Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.

We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an approximately 12 Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with a LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison to wild type STXBP5L. Furthermore, wild type STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

Hum Mol Genet 2014

Increased risk of Bell palsy in patients with migraine

Objective: To evaluate the association between migraine and Bell palsy and to examine the effects of age, sex, migraine subtype, and comorbid risk factors for Bell palsy.

Methods: This nationwide cohort study was conducted using data from the Taiwan National Health InsuranceResearch Database. Subjects aged 18 years or older with neurologist-diagnosed migraine from 2005 to 2009 were included. A nonheadache age- and propensity score–matched control cohort was selected for comparison. All subjects were followed until the end of 2010, death, or the occurrence of a Bell palsy event. Cox proportional hazards regression was used to calculate the adjusted hazard ratios and 95% confidence intervals to compare the risk of Bell palsy between groups.

Results: Both cohorts (n = 136,704 each) were followed for a mean of 3.2 years. During the follow-up period, 671 patients (424,372 person-years) in the migraine cohort and 365 matched control subjects (438,677 person-years) were newly diagnosed with Bell palsy (incidence rates, 158.1 and 83.2/100,000 person-years, respectively). The adjusted hazard ratio for Bell palsy was 1.91 (95% confidence interval, 1.68–2.17; p < 0.001). The association between migraine and Bell palsy remained significant in sensitivity analyses, and tests of interaction failed to reach significance in all subgroup analyses.

Conclusion: Migraine is a previously unidentified risk factor for Bell palsy. The association between these 2 conditions suggests a linked disease mechanism, which is worthy of further exploration.

Neurology 2014

Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective.

Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B).

Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival.

Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation.

Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.

Neurology 2014

ATXN2 polyQ intermediate repeats are a modifier of ALS survival

Objective: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).

Methods: PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.

Results: In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3–2.2; polyQ <31, 2.7 years, IQR 1.6–5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5–3.4; polyQ <31, 3.2 years, IQR 2.0–6.4; p = 0.007).

Conclusions: ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.

Neurology 2014

The amygdala Functional organization and involvement in neurologic disorders

The amygdala consists of a group of heterogeneous nuclei located in the medial portion of the temporal lobe and is involved in multimodal information processing important for emotional recognition and behavior. Its complex structure includes basolateral, centromedial, and cortical nuclear complexes that have extensive connections with several cortical and subcortical structures. Pioneering studies on rodents established that the amygdala is critical for theacquisition and expression of conditioned (Pavlovian) fear responses and yielded important insights into its intrinsic connectivity and synaptic plasticity. More recent studies indicate that neurons of the amygdala differentially respond to the valence (positive or negative affective significance) of stimuli and that the amygdala, via its interconnections with the prefrontal cortex, is necessary for representation of value that is required for reward-based decision-making. Functional neuroimaging and electrophysiologic and psychometric approaches both in healthy persons and in patients with selective damage of the amygdala in genetic disorders such as lipoid proteinosis (Urbach-Wiethe disease) support its role in many aspects of emotional processing, including recognition of emotional expression in faces. The amygdala is affected in several neurologic disorders and psychiatric disorders including Alzheimer disease (AD), temporal lobe epilepsy (TLE), and anxiety, and depression. The anatomy and physiology of the amygdala and its role in emotion and behavior has been reviewed.

Neuurology 2014

The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5–2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2–12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.

Epilepsia 2014

Disturbed mitochondrial dynamics and neurodegenerative disorders

Mitochondria form a highly interconnected tubular network throughout the cell via a dynamic process, with mitochondrial segments fusing and breaking apart continuously. Strong evidence has emerged to implicate disturbed mitochondrial fusion and fission as central pathological components underpinning a number of childhood and adult-onset neurodegenerative disorders. Several proteins that regulate the morphology of the mitochondrial network have been identified, the most widely studied of which are optic atrophy 1 and mitofusin 2. Pathogenic mutations that disrupt these two pro-fusion proteins cause autosomal dominant optic atrophy and axonal Charcot–Marie–Tooth disease type 2A, respectively. These disorders predominantly affect specialized neurons that require precise shuttling of mitochondria over long axonal distances. Considerable insight has also been gained by carefully dissecting the deleterious consequences of imbalances in mitochondrial fusion and fission on respiratory chain function, mitochondrial quality control (mitophagy), and programmed cell death. Interestingly, these cellular processes are also implicated in more-common complex neurodegenerative disorders, such as Alzheimer disease and Parkinson disease, indicating a common pathological thread and a close relationship with mitochondrial structure, function and localization. Understanding how these fundamental processes become disrupted will prove crucial to the development of therapies for the growing number of neurodegenerative disorders linked to disturbed mitochondrial dynamics.

Nature Reviews Neurology 2014