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.
Background and objectives: Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the loss or presence of point pathogenic variants in the SMN1 gene. The main positive modifier of the SMA phenotype is the number of copies of the SMN2 gene, a paralog of SMN1, which only produces around 10%-15% of functional SMN protein. The SMN2 copy number is inversely correlated with phenotype severity; however, discrepancies between the SMA type and the SMN2 copy number have been reported. The presence of SMN2-SMN1 hybrids has been proposed as a possible modifier of SMA disease.
Methods: We studied 31 patients with SMA, followed at a single center and molecularly diagnosed by Multiplex Ligand-Dependent Probe Amplification (MLPA), with a specific next-generation sequencing protocol to investigate their SMN2 genes in depth. Hybrid characterization also included bioinformatics haplotype phasing and specific PCRs to resolve each SMN2-SMN1 hybrid structure.
Results: We detected SMN2-SMN1 hybrid genes in 45.2% of the patients (14/31), the highest rate reported to date. This represents a total of 25 hybrid alleles, with 9 different structures, of which only 4 are detectable by MLPA. Of particular interest were 2 patients who presented 4 SMN2-SMN1 hybrid copies each and no pure SMN2 copies, an event reported here for the first time. No clear trend between the presence of hybrids and a milder phenotype was observed, although 5 of the patients with hybrid copies showed a better-than-expected phenotype. The higher hybrid detection rate in our cohort may be due to both the methodology applied, which allows an in-depth characterization of the SMN genes and the ethnicity of the patients, mainly of African origin.
Discussion: Although hybrid genes have been proposed to be beneficial for patients with SMA, our work revealed great complexity and variability between hybrid structures; therefore, each hybrid structure should be studied independently to determine its contribution to the SMA phenotype. Large-scale studies are needed to gain a better understanding of the function and implications of SMN2-SMN1 hybrid copies, improving genotype-phenotype correlations and prediction of the evolution of patients with SMA.
Objectives: This study characterizes oculopharyngodistal myopathy in 4 Thai patients from 3 families with CGG/CCG repeat expansion in LOC642361/NUTM2B-AS1.
Methods: Repeat-primed PCR analyzed CGG/CCG repeat size in LOC642361/NUTM2B-AS1 in 4 Thai patients suspected of oculopharyngodistal myopathy (OPDM). Clinical records were reviewed for clinicopathologic features.
Results: All patients exhibited strong somatic instabilities of the expanded CGG/CCG repeats, primarily manifesting as oculopharyngeal weakness. Patient 1 had mild finger extensor and intrinsic hand muscle weakness, and although patient 2 lacked limb weakness, both siblings showed electrophysiologic evidence of distal myopathy, indicative of OPDM. Patient 3, the daughter of a sibling with OPDM reported in 2004, lacked limb weakness or leukoencephalopathy on brain MRI. Patient 4, initially misdiagnosed with refractory myasthenia gravis, had generalized muscle weakness.
Discussion: While initially characterized as oculopharyngeal myopathy with leukoencephalopathy (OPML) in a Japanese family, our study suggests a stronger association between CGG/CCG expansion in LOC642361/NUTM2B-AS1 and oculopharyngodistal myopathy (OPDM) rather than OPML. The variable presence or absence of leukoencephalopathy further supports OPDM as the predominant clinical manifestation linked to CGG/CCG expansion in LOC642361/NUTM2B-AS1.
Objectives: To provide a comprehensive description of neuroradiologic findings in a patient with a probable pathogenic variant of HUWE1, particularly in relation to pontine and cerebellar hypoplasia.
Methods: We first report prenatal and postnatal neuroradiologic phenotype of a female patient carrying a HUWE1 likely pathogenic variant and discuss its function.
Results: An ultrasound shows borderline ventriculomegaly, rotated cerebellar vermis, and dysgenetic corpus callosum. An MR study identify a short, thin corpus callosum, falcine sinus persistence, reduced cerebellar vermis size, wide inferior IV ventricle, and reduced pontine bulging.
Discussion: HUWE1 is a gene encoding an E3 ubitiquine ligase protein involved in nervous system development, function, and disease. The mechanisms by which HUWE1 gene affects nervous system are still largely unclear, but a growing body of literature described disease-causing variants in this gene. This report may help prenatal diagnostic experts in consider also this entity, especially when dealing with pontine and cerebellar hypoplasia findings.
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