Transient response to high-dose niacin therapy in a patient with NAXE deficiency.

Background: NAXE-encephalopathy or early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL-1) and NAXD-encephalopathy (PEBEL-2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation. Methods: We describe a patient with a confirmed PEBEL-1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL-1 and PEBEL-2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off-label use of a COX2 inhibitor to treat niacin-related urticaria in NAXE-encephalopathy. Results: So far, seven patients with PEBEL-1 and PEBEL-2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL-1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient. Conclusion: Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date.

Guillain-Barré Syndrome Associated with SARS-CoV-2 in Two Pediatric Patients.

Guillain-Barré syndrome (GBS) is a recognised complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report two children with GBS associated with SARS-CoV-2 who presented to a tertiary centre in Muscat, Oman in 2021: The first patient was a three-month-old female infant who presented with bradypnea, encephalopathy, and generalised weakness that required mechanical ventilation. Polymerase chain reaction (PCR) testing of the nasopharyngeal swabs (NPS) was positive for SARS-CoV-2. She had axonal variant GBS based on a nerve conduction study, cerebrospinal fluid analysis, and neuroimaging findings. The second patient was a six-year-old girl with fever, vomiting, and diarrhea followed by ascending weakness who presented with quadriplegia and facial weakness. Subsequently, she developed respiratory muscle weakness and required mechanical ventilation. PCR testing of NPS was negative for SARS-Cov-2, however IgG serology analysis was positive. The clinical course of these two patients was rapidly progressive and both of them required mechanical ventilation. The patient with axonal variant GBS made an incomplete recovery.

Autosomal Recessive NOTCH3-Related Leukodystrophy in Two Siblings and Review of the Literature.

BACKGROUND: NOTCH3, a large type I transmembrane receptor expressed on arterial smooth muscle cells and capillary pericytes, features a diverse extracellular domain with 34 epidermal growth factor-like repeats. It exhibits distinct phenotypes due to variant zygosity and type; missense mutations cause CADASIL with cerebral vasculopathy, while null mutations lead to severe congenital manifestations. METHODS: This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations. RESULTS: These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3. CONCLUSIONS: The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.

Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects.

Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as MYH2, TPM2, and TNNI2 that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in ACTC1 and suggests that some functions of ACTC1 are shared in cardiac and skeletal muscle.

Case report: Cyclosporine A-induced extrapyramidal syndrome following hematopoietic stem cell transplantation.

Introduction: Cyclosporine A-associated neurotoxicity has been reported in up to 40% of patients and its wide range of neurological adverse effects have been reported, ranging from mild tremors to fatal leukoencephalopathy. Extrapyramidal (EP) neurotoxicity is a rare manifestation of cyclosporine. Cyclosporine-induced extrapyramidal syndrome remains a rare adverse reaction. Design/methods: A database search was performed for studies in patients from all age groups. We found a total of 10 articles reporting EP as an adverse effect of cyclosporine A. A total of 16 patients were found, and a thorough review of these patients was performed. A comparison of patients was performed to highlight common clinical presentations, investigations during the symptomatic phase, and prognosis. In addition, we describe an 8-year-old boy who developed cyclosporine-related extrapyramidal signs on day 60 post-hematopoietic stem cell transplantation for beta-thalassemia. Conclusion: Cyclosporine A can induce neurotoxicity resulting in diverse symptoms. Signs of EP are rare manifestations of cyclosporine neurotoxicity and should be considered when evaluating post-transplant recipients of cyclosporine when they are present with any EP symptoms. Discontinuation of cyclosporine results in good recovery in most patients.

Characteristics of Children With Cerebral Palsy in the Post-Therapeutic Hypothermia Era.

Objectives: To explore the profile of children with cerebral palsy secondary to intrapartum asphyxia treated with therapeutic hypothermia after birth and to compare characteristics of children treated with therapeutic hypothermia with mild vs severe cerebral palsy outcome. Study Design: We identified all children treated with therapeutic hypothermia for intrapartum asphyxia in a single-center tertiary-level neonatal intensive care unit from 2008 to 2018 with a cerebral palsy outcome. We collected perinatal and outcome measures from patient charts. We searched the literature for characteristics of children with cerebral palsy prior to therapeutic hypothermia (historical cohort) to compare to our cohort. We subdivided our cohort into mild vs severe cerebral palsy and compared neonatal characteristics to identify predictors of severe phenotype. Results: Thirty of 355 cooled neonates (8%) developed cerebral palsy. More children had spastic quadriparesis and epilepsy, and fewer had visual impairment in the post-therapeutic hypothermia era compared to the historical cohort, but had similar Gross Motor Function Classification System scores. In our cohort, more children had severe (19 of 30, 63%) compared to mild cerebral palsy (11 of 30, 37%). The severe group had higher mean birth weight, lower 5- and 10-minute Apgar scores, and more often white matter injury with associated deep gray matter injury or near-total injury pattern (P < .05). Conclusions: Our data demonstrated more infants with severe rather than mild cerebral palsy in our cohort treated with therapeutic hypothermia. Birthweight, 5- and 10-minute Apgar scores, and magnetic resonance imaging (MRI) findings were significantly different between mild and severe phenotype groups. Our findings can guide clinicians how to better weigh these factors, when counseling parents in the neonatal period.

MLIP-Associated Myopathy: A Case Report and Review of the Literature.

BACKGROUND: Muscular A-type lamin-interacting protein (MLIP) has a regulatory role in myoblast differentiation and organization of myonuclear positioning in skeletal muscle. It is ubiquitously expressed but abundantly in cardiac, skeletal, and smooth muscles. Recently, two studies confirmed the causation of biallelic pathogenic variants in the MLIP gene of a novel myopathy phenotype. OBJECTIVE: Description of the phenotypic spectrum and features of MLIP-related myopathy. METHODS: report a patient with biallelic variants in MLIP gene with the clinical features, and histomorphological findings of MLIP-related myopathy and provide a literature review of the previously reported 12 patients. RESULTS: MLIP-related myopathy is characterized by episodes of rhabdomyolysis, myalgia triggered by mild to moderate exercise, mild muscle weakness, and sometimes cardiac involvement characterized by cardiomyopathy and cardiac rhythm abnormalities. CONCLUSIONS: This report reviews and extends the clinical features of a novel myopathy caused by biallelic pathogenic variants in the MLIP gene.

Respiratory characteristics in children with spinal muscular atrophy type 1 receiving nusinersen.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a neuromuscular disorder with a natural history of chronic respiratory failure and death during infancy without ventilation. Recently, disease-modifying therapies such as nusinersen have improved disease trajectory. However, objective data on the trajectory of polysomnography outcomes, the relationship between motor scores and respiratory parameters, respiratory technology dependence and healthcare utilization in children with SMA1 remain to be elucidated. METHODS: This was a retrospective observational study of children with SMA1 receiving nusinersen between October 2016 and February 2021 at two tertiary care hospitals in Canada. Baseline polysomnography data, motor scores, respiratory technology, and unanticipated healthcare utilization were examined. RESULTS: Eleven children (five females, two SMN2 copies each) were included. Median (interquartile range [IQR]) age at diagnosis was 3.6 (2.8-5.0) months and age at diagnostic polysomnogram following nusinersen initiation was 9.4 (5.3-14.0) months. Nusinersen was initiated at a median (IQR) age of 5.4 (3.4-7.6) months and 8/11 children had respiratory symptoms at that time. Diagnostic polysomnography data showed a median (IQR) central apnea-hypopnea index (AHI) of 4.1 (1.8-10.0) and obstructive AHI of 2.2 (0-8.0) events/h. We observed an inverse relationship between motor scores and central apnea-hypopnea indices. All children required ventilatory support at the end of the study period. CONCLUSION: This study showed abnormal polysomnography parameters and need for ventilation despite nusinersen suggesting ongoing need for regular monitoring with polysomnography. Understanding the respiratory disease trajectory of children undergoing treatment with nusinersen will inform decision-making regarding optimal timing of ventilatory support initiation.

Distinctive Neuroimaging Pattern in Term Newborns With Neonatal Placental Encephalopathy: A Case Series.

BACKGROUND: Identifying antepartum versus intrapartum timing and the cause of neonatal encephalopathy (NE) often remains elusive owing to our limited understanding of the underlying pathophysiological processes and lack of appropriate biomarkers. OBJECTIVES: This retrospective observational study describes a case series of term newborns with NE who displayed a recognizable magnetic resonance imaging pattern of immediately postnatal brain abnormalities that rapidly evolved toward cavitation. Our aim is to (1) report this neuroimaging pattern, (2) look for placental determinants, and (3) depict the outcome. DESIGN/METHODS: This is a unicentric retrospective case series reporting the clinical, radiological, and laboratory findings of NE associated with a distinctive neuroimaging pattern, that is, immediately postnatal extensive corticosubcortical T2 hyperintensities, followed by rapid corticosubcortical cavitation that does not match the neuroimaging picture of intrapartum hypoxic-ischemic encephalopathy (HIE). RESULTS: Seven term newborns presented bilateral corticosubcortical hyperintensities that were detected on T2 between day of life (DOL) 1-4, which rapidly evolved toward cystic encephalomalacia, that is, between DOL9 and DOL12. All these newborns presented with moderate/severe NE. The outcome was either neonatal death or quadriplegic cerebral palsy and epilepsy. None of the reported patients fulfilled the criteria of a high likelihood of acute intrapartum hypoxic-ischemic or quadriplegic cerebral palsy. All these newborns were exposed to chronic and/or acute placental inflammation and/or hypoxic-ischemic. CONCLUSIONS: To further define the antepartum causes of NE, early neuroimaging and a placental examination are recommended. Brain T2 hyperintense injuries before DOL4 followed by rapid cavitation before DOL12 might be biomarkers of NE from an antepartum/placental origin.

Death after Birth Asphyxia in the Cooling Era.

In asphyxiated newborn infants treated with hypothermia, 31 of 50 (62%) deaths occurred in unstable infants electively extubated before completing hypothermia treatment. Later deaths occurred after consultation with palliative care (13/19) or clinical ethics (6/19) services, suggesting these decisions were challenging and required support, particularly if nutrition and hydration were withdrawn (n = 4).

Prediction of outcome in asphyxiated newborns treated with hypothermia: Is a MRI scoring system described before the cooling era still useful?

AIM: To determine whether an MRI scoring system, which was validated in the pre-cooling era, can still predict the neurodevelopmental outcome of asphyxiated newborns treated with hypothermia at 2 years of age. PATIENTS AND METHOD: We conducted a retrospective cohort study of asphyxiated newborns treated with hypothermia. An MRI scoring system, which was validated in the pre-cooling era, was used to grade the severity of brain injury on the neonatal brain MRI. Their neurodevelopment was assessed around 2 years of age; adverse outcome included cerebral palsy, global developmental delay, and/or epilepsy. RESULTS: One hundred and sixty-nine newborns were included. Among the 131 newborns who survived and had a brain MRI during the neonatal period, 92% were evaluated around 2 years of age or later. Of these newborns, 37% displayed brain injury, and 23% developed an adverse outcome. Asphyxiated newborns treated with hypothermia who had an adverse outcome had a significantly higher MRI score (p <0.001) compared to those without an adverse outcome. CONCLUSION: An MRI scoring system that was validated before the cooling era is still able to reliably differentiate which of the asphyxiated newborns treated with hypothermia were more prone to develop an adverse outcome around 2 years of age.

Intravenous Immunoglobulin as a Treatment for Intractable Epilepsy Secondary to Focal Cortical Dysplasia: A Meta-analysis.

BACKGROUND: The observation of a dramatic response to intravenous immunoglobulin (IVIG) by a child from our center with intractable epilepsy due to focal cortical dysplasia prompted us to perform a meta-analysis on the efficiency of IVIG in this condition. Focal cortical dysplasia is a common cause of intractable epilepsy. Microglial activation and upregulation of neuroinflammatory pathways have been documented in brain specimen from surgically treated patients with intractable epilepsy and focal cortical dysplasia. IVIG has been used for decades to treat patients with intractable epilepsy; however, there is little evidence regarding its efficacy, possibly because of the pathophysiological heterogeneity of patients included in most of the published studies. METHODS: A search for studies in patients from 0 to 18 years was performed in databases. We found four observational studies-prospective or retrospective-including patients with focal cortical dysplasia with intractable epilepsy treated with IVIG. The primary outcome was a reduction of seizure frequency by more than 50%. RESULTS: A total of eight patients were included in this meta-analysis. The intravenous immunoglobulin doses ranged from 0.2 to 1 g/kg/day, repeated three to six times over one to 14 months (median: five months). Intravenous immunoglobulin was associated with reduced seizure frequency in six out of eight patients (P < 0.05). Among these six patients, the reduction of seizure frequency lasted for nine months to nine years (median: 3.7 years). There were either no or mild adverse effects of IVIG infusion including postinfusion paresthesia (n = 1) and a transient increase in temperature (n = 1). CONCLUSIONS: Despite obvious limitations, mainly because of the small number of patients, and the selection biases, this study suggests that, based on the available data, IVIG might be effective in the treatment of intractable epilepsy secondary to focal cortical dysplasia. Further therapeutic trials are mandatory to further clarify the efficacy of IVIG in this condition.

Early Imaging and Adverse Neurodevelopmental Outcome in Asphyxiated Newborns Treated With Hypothermia.

BACKGROUND: Brain injury can be identified as early as day two of life in asphyxiated newborns treated with hypothermia, when using diffusion magnetic resonance imaging (MRI). However, it remains unclear whether these diffusion changes can predict future neurodevelopment. This study aimed to determine whether abnormal early diffusion changes in newborns treated with hypothermia are associated with adverse neurodevelopmental outcome at age two years. METHODS: Asphyxiated newborns treated with hypothermia were enrolled prospectively. They underwent magnetic resonance imaging (MRI) at specific time points over the first month of life, including diffusion-weighted imaging and diffusion-tensor imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in different regions of interest. Adverse neurodevelopmental outcome was defined as cerebral palsy, global developmental delay, and/or seizure disorder around age two years. ADC and FA values were compared between the newborns developing or not developing adverse outcome. RESULTS: Twenty-nine asphyxiated newborns treated with hypothermia were included. Among the newborns developing adverse outcome, ADC values were significantly decreased on days two to three of life and increased around day ten of life in the thalamus, posterior limb of the internal capsule, and the lentiform nucleus. FA values decreased in the same regions around day 30 of life. These newborns also had increased ADC around day ten of life and around day 30 of life, and decreased FA around day 30 of life in the anterior and posterior white matter. CONCLUSIONS: Diffusion changes that were evident as early as day two of life, when the asphyxiated newborns were still treated with hypothermia, were associated with later abnormal neurodevelopmental outcome.