Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

The deleterious effects of methamphetamine use on initial presentation and clinical outcomes in aneurysmal subarachnoid hemorrhage.

OBJECT: The objective of this study was to retrospectively look at methamphetamine (MA) use in patients with aneurysmal subarachnoid hemorrhage (SAH) to determine if MA use affects clinical presentation and outcomes after aneurysmal SAH. METHODS: A retrospective review of patients admitted to the Oregon Health & Science University neurosurgical service with aneurysmal SAH during the past 6 years was undertaken. Variables analyzed included MA use, age, sex, cigarette use, Hunt and Hess grade, Fisher grade, admission blood pressure, aneurysm characteristics, occurrence of vasospasm, hospital length of stay (LOS), cerebral infarction, aneurysm treatment, and Glasgow Outcome Scale (GOS) score. Data differences between MA users and nonusers were statistically analyzed using multivariate logistic regression analysis. A separate comparison with randomly selected age-matched nonuser controls was also performed. RESULTS: Twenty-eight (7%) of 374 patients with aneurysmal SAH were identified as MA users. Methamphetamine users were younger than nonusers (45.2 vs 55.9 years, respectively; p <0.001). Despite a younger age, MA users had significantly higher Hunt and Hess grades than nonusers (3.0 vs 2.5, respectively; p <0.020) and age-matched controls (3.0 vs 2.0, respectively; p <0.001). Earliest available mean arterial pressure was significantly higher in MA users (122.1 vs 109.7, respectively; p = 0.005) than all nonusers but not age-matched controls. Methamphetamine users had significantly higher vasospasm rates than nonusers (92.9% vs 71.1%, respectively; p = 0.008) but similar rates as age-matched controls (92.9% vs 89.3%, respectively; p = 0.500). Glasgow Outcome Scale score did not differ significantly between users and nonusers (3 vs 4, respectively; p = 0.170), but users had significantly lower GOS scores than age-matched controls (3 vs 5, respectively; p <0.001). There was no statistically significant difference in the LOS between users and nonusers (18 days vs 16 days, respectively; p = 0.431) or users and age-matched controls (18 days vs 14 days, respectively; p = 0.250). In the multivariate analysis, MA use (OR 3.777, p = 0.018), age (p <0.001), Fisher grade (p = 0.011), Hunt and Hess grade (p <0.001), and cerebral infarction (p <0.001) were predictors of poor GOS score. The only predictor of vasospasm was age (p <0.001), although a strong predictive trend in MA use (p = 0.149) was found. Predictors of a hospital LOS >15 days included age (p = 0.002), Fisher grade (p = 0.002), Hunt and Hess grade (p <0.001), and cerebral infarction (p <0.001). Predictors of cerebral infarction include male sex (p = 0.022) and Hunt and Hess grade (p = 0.006), with vasospasm demonstrating a strong trend (p = 0.056). CONCLUSIONS: A history of MA use may predict poorer outcomes in patients who present with aneurysmal SAH. Methamphetamine users have significantly worse presentations and outcomes when compared with age-matched controls.