Background and objectives: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.
Methods: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.
Results: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.
Discussion: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.
Background and objectives: De novo gain-of-function variants in the CACNA1D gene, encoding the L-type voltage-gated Ca2+ channel CaV1.3, cause a multifaceted syndrome. Patients show variable degrees of autism spectrum disorder, developmental delay, epilepsy, and other neurologic and endocrine abnormalities (primary aldosteronism and/or hyperinsulinemic hypoglycemia). We study here a novel variant [c.3506G>A, NM_000720.4, p.(G1169D)] in 2 children with the same CACNA1D mutation but different disease severity.
Methods: The clinical data of the study patients were collected. After molecular analysis and cloning by site-directed mutagenesis, patch-clamp recordings of transfected tsA201 cells were conducted in whole-cell configuration. The functional effects of wild-type and mutated channels were analyzed.
Results: One child is a severely affected boy with a novel de novo CACNA1D variant with additional clinical symptoms including prenatal-onset tremor, congenital respiratory insufficiency requiring continuous positive airway pressure ventilation, and sensorineural deafness. Despite episodes of hypoglycemia, insulin levels were normal. Aldosterone:renin ratios as a screening parameter for primary aldosteronism were variable. In the second patient, putative mosaicism of the p.(G1169D) variant was associated with a less severe phenotype. Patch-clamp electrophysiology of the p.(G1169D) variant in a heterologous expression system revealed pronounced activity-enhancing gating changes, including a shift of channel activation and inactivation to more hyperpolarized potentials, as well as impaired channel inactivation and deactivation. Despite retained sensitivity to the Ca2+ channel blocker isradipine in vitro, no beneficial effects of isradipine or nifedipine treatment were observed in the index case.
Discussion: Through this report, we expand the knowledge about the disease presentation in patients with CACNA1D variants and show the novel variant's modulatory effects on CaV1.3 gating.
Objectives: DEPDC5-related epilepsy carries an increased risk of sudden unexpected death in epilepsy. We evaluated the occurrence and features of ictal central apnea (ICA) in patients with pathogenic sequence variant in DEPDC5.
Methods: We reviewed data of 108 patients collected in 2 independent cohorts of patients with focal epilepsy who prospectively underwent long-term video-EEG monitoring (LTVM) with cardiorespiratory polygraphy. All patients underwent (1) at least an overnight polysomnography, (2) a high-field (3T) brain MRI study, and (3) CSF analysis when clinically indicated. Genetic testing (next-generation sequencing [NGS]) was offered for diagnostic purposes to patients with focal epilepsy of unknown etiology.
Results: In this cohort, NGS was finally performed in 29 patients, resulting in DEPDC5 pathogenic mutations in 5 patients. According to the presence of ictal apnea events, 5 of 14 patients with ICA showed pathogenic DEPDC5 variants (35%) while none of the 15 patients without ICA showed pathogenic mutation. Notably, DEPDC5 patients showed ICA in all recorded seizures (n = 15) with apnea duration ranging from 20 seconds to more than 1 minute. All seizures were characterized by motor arrest without overt automatic behaviors during ictal apnea. Scalp EEG showed the involvement of temporal lobe leads in all events. Severe oxygen desaturation was observed in 2 cases.
Discussion: In our cohort, ictal central apnea was a common finding in DEPDC5. These results support (1) the need for respiratory polygraphy during LTVM in DEPDC5-related epilepsy and (2) the potential relevance of genetic testing in patients with focal epilepsy of unknown etiology and ictal apnea.
Background: Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders.
Objective: To determine whether a single heterozygous nonsense variant in TTN can be responsible for the observed dominant myopathy in a large family.
Methods: In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically.
Results: All affected family members showed a similar clinical phenotype with a combination of cardiac and skeletal muscle involvement. Muscle imaging data revealed titin-compatible hallmarks. Genetic analysis revealed in all affected patients a nonsense TTN variant c.70051C>T p.(Arg23351*), in exon 327. RNA sequencing confirmed the lack of complete nonsense-mediated decay, and protein studies convincingly revealed expression of a shortened titin fragment of the expected size.
Discussion: We conclude that a single heterozygous nonsense variant in titin occasionally can cause a dominant myopathy as shown in this large family. Therefore, monoallelic titin truncating variants should be considered as possible disease-causing variants in unsolved patients with a dominant myopathy. However, large segregation studies, muscle imaging, and RNA and protein assays are needed to support the clinical and genetic interpretation.
Objectives: Here, we report detailed clinicopathologic evaluation of 2 individuals with pathogenic variants in TBK1, including one novel likely pathogenic splice variant. We describe the striking diversity of clinical phenotypes among family members and also the brain and spinal cord neuropathology associated with these 2 distinct TBK1 variants.
Methods: Two individuals with pathogenic variants in TBK1 and their families were clinically characterized, and the probands subsequently underwent extensive postmortem neuropathologic examination of their brains and spinal cords.
Results: Multiple affected individuals within a single family were found to carry a previously unreported c.358+3A>G variant, predicted to alter splicing. Detailed histopathologic evaluation of our 2 TBK1 variant carriers demonstrated distinct TDP-43 pathologic subtypes, but shared argyrophilic grain disease (AGD) tau pathology.
Discussion: Although all pathogenic TBK1 variants are associated with TDP-43 pathology, the clinical and histologic features can be highly variable. Within one family, we describe distinct neurologic presentations which we propose are all caused by a novel c.358+3A>G variant. AGD is typically associated with older age, but it has been described as a copathologic finding in other TBK1 variant carriers and may be a common feature in FTLD-TDP due to TBK1.
Objectives: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome results from variations in RFC1 and is mostly caused by intronic biallelic pathogenic expansions (RE-RFC1). Refractory chronic cough (RCC) is frequently observed for years to decades preceding ataxia onset. Whether peripheral nerves are involved in the presymptomatic phase characterized by RCC is uncertain.
Methods: Here, patients previously screened for RCC and identified as having at least one RE-RFC1 intronic expansion underwent a comprehensive clinical and neurophysiologic assessment and were screened for additional exonic variations.
Results: Fourteen patients with RCC and RE-RFC1 were investigated. Seven patients presented with biallelic RE-RFC1 (Bi-RE-RFC1) while 7 presented with monoallelic RE-RFC1 (Mono-RE-RFC1). In patients with Mono-RE-RFC1, no additional exonic variation was identified, and clinical examinations were normal. Most of the patients with Bi-RE-RFC1 presented with subtle neurologic impairment, mainly exhibiting decreased lower limb vibration sense (85.7%). Nerve conduction studies revealed that all patients with Bi-RE-RFC1 exhibited lower sensory sum scores than patients with Mono-RE-RFC1 (median 20.2 µV vs 84.9 µV, p = 0.0012). In addition, the radial-to-sural sensory ratios were null or inverted (>0.5) in all patients but one with Bi-RE-RFC1, which is consistent with sensory neuronopathy.
Discussion: Patients with Bi-RE-RFC1 already exhibit widespread sensory neuron involvement at the time of apparently isolated RCC.
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