Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

What is the safe observation period for seizure recurrence in pediatric emergency departments?

BACKGROUND: Afebrile seizures are the common causes of emergency department (ED) admissions in childhood, and there is limited data on the observation period in emergency service follow-up of these patients in terms of seizure recurrence in the literature. This study aims to determine the seizure recurrence time in afebrile seizures and the risk factors that determine it. METHODS: Patients aged between 1 month and 18 years with afebrile seizures were included in the study. Seizure recurrence times, demographic data, diagnosis of epilepsy, use of antiseizure medications, Electroencephalography (EEG) and imaging results, structural abnormalities, hospitalizations, and treatments were recorded. RESULTS: The median age of 623 patients included in the study was 42 months (16.0-94.0 months) and 59.9% were male. Epilepsy was diagnosed in 372 (59.7%) of the patients. Short-acting benzodiazepine was administered in 249 of the cases. The mean observation time of the patients was 36 hours (24-98 hours). Electroencephalography (EEG) was applied in 437 (70.1%) of the patients and abnormality was detected in 53.5%. Seizure recurrence was observed in 149 patients (23.9%). The median time of seizure recurrence was 1.0 hour (0.5-4.0 hours). Eighty-six percent of the seizure recurrences (n = 129) occurred within the first six hours and 95.3% (n = 142) within the first 12 hours. Risk factors included a history of febrile seizures (p = 0.001, OR = 2.7), not receiving short-acting benzodiazepine therapy (p = 0.026, OR 1.7), previous structural abnormalities (p = 0.018, OR 1.8), and cluster seizures (p = 0.001, OR 6.7) for all patients and also EEG abnormalities in pediatric ED for first seizure (p = 0.012, OR 2.4). CONCLUSION: Patients with a history of febrile seizure, previous structural abnormalities, cluster seizures, EEG abnormalities in pediatric ED, and patients who didn't receive BZD treatment were at risk for seizure recurrence in the early period. Since most seizure recurrences occur within the first 6 hours, this period is the most critical time for recurrence risk.

Blood neurofilament light chain and thrombospondin-1 levels of patients with autism spectrum disorder.

BACKGROUND: Neurofilaments are intermediary filaments associated with neurodegenerative processes. Thrombospondin-1 (TSP-1) is a biological marker playing a role in synaptogenesis. This study aimed to investigate serum neurofilament light chain (NFL), and TSP1 levels of patients with autism spectrum disorder (ASD) compared to typically developing (TD) children. METHODS: Forty-three patients with ASD and forty-five TD children were included. Serum biomarker levels were measured using the sandwich ELISA technique. The Childhood Autism Rating Scale (CARS) was implemented to measure the severity of ASD. RESULTS: NFL and TSP1 levels did not differ between study groups (For NFL, ASD = 47.8 ± 11.4 vs. TD = 48.2 ± 15.3 pg/mL, p = 0.785; for TSP1, ASD = 224.4 ± 53.7 vs. TD = 224.7 ± 69.0 ng/mL, p = 0.828). Stereotyped behavior and sensory sensitivity domain of the CARS scale was negatively correlated with serum TSP-1 (r = -0.390, p = 0.010) and NFL (r = -0.377, p = 0.013) levels. Age was also positively correlated with NFL levels (r = 0.332, p = 0.030) in the ASD groups but not in the TD group. DISCUSSION: Our results did not support the neurodegenerative process of ASD. Future studies are needed to investigate neuroprogression in a longitudinal follow-up.

The effectiveness and tolerability of clobazam in the pediatric population: Adjunctive therapy and monotherapy in a large-cohort multicenter study.

OBJECTIVE: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups. METHODS: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. RESULTS: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptic syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy with genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs. CONCLUSIONS: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.

BACKGROUND: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. RESULTS: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. CONCLUSIONS: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy.

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.

VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain.

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

OCLN gene variants identified in three patients with severe neurodevelopmental disorder associated with epilepsy, intellectual disability and malformation of cortical development.

Homozygous OCLN variants have been reported in patients with band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) which is characterized by microcephaly, intracranial calcification and severe developmental delay. The OCLN gene encodes the integral membrane protein, occludin. Herein, we report three additional cases with homozygous OCLN variants that were identified via Trio-WES in two consanguineous unrelated families. We detected a previously reported frameshift variant in two cases in Family 1 and a novel missense variant in a case in Family 2. The potential pathogenicity of both variants in the index cases was investigated using in silico tools, and both variants were determined to be rare and predicted to be pathogenic. All of the presented cases exhibited clinical features in common with earlier reported patients, such as severe intellectual disability, microcephaly, polymicrogyria, epilepsy, hypotonia and severe developmental delay. On the other hand, in addition to the common phenotypic features, our two cases in Family 1 showed features similar to those previously reported in cases from two Turkish families carrying the same frameshift variant, such as renal failure. We herein expand the spectrum of OCLN gene variants with a description of an additional novel homozygous missense variant. The frameshift variant in Turkish cases may thus be a phenotype associated with renal failure in addition to the core phenotype associated with other OCLN gene variants, and such variants could be important for rapid molecular diagnosis and treatment. The frameshift variant in Turkish cases might also be investigated for both a potential founder effect and mutational hot spot.

Rare presentation of levamisole-induced leukoencephalopathy in a pediatric patient: seizure.

BACKGROUND: Levamisole is an imidazole derivative used in the treatment of various cancers, dermatological diseases, and parasitosis. Illegal use of levamisole by mixing it with cocaine in order to increase the psychotropic effects has also increased in recent years. Leukoencephalopathy is one of levamisole`s most prominent neurological side effects. CASE: Here we present the clinical, laboratory, imaging findings, treatment, and follow-up information of a 12-year-old girl who presented with seizures due to levamisole, which was prescribed to treat vitiligo. CONCLUSION: Levamisole-induced leukoencephalopathy should be considered in the differential diagnosis of demyelinating diseases, the neurotoxic effects of the drug should be well understood, and treatment should be initiated as soon as possible.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Clinical predictors of drug-resistant epilepsy in children

Background/aim: In up to 20% of epilepsy patients, seizures may not be controlled despite the use of antiepileptic drugs, either alone or in combination. These individuals are considered to have drug-resistant epilepsy. Drug-resistant epilepsy is usually associated with intellectual disability, psychiatric comorbidity, physical injury, sudden unexpected death, and low quality of life. Early detection and prediction of drug-resistant epilepsy are essential in determining the patient's most appropriate treatment option. This retrospective study aimed to determine the clinical, electroencephalographic, and radiological factors associated with medically intractable childhood seizures. Materials and methods: Data regarding 177 patients diagnosed with drug-resistant epilepsy were compared with 281 patients with drug-responsive epilepsy. Results: Univariate analysis showed that age at seizure onset, having mixed seizure types, history of status epilepticus, history of neonatal seizures, history of both having febrile and afebrile seizures, daily seizures at the onset, abnormality on the first electroencephalogram, generalized epileptic abnormality on electroencephalogram, abnormal neurodevelopmental status, abnormal neuroimaging, and having symptomatic etiology were significant risk factors for the development of drug-resistant epilepsy (p < 0.05). In multivariable analysis, having mixed seizure types, history of status epilepticus, having multiple seizures in a day, intellectual disability, symptomatic etiology, and neuroimaging abnormality remained significant predictors for developing drug-resistant epilepsy. Conclusions: In the course of childhood epilepsy, some clinical features may predict the outcome. Early identification of patients with high risk for drug-resistant epilepsy will help plan the appropriate treatment option. Further prospective studies should confirm these findings.

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

Intravenous Levetiracetam for Treatment of Seizures in Term and Preterm Neonates.

CONTEXT: Seizures are the most frequent neurological disturbance in the neonatal period, and there are no evidence-based guidelines for the treatment of neonatal seizures. Here we report a study on the use of levetiracetam as second-line therapy in the treatment of seizures in term and preterm neonates. AIM: The aim of this study was to assess the efficacy and safety of levetiracetam for seizures of term and preterm neonates. SETTINGS AND DESIGN: We retrospectively analyzed data of the patients who had seizures and who were treated with levetiracetam as an add-on therapy to phenobarbital during the neonatal period. STATISTICAL ANALYSIS: The Statistical Package for the Social Sciences (SPSS) software, version 15.0 (SPSS, Chicago, Illinois), was used for statistical analysis. Continuous variables were expressed as mean values and standard deviations. RESULTS: Thirty-six patients (8 term and 28 preterm) received levetiracetam. Mean dose of levetiracetam was 31.67 ± 14.83mg/kg/day. Twenty-five of the patients (69.4%) were seizure free with levetiracetam treatment. Electroencephalography recordings improved in 28 (77.8%) of the patients after levetiracetam. No severe adverse effects were observed. CONCLUSION: Our data suggest that levetiracetam may be a safe and effective treatment for neonatal seizures, which are unresponsive to phenobarbital.

Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype. METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.

COL4A1-related autosomal recessive encephalopathy in 2 Turkish children.

OBJECTIVE: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases. METHODS: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents. RESULTS: We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease. CONCLUSIONS: COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

Herpes simplex virus-1 as a rare etiology of isolated acute cerebellitis: case report and literature review.

Acute cerebellitis is one of the most common cerebellar disorders and occurs due to para-infectious, post-infectious, or post-vaccination cerebellar inflammation. Herpes simplex virus-1 (HSV-1) is known as a common infectious cause of sporadic encephalitis. Cerebellar involvement of HSV-1 is rare and almost always associated with meningoencephalitis. To date, HSV-1 has been identified as the cause of acute isolated cerebellitis in only two patients. Here we report another case of isolated acute cerebellitis caused by HSV-1 in a 20-month-old boy.

Severe neurodevelopmental disease caused by a homozygous TLK2 variant.

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

Dihydropyridine Receptor Congenital Myopathy In A Consangineous Turkish Family.

Dihydropyridine receptor congenital myopathy is a recently described congenital myopathy caused by dominant or recessive mutations in the CACNA1S gene. To date, only 11 cases from 7 families were described in a single report. Here, we describe a consanguineous family with three affected children, presenting congenital hypotonia, contractures, ophthalmoplegia and respiratory insufficiency, with a novel homozygous mutation in the CACNA1S gene. They also showed cognitive delay, pes equinovarus deformity and neurogenic changes that have not been associated with this myopathy in the previous reports. This report expands the phenotypic spectrum of dihydropyridine receptor congenital myopathy and underscores the importance of whole exome sequencing in early onset neuromuscular disorders.