying headache etiology in 27% of pregnant women. Further research with a larger sample size is needed to determine what clinical factors are predictive of a pathologic condition on neuroimaging studies.