Search

BackgroundBiallelic pathogenic variants inFXR1have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood.ObjectiveWe report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 ofFXR1.MethodsWhole exome sequencing was used to detect variants inFXR1.ResultsCommon clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients withFXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei.ConclusionFXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants inFXR1can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype–phenotype correlations difficult. Our work broadens the phenotypic spectrum ofFXR1-related congenital myopathy.

Yüksek oranda yağ, yeterli miktarda protein ve düşük karbonhidrat içeren ve açlıkta olduğu gibi vücudu glukoz yerine başlıca yağlardan enerji sağlayacak şekilde yönlendiren ketojenik diyet, geçmişten günümüze ilaca dirençli epilepsi hastalarının tedavisinde ilk akla gelen tedavi seçeneğidir. İlk olarak 1920’li yılların başında ‘klasik ketojenik diyet’ ile başlayan geleneksel KD tedavisini, diyetin yeni etki mekanizmalarının keşfedilmesi ile birlikte 2000’li yılların başından itibaren ortaya çıkan ve daha az kısıtlama yapılan alternatif KD’ler izlemiştir. Alternatif diyetler çoğunlukla diyete uyumun azaldığı adölesan (12-18 yaş) dönemde tercih edilse de, ciddi davranış sorunları olan ve diyetten fayda görmesine rağmen diyete uyumun azalması nedeniyle nöbet kontrolü sağlanamayan daha küçük yaştaki çocuklarda da göz önünde bulundurulması gerekebilir. Bu alternatif KD’lerden birisi olan düşük glisemik indeks tedavisi (LGIT) kan glukoz düzeylerini minimal ve stabil düzeyde tutmayı amaçlar ve bu şekilde epileptik nöbetler kontrol altına alınır. LGIT, klasik KD’e oranla daha fazla karbonhidrat (enerjinin yaklaşık %10’u, günde 40-60 g/gün düşük glisemik indeksli karbonhidratlar) ve protein (enerjinin %25’i) alımına, dolayısı ile daha fazla besin tüketimine olanak sağlar. Bu olgu sunumunda, preadölesan dönemde olan ve hafif nöbet bulguları, şiddetli elektroansefalogram (EEG) bozukluğu ve davranış bozuklukları ile izlenen bir vakada, klasik KD uygulamasındaki zorluklar ve LGIT diyetine geçişin tedavinin etkinliği üzerindeki etkileri tartışılmıştır.

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Objective To evaluate the clinical phenotype, disease course, laboratory, and genetic features of patients with CLN2 disease over a 20 year period with a special emphasis on risk factors for diagnostic delay. Methods Thirty patients (23 families) with CLN2 disease, evaluated between 1996 and 2019 in a tertiary referral center in Turkey, were included. Clinical features, diagnostic pathway, disease course, genetic data, electrophysiological, and neuroimaging findings were analyzed, retrospectively. The patients diagnosed between 1996 and 2009, and 2010–2019 were defined as group 1 (G1), and group 2 (G2), respectively. Patients in these two groups were also compared. Results The median age at symptom-onset was 36 months (20 months-7 years). Most common presenting symptoms were seizures (70%), followed by language delay (43%), and psychomotor regression (27%). Median age at diagnosis was 5.2 years (1.6–11 years) with a median 27 months (1 month-7 years) of diagnostic delay. Age at diagnosis was earlier in G2 (4.6 years vs 7 years, p = 0.002), with a shorter time to diagnosis (21 months vs 39 months, p = 0.004). Median time between the onset of first symptoms and death was 8.3 years (SE 1.0). Electroencephalograms (EEG) revealed abnormal features predominantly in posterior hemispheral regions and a photoparoxysmal response to intermittent photic stimulation was detected in 53% of the patients. Cerebellar (96%)/cerebral atrophy (83%), and white matter changes (57%) were the most common radiological abnormalities. Conclusions Most of our patients presented with late-infantile onset seizures. Despite increased availability of enzymatic and molecular testing, there is still a considerable diagnostic delay.

Aim: We aimed to evaluate clinical and laboratory features in children who presented unprovoked seizure for the first time and also to determine possible risk factors for seizure recurrence. Materials and Methods: A total of 219 patients (113 female, 106 male) who presented a first unprovoked seizure were included in the study. Demographic, clinical findings (type and duration of seizures, seizure recurrence, antiseizure drugs), neuroimaging findings and electroencephalography (EEG) results were recorded retrospectively. Results: The median age was 30 months (IQR 12-66). A history of birth hypoxia and/or phototherapy and family history of epilepsy were present in 21% and 17.4% of cases, respectively. Generalized seizures were the most common seizure type (42%), with a predominance at 2 years of age (p

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (ASNS_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (ASNS_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies., Amino acid deficiency: Asparagine supplementation for a neurometabolic disorder Study of two cases with a rare metabolic disorder, asparagine synthetase deficiency (ASNSD), has identified a new mutation and a potential treatment. Healthy individuals produce the amino acid asparagine, but patients with ASNSD cannot, resulting in severe seizures and cognitive impairment. Sequencing all protein-coding genes, Sebahattin Cirak, University of Cologne, Germany, and co-workers identified a novel mutation in two brothers with ASNSD. Only 31 cases have been reported, and there is no curative treatment available. This disorder can currently only be diagnosed by genetic testing. The disease symptoms seem not to progress once the patients were given an oral asparagine supplementation. The researchers emphasize to be cautios since this is an anectodal experience, and note that newborns with seizures should be genetically tested and further controlled clinical efficacy trials are required.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of cranial radiotherapy characterized by migraine-like headache and transient neurological deficits with typical gyriform enhancement on magnetic resonance imaging (MRI). Potential underlying mechanisms are endothelial damage or dysfunction, vascular instability, vasospasm and, neuronal dysfunction.We report an 11-year-old girl with a primary diagnosis of medulloblastoma presented with acute-onset severe headache and left-sided weakness, 20 months after completing cranial radiotherapy. MRI demonstrated unilateral cortical swelling and concomitant leptomeningeal, gyral contrast enhancement, and MR perfusion imaging showed increased cortical perfusion in the right temporo-parieto-occipital region. Her symptoms resolved spontaneously over several days.SMART syndrome appears to be a reversible, long-term complication of cranial radiotherapy. So far, a limited number of pediatric patients with SMART syndrome have been reported. Prompt recognition of clinical signs and radiological imaging of SMART syndrome may help prevent unnecessary interventions and initiate appropriate diagnostic workup and management.

Introduction Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS. Methods We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with ≥ 50% reduction of seizure frequency compared with the baseline were defined as “responders”. The clinical characteristics of responders and nonresponders were compared. Results A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7 years (3 months to 20 years) were included. The mean age at implantation was 12.4 years (4.5 to 18.5 years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (p = .07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction. Conclusion Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges.

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.

Inherited CD59 deficiency is a rare autosomal recessive disorder characterized by chronic hemolysis, recurrent ischemic central nervous system strokes, and early-onset relapsing peripheral demyelinating neuropathy mimicking recurrent Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). We report a 7-year-old girl who presented with neonatal-onset relapsing weakness accompanied by diffuse sensory-motor demyelinating peripheral polyneuropathy. She was diagnosed as having a CIDP-like disease and partially responded to immunomodulatory treatments. Cranial magnetic resonance imaging showed multiphasic brainstem and cerebellar ischemic lesions consistent with vasculopathy and chronic left middle cerebral artery infarction. Whole exome sequencing (WES) analysis revealed a frameshift deletion in CD59 (c.146delA, p.Asp49Valfs*31). Inherited CD59 deficiency should be considered in the differential diagnosis of patients with early-onset severe neurologic symptoms even without an overt hemolysis. We would like to highlight the role of WES in the diagnosis of a condition with a targeted therapy.

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

The posterior reversible encephalopathy syndrome (PRES) is a well-known clinical and radiologic entity mainly affecting the territory of the posterior cerebral circulation. Spinal cord involvement is extremely rare, and as of yet, only a few cases have been reported in the literature. The present case describes a reversible, longitudinal spinal cord lesion in a patient with high blood pressure. We discuss the differential diagnosis of longitudinal myelopathy and focus on the clinical presentation, diagnosis, and management of the “spinal cord variant of PRES.”

Dystroglycanopathies are a heterogeneous group of muscular dystrophies often associated with variable brain and eye involvement. Glycosylated alpha-dystroglycan (ADG) plays a key role in the development and stability of basement membranes as well as organizing axon guidance in the central nervous system. Congenital mirror movements, either isolated or in association with several genetic syndromes, are defined as inability to perform unimanual movements. We report an adolescent boy with limb-girdle muscular dystrophy due to ADG deficiency and coexisting congenital mirror movements. Genetic work-up revealed a novel homozygous missense mutation in the protein O-mannose kinase (POMK) gene. To our knowledge, this is the first patient in the literature with POMK mutation and congenital mirror movements.

UNLABELLED OBJective: To determine the demographic and clinical characteristics of type 1 diabetes (T1D) in the past two decades, and to analyze changing trends over the past 40 years. METHODS Patients with a diagnosis of T1D in 1990-2010 were included. Patients diagnosed in the first half of the period comprised Period I, and those from the second half comprised Period II. Age at onset, gender, seasonal distribution, infectious etiology, and clinical picture at onset are analyzed and compared in two periods. In addition, we compared these data with that of the preceding two decades (1969-1991), which was reported in a previous publication. RESULTS A total of 354 children with T1D were included in the study. The median age at diagnosis of T1D was 7 years in the period 1990-2010 in comparison to 9.5 years during the period 1969-1991. Patients were diagnosed mostly in winter and autumn, and 32.3% of the children had an infection at the time of diagnosis. Frequency of diabetic ketoacidosis was 50.8% at diagnosis. The peak age at onset was 4 to 6 years. CONCLUSIONS Our study provides substantial information about the clinical characteristics of Turkish children. The age of onset of T1D decreased in the past 20 years, as observed in other parts of the world. Our findings also suggest seasonality at onset of T1D. This study shows the changes of demographic and clinical characteristics of T1D in central and northeastern parts of our country over a 40 year period.