A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.

OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years. RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

Detection of HSV-1, HSV-2 and VZV Isolated from Cerebrospinal Fluid Samples of Children Suspected to Encephalitis.

Background: Encephalitis is an uncommon, serious brain infection that can cause fatality among children. The cause of most encephalitis remained unknown, yet viruses are the most well-known infectious agents that cause encephalitis. This study aimed to determine varicella-zoster virus (VZV) and herpes simplex virus type 1, 2 (HSV1/2) among individuals who are under 5 years of age in Iran. Materials and Methods: In this study, 149 cerebrospinal fluid samples of suspected patients of encephalitis were analyzed with some symptoms, such as seizure, fever, nausea loss of consciousness, and dizziness from Mofid Children's Hospital in Tehran, Iran. Then, the molecular evaluation of samples was performed using multiplex Polymerase Chain Reaction (PCR) for detecting HSV1/2 and VZV. Results: The mean age of the patients was 1.8 years. Also, 63.4% of children were male and 36.6% were female. Out of 149 tested samples, 11 (7.3%) showed the viral DNA for one of the herpes viruses (7.3%). Nine samples were HSV1 positive (6.0%) and two samples were VZV positive (1.3%). Fever and vomiting were the most frequent symptoms. The mean ± standard deviation (SD) WBC and counts in cerebrospinal fluid (CSF)-positive samples, and all included samples were 298.8 ± 552.7 cells/µL and 131.1 ± 474.6 cells/µL, respectively. Conclusions: Although viral encephalitis is considered a threat to children's health, with accurate diagnosis and appropriate antiviral drugs, death and neurological complications in children can be prevented.

Clinical and MRI characteristics of multiple sclerosis in Iranian Children and Adolescents.

Objective: To determine the clinical and MRI characteristics of multiple sclerosis (MS) in the children and adolescents. Material & Methods: In this cross-sectional study, information of 95 MS patients was obtained from the Iranian MS registry. Disease characteristics and imaging data were collected using medical records. Results: Ninety-five patients including 64 female and 31 male subjects with mean age of 13.97±2.4 years (range, 8-18) years were enrolled. The most frequent signs and symptoms were ophthalmic symptoms (n=61, 64.2%), brainstem signs (n=44, 46.3%), cerebellar signs (n=32, 33.6%) and pyramidal signs (n=26, 27.3%). Blurred vision (n=21, 34.4%) was the most common ophthalmic symptom and ataxia (n=24, 75%) the most prevalent cerebellar sign. The most common brainstem signs/symptoms were motor symptoms and vertigo (each n=14, 31.8%) and the most common pyramidal sign/symptom was right upper monoparesis (n=14, 23.3%). Active demyelinating lesions were reported in brain MRI of all patients, mostly appeared as periventricular (n=91, 95.8%) and pericallosal (n=55, 57.9%) lesions. Acute demyelinating spinal lesions were presented in 38 patients (51.3%) with a prominent involvement of the cervical spine (n=33, 86.8%). Conclusion: In our study, the most frequent signs and symptoms were eye symptoms, brainstem signs, cerebellar signs and pyramidal signs, respectively. Moreover, our results showed that MRI plays a critical role in the diagnostic evaluation of MS in children with presence of brain lesions in all patients and spinal lesion in a considerable portion of patients.

Investigation of cross-reactivity between phenobarbital and levetiracetam in children with epilepsy: A prospective, observational multicenter study.

Objectives: Pharmaceutical allergic reactions due to antiseizure medications (ASMs) are one of the major concerns in the management of patients. Finding an alternative ASM which does not cause allergic reactions and has acceptable effectiveness can be difficult. In this regard, the present study attempts to investigate the cross-reactivity between phenobarbital and levetiracetam in children under treatment for seizure control. Materials & Methods: The present study is a prospective, observational independent assessor study. 30 children with epilepsy who were hypersensitive to phenobarbital therapy were studied. In order to evaluate the cross-reactivity of the drugs, levetiracetam replaced phenobarbital to control seizure. Within 6 months, any allergic reactions and seizure recurrences were evaluated in the patients. Results: 53 % of the children in this study were female. The mean age of patients was 42.4 months. In patients' follow up no cross-reactive responses were observed in any of the patients. Seizure recurrence rate was 30 % in the first six months of follow up that with increasing dosage in the second six months of follow-up, decreased to 10 %. Conclusion: Based on the results of this study, in children with epilepsy controlled by phenobarbital if allergic reactions to phenobarbital occur, levetiracetam may be used as a suitable alternative medicine.

Neuroimaging Findings of the High-risk Neonates and Infants Referred to Mofid Children's Hospital.

Objectives: Neuroimaging in high-risk neonates and infants is done to help child neurologists predict the future neurodevelopmental outcome of these children. In this study, we assessed high-risk neonates and infants admitted to the NICU or neonatal wards of Mofid children's Hospital, especially regarding clinical development and brain imaging. Materials & Methods: This cross-sectional study was conducted on 170 patients admitted to the neonatal and NICU ward of Mofid children's Hospital. Considering the inclusion criteria, 112 patients were included in this project. Brain ultrasonography was performed on almost all of these babies by a single radiologist. Some patients underwent a brain CT scan, and brain MRI without contrast was done on the others. These images were interpreted and compared by a single pediatric neuro-radiologist blinded to clinical data. All of these babies were followed up until 18 months of age. Results: In this study, 57.1% of the patients were male and 42.9% were female. Of 44 patients who obtained Electroencephalogram (EEG) during the hospitalization period with probable seizure, 25 (56.8%) had normal EEGs. Of 89 babies who were examined by ultrasound, 19 (21.3%) had abnormal findings; ventriculomegaly and then germinal matrix hemorrhage (GMH) were the most common abnormalities. Also, 27 cases (71.1%) of 38 patients undergoing a CT scan had abnormal findings. The most common findings were a hypodense area in the white matter and ventriculomegaly. Of 41 patients who underwent MRI between 1 and 27 months, 34 cases (82.9%) had an abnormal MRI. The most common findings were periventricular hyperintensities in 17 cases (41.5%), mildly delayed myelination in 15 cases (36.6%), and severe brain atrophy or thinning of corpus callosum or white matter volume loss in seven cases (17.1%). During the follow-up period, which was 18.55 ± 6.56 months, 79 (70.5%) of the children had normal development and 33 (29.5%) were suffering from a global neurodevelopmental delay. More precisely, 49 (43.7%) and 35 (31.2%) patients had motor development delay and delayed verbal development, respectively. The abnormal findings of brain imaging in the ultrasound, CT scan, and MRI were all significantly associated with an adverse neurodevelopmental outcome (P <0.001, P = 0.02, and P <0.001, respectively). Conclusion: In this study, we showed that at any time before six months or after one year of age, the result of brain MRI was a strong predictor of the patient's outcome.

Incidence of Pediatric Multiple Sclerosis in Iran within 2000-2019.

OBJECTIVES: Due to a lack of data on pediatric multiple sclerosis (MS) epidemiology in Iran, this study aimed to determine the incidence rate of pediatric MS in Iran. MATERIALS & METHODS:  All the data of the patients with MS registered in the Ministry of Health and Medical Education of Iran for 20 years were collected in this study; those born in 1982 and diagnosed with the disease and treated since 2000 were included in this study. Therefor The collected variables were patients' age at the time of diagnosis, gender, year of diagnosis, urban or rural residency, and province of residence. Additionally, age-specific incidence rates per 100,000 of the population were calculated. RESULTS: This study was performed on 4544 cases of pediatric MS within 2000-2019, of which 997 patients (21.9%) were male. The mean age of the patients with MS at the time of diagnosis was 14.3±4.6 years, and 4414 children (97.1%) lived in urban areas. The incidence rate of pediatric MS in Iran during 20 years increased from 0.26 per 100,000 of the population in 2000 to 1.53 in 2019. CONCLUSION: The incidence of pediatric MS in Iran is high, and the development of diagnostic practices in the past decade in Iran has contributed to the detection of this high incidence.

How Antiepileptics May Change the Serum Level of Vitamin D, Calcium, and Phosphorus in Children with Epilepsy.

OBJECTIVE: Studies have shown vitamin (Vit) D deficiency and bone disease in long-term use of antiepileptics, especially in young individuals. This study aimed to determine the relationship between antiepileptic drugs and the level of Vit D, calcium (Ca), and phosphorus (P) in children with epilepsy at the Shohada Hospital from 2016 to 2017. MATERIALS & METHODS: In this case-control study, 60 consecutive children with epilepsy at the Shohada Hospital from 2016 to 2017 under treatment with anticonvulsions for more than six months were enrolled as the case group. The level of Vit D, Ca, and P was determined in the case group and compared with 60 children without seizure as the control group. RESULTS: The mean Ca and P were alike across the groups (P > 0.05). The mean Vit D3 level was 31.3 and 40 in the case and control groups, respectively, with significant difference (P=0.0001). The mean Ca and P were alike across the types of drug in the case group (P > 0.05); however, the mean Vit D3 level was lower in the case versus control group with significant difference (P=0.040). CONCLUSION: Totally, according to the obtained results, it may be concluded that treatment with antiepileptic drugs, especially stimulant type, is related to the lower Vit D3 level, but not to the Ca and P levels.

Hopkins Syndrome in a 14 Year Old Boy; a Case Report.

Hopkins syndrome (HS) is a flaccid paralysis resembling poliomyelitis that has been seen in some children who are recovering from an acute episode of asthma. This syndrome should be suspected based on clinical findings even before the occurrence of characteristic breathing patterns and epilepsy. We report a 14-year-old boy who had experienced an episode of HS.

Prediction of Response to Treatment in Children with Epilepsy.

OBJECTIVE: This study was conducted to predict the response to treatment in patients treated with anti-epilepsy drugs. MATERIAL AND METHODS: This analytical questionnaire-based study was conducted in 2014 among 128 patients with epilepsy admitted to Mofid Children's Hospital, Tehran, Iran. The inclusion criteria were children 2 months to 12 yr of age with epilepsy and patients who experienced fever and seizure attacks at least once were excluded from the study. Patients were followed up for 6 months and the response to their treatment was recorded. The good response to treatment was defined as the absence of seizure with two drugs during follow up. RESULTS: Seventy-two patients (56.3%) were boys. The age of the first seizure was under 2 yr old in 90 patients (70.3%). History of febrile convulsion, family history of epilepsy and history of asphyxia was found in 16 (12.5%), 41 (32%), and 27 (21.1%) patients, respectively. Seizure etiology was idiopathic in 90 patients (70.3%), and the number of seizures was 1-2 in 36 patients (28.1%). Overall, 57 patients (44.5%) had cerebral lesion according to CT scan or MRI, and EEG was abnormal in 101 patients (78.9%). In 6-month follow-up, 40 patients (31.3%) responded well to the treatment and 88 patients (68.8%) responded poorly to the treatment. History of asphyxia (OR = 6.82), neonatal jaundice (OR = 2.81) and abnormal EEG (OR = 0.19) were effective factors in response to treatment. CONCLUSION: Abnormal EEG is an effective factor in treatment response in the children studied.

GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series).

OBJECTIVE: GM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay-Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creating hexosaminidases A, B, and AB. MATERIALS & METHODS: Patients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children's Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and AB in reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease. RESULTS: 83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint. 38%of patients had a history of developmental delay or regression and 22% had seizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowing disorders. Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). CONCLUSION: According to the results of this study, we suggest that cherry-red spots, hyperacusis, refractory seizures, and relative parents in children with developmental delay and/or regression should be considered for assessment of GM2-Gangliosidosis disease.

Evaluation of one hundred pediatric muscle biopsies during a 2-year period in mofid children and toos hospitals.

OBJECTIVE: Muscle biopsy is a very important diagnostic test in the investigation of a child with suspected neuromuscular disorder. The goal of this study was to review and evaluate pediatric muscle biopsies during a 2-year period with focus on histopathology diagnosis and correlations with other paraclinic studies. MATERIALS & METHODS: We investigated 100 muscle biopsies belonging to patients with clinical impression of neuromuscular disorder. These patients have been visited consecutively by pediatric neurologists during 2010 to 2012. Samples were investigated by standard enzyme histochemical and immunohistochemical techniques. RESULT: Sixty-nine (69%) males and 39 (39%) females with a mean age of 5.7 years were evaluated. Major pathologic diagnoses were Muscular dystrophy (48 cases), Neurogenic atrophy (18 cases), nonspecific myopathic atrophy (12cases), congenital myopathy (6 cases), storage myopathies (4 cases) and in 6 cases there was no specific histochemical pathologic finding. EMG was abnormal in 79 cases. Degree of correlation between EMG and biopsy result was significant in children ≥ 2 years of age. CONCLUSION: This study confirms the high diagnostic yields of muscle biopsy especially only if standard and new techniques such as enzyme study and immunohistochemistry are implemented. Also, we report 11 cases of Merosin negative congenital muscular dystrophy. This is the largest documented case series of Merosin deficient congenital muscular dystrophy reported from Iran.

Methylmalonic acidemia: diagnosis and neuroimaging findings of this neurometabolic disorder (an Iranian pediatric case series).

OBJECTIVE: Methylmalonic acidemia is one of the inborn errors of metabolism resulting in the accumulation of acylcarnitine in blood and increased urinary methylmalonic acid excretion. This disorder can have symptoms, such as neurological and gastrointestinal manifestations, lethargy, and anorexia. MATERIALS & METHODS: The patients who were diagnosed as methylmalonic acidemia in the Neurology Department of Mofid Children's Hospital in Tehran, Iran, between 2002 and 2012 were included in our study. The disorder was confirmed by clinical findings, neuroimaging findings, and neurometabolic and genetic assessment in reference laboratory in Germany. We assessed the age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 20 patients with methylmalonic acidemia. RESULTS: Eighty percent of the patients were offspring of consanguineous marriages. Half of the patients had Failure to thrive (FTT) due to anorexia; 85% had history of developmental delay or regression, and 20% had refractory seizure, which all of them were controlled. The patients with methylmalonic acidemia were followed for approximately 5 years and the follow-up showed that the patients with early diagnosis had a more favorable clinical response in growth index, refractory seizure, anorexia, and neurodevelopmental delay. Neuroimaging findings included brain atrophy, basal ganglia involvement (often in putamen), and periventricular leukomalacia. CONCLUSION: According to the results of this study, we suggest that early assessment and diagnosis have an important role in the prevention of disease progression and clinical signs.