Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy

Objective

The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants.

Methods

Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools.

Results

The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide.

Interpretation

A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.

 Ann Neurol 2016

Decline in Weight and Incident Mild Cognitive Impairment Mayo Clinic Study of Aging

Importance  Unintentional weight loss has been associated with risk of dementia. Because mild cognitive impairment (MCI) is a prodromal stage for dementia, we sought to evaluate whether changes in weight and body mass index (BMI) may predict incident MCI.

Objective  To investigate the association of change in weight and BMI with risk of MCI.

Design, Setting, and Participants  A population-based, prospective study of participants 70 years of age or older from the Mayo Clinic Study of Aging, which was initiated on October 1, 2004. Maximum weight and height in midlife (40-65 years of age) were retrospectively ascertained from the medical records of participants using a medical records–linkage system. The statistical analyses were performed between January and November 2015.

Main Outcomes and Measures  Participants were evaluated for cognitive outcomes of normal cognition, MCI, or dementia at baseline and prospectively assessed for incident events at each 15-month evaluation. The association of rate of change in weight and BMI with risk of MCI was investigated using proportional hazards models.

Results  Over a mean follow-up of 4.4 years, 524 of 1895 cognitively normal participants developed incident MCI (50.3% were men; mean age, 78.5 years). The mean (SD) rate of weight change per decade from midlife to study entry was greater for participants who developed incident MCI vs those who remained cognitively normal (−2.0 [5.1] vs −1.2 [4.9] kg; P = .006). A greater decline in weight per decade was associated with an increased risk of incident MCI (hazard ratio [HR], 1.04 [95% CI, 1.02-1.06]; P < .001) after adjusting for sex, education, and apolipoprotein E (APOE) ε4 allele. A weight loss of 5 kg per decade corresponds to a 24% increase in risk of MCI (HR, 1.24). A higher decrease in BMI per decade was also associated with incident MCI (HR, 1.08 [95% CI, 1.03-1.13]; P = .003).

Conclusions and Relevance  These findings suggest that increasing weight loss per decade from midlife to late life is a marker for MCI and may help identify persons at increased risk for MCI.

JAMA Neurology

Factors Associated With 8-Year Mortality in Older Patients With Cerebral Small Vessel Disease The Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study

Importance  Gait and cognition have been related to mortality in population-based studies. This association is possibly mediated by cerebral small vessel disease (SVD), which has been associated with mortality as well. It is unknown which factors can predict mortality in individuals with SVD. Identification of high-risk patients may provide insight into factors that reflect their vital health status.

Objectives  To assess mortality in patients with cerebral SVD and identify potential clinical and/or imaging factors associated with mortality.

Design, Setting, and Participants  A prospective, single-center cohort study was conducted. The present investigation is embedded in the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study. Between January 17, 2006, and February 27, 2007, all participants underwent a cognitive and motor assessment and cerebral magnetic resonance imaging (MRI) including a diffusion tensor imaging sequence to assess microstructural integrity of the white matter. Participants were followed up until their death or November 24, 2014. Participants included 503 older adults with SVD noted on brain imaging. Data analysis was performed from November 26, 2014, to February 2, 2015.

Main Outcomes and Measures  Eight-year all-cause mortality.

Results  Of 503 participants (mean [SD] age, 65.7 [8.8] years; range, 50-85 years; 284 [56.5%] were male), 80 individuals (15.9%) died during a mean (SD) follow-up of 7.8 (1.5) years. In the final analysis, 494 (98.2%) were included, of whom 78 (15.8%) died. Gait speed, cognitive index, conventional MRI markers of SVD (white matter hyperintensity volume, brain volume, and lacunes), and diffusion measures of the white matter were associated with an 8-year risk of mortality independent of age, sex, and vascular risk factors. The prediction of mortality was determined using Cox proportional hazards models with backward stepwise selection and including age, sex, vascular risk factors, gait speed, cognitive index, MRI, and diffusion measures. Results are reported as hazard ratios (HRs) (95% CI). Older age (1.05 per 1-year increase [1.01-1.08]), lower gait speed (1.15 per 0.1-m/s slower gait [1.06-1.24]), lower gray matter volume (0.72 per 1-SD increase [0.55-0.95]), and greater global mean diffusivity of the white matter (1.51 per 1-SD increase [1.19-1.92]) were identified as the main factors associated with mortality. Cognitive index and other conventional SVD markers were not retained in the prediction model.

Conclusions and Relevance  Gait, cognition, and imaging markers of SVD are associated with 8-year risk of mortality. In the prediction of mortality, an older age, lower gait speed, lower gray matter volume, and greater global mean diffusivity of white matter at baseline best predicted mortality in our population. Further research is needed to investigate the reproducibility of this prediction model and to elucidate the association between the factors identified and mortality.

JAMA Neurology 2016

Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease.

CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.

European Journal of Human Genetics 2016

Amyloid pathology and axonal injury after brain trauma

Objective: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD).

Methods: Patients 11 months to 17 years after moderate–severe TBI underwent ¹¹C-Pittsburgh compound B (¹¹C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BP_ND) images of ¹¹C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BP_ND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with ¹¹C-PiB BP_ND.

Results: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased ¹¹C-PiB BP_ND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum.

Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

Neurology 2016

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies.

Methods: In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested.

Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155–negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n = 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.

Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments.

Neurology 2016

CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia

The CSTB gene encodes for cystatin B, an inhibitor of lysosomal cysteine protease (cathepsins B, H, L, and S). CSTBmutations have been associated with type 1 progressive myoclonic epilepsy, also known as Unverricht-Lundborg (ULD) disease, or Baltic myoclonus. A total of 90% of all disease alleles consists of an expansion of at least 30 times of an unstable 12-nucleotide stretch (dodecamer 5′-CCCCGCCCCGCG-3′) in the CSTB promoter region. Homozygosity for this expansion is considered the founder mutation in the Finnish population. Few other mutations have been described, among these the p.Arg68*, but until now only as compound heterozygous with the dodecamer expansion. Expression of the p.Arg68* mutation in vitro indicates that the truncated protein is rapidly degraded, confirming that it is a null mutation. Between the ages of 6 and 16 years, ULD begins with stimulus-sensitive myoclonus and generalized tonic-clonic seizures, which can be worsened by phenytoin, followed by ataxia and slow neurodegeneration. Here we report on the first 2 patients with a homozygous p.Arg68* null mutation.


Neurology 2016