Homozygosity Mapping and Targeted Sanger Sequencing Identifies Three Novel CRB1 [Crumbs homologue 1] Mutations in Iranian Retinal Degeneration Families

Background: Inherited retinal diseases [IRDs] are a group of genetic disorders with high degrees of clinical, genetic and allelic heterogeneity. IRDs generally show progressive retinal cell death resulting in gradual vision loss

IRDs constitute a broad spectrum of disorders including retinitis pigmentosa and Leber congenital amaurosis. In this study, we performed genotyping studies to identify the underlying mutations in three Iranian families

Methods: Having employed homozygosity mapping and Sanger sequencing, we identified the underlying mutations in the crumbs homologue 1 gene. The CRB1 protein is a part of a macromolecular complex with a vital role in retinal cell polarity, morphogenesis, and maintenance

Results: We identified a novel homozygous variant [c.1053-1061del; p.Gly352-Cys354del] in one family, a combination of a novel [c.2086T>C; p.Cys696Arg] and a known variant [c.2234C>T, p.Thr745Met] in another family and a homozygous novel variant [c.3090T>A; p.Asn!030Lys] in a third family

Conclusion: This study shows that mutations in CRB1 are relatively common in Iranian non-syndromic IRD patients

Whole exome sequencing reveals a BSCL2 mutation causing progressive encephalopathy with lipodystrophy [PELD] in an Iranian pediatric patient

Background: Progressive encephalopathy with or without lipodystrophy is a rare autosomal recessive childhoodonset seipin-associated neurodegenerative syndrome, leading to developmental regression of motor and cognitive skills. In this study, we introduce a patient with developmental regression and autism. The causative mutation was found by exome sequencing

Methods: The proband showed a generalized hypertonia and regression of all developmental milestones. Based on the advantages of next-generation sequencing [NGS], whole exome sequencing [WES] was requested. The functional significance of variants was evaluated by NGS-specific prediction servers. Sanger sequencing was used for segregation analysis in the family

Results: There was no specific sign in the clinical and paraclinical investigations of the patient to establish a conclusive clinical diagnosis. WES detected a known homozygous nonsense mutation in BSCL2 [NM_001122955.3:c.985C>T; p.Arg329*]. The variant is segregating in the pedigree with an autosomal recessive pattern

Conclusion: Exome sequencing is a robust method for identifying the candidate gene variants in Mendelian traits

comparison of buccal midazolam and intravenous diazepam for the acute treatment of seizures in children

The purpose of the present study is to compare efficacy and safety of buccal midazolam with intravenous diazepam in control of seizures in Iranian children. This is a randomized clinical trial. 92 patients with acute seizures, ranging from 6 months to 14 years were randomly assigned to receive either buccal midazolam [32 cases] or intravenous diazepam [60 cases] at the emergency department of a children's hospital. The primary outcome of this study was cessation of visible seizure activity within 5 minutes from administration of the first dosage. The second dosage was used in case the seizure remained uncontrolled 5 minutes after the first one. In the midazolam group, 22 [68.8%] patients were relieved from seizures in 10 minutes. Meanwhile, diazepam controlled the episodes of 42 [70%] patients within 10 minutes. The difference was, however, not statistically significant [P=0.9]. The mean time required to control the convulsive episodes after administration of medications was not statistically significant [P=0.09]. No significant side effects were observed in either group. Nevertheless, the risk of respiratory failure in intravenous diazepam is greater than in buccal midazolam. Buccal midazolam is as effective as and safer than intravenous diazepam in control of seizures

efficacy and safety of oxcarbazepine as add-on therapy in intractable epilepsy in children

1-3% of the population suffer from epilepsy. Up to 30% of them develop refractory epilepsy and their seizures occur more than once per month despite receiving at least 2 first line antiepileptic drugs. In this group, more efficacious antiepileptics are needed. This study was undertaken to evaluate the efficacy and safety of Oxcarbazepine as an adjunction therapy in children with refractory epilepsy. From Feb 2004 until Sep 2006, 30 patients with refractory epilepsy aged between 4 and 14 years were evaluated in a before and after type study. The patients had seizure ranging from once monthly to more than 10 times daily and none of them had used Oxcarbazepine previously. They received Oxcarbazepine 30 to 50 mg/kg/day orally in combination with their current antiepileptic drugs and were regularly assessed for seizure frequency and side effects for 10 months. With Oxcarbazepine adjunction therapy, 10% of the patients became seizure-free, 36.6% experienced more than 50% reduction in seizure frequency, and 13.3% had increasing seizures. The drug was especially effective in the patients with partial seizures [77.7%]. Brief and transient adverse effects were seen in 36.6% of the patients which disappeared with treatment continuation. Wilcoxon signed ranks test showed that oxcarbazepine was effective in the treatment of refractory seizures [P=0.003] and as shown by Fisher's exact test, it was more effective in partial seizures [P=0.0043]. The results showed that Oxcarbazepine was a useful medication in the treatment of refractory epilepsy, especially the partial type, in children

Intractable epilepsy in children

Epilepsy is a common disorder affecting approximately 1% of the population. It is estimated that about 20- 30% of the patients become refractory to proper medical therapies. Such cases are often termed intractable. Intractable epilepsy [IE] is a serious condition in children, leading to significant impairment in quality of life, as well as behavioral and psychiatric problems. In this review, we tried to define intractability, mention the causes of intractable epilepsy and its predictive factors in children, and outline the management and various treatments of intractable epilepsy

Assessment of cognitive and motor development in 150 children with refractory epilepsy

Neuropsychological impairment is an important co-morbidity of chronic epilepsy. The aim of this study was to determine the state of the cognitive and motor development of patients with refractory epilepsy. We studied 150 consecutive children with epilepsy who were referred to Mofid Children Hospital, a third level public referral University Hospital in Tehran, Iran from October 2007 to October 2008. Refractory epilepsy was defined as therapeutic failure of three antiepileptic drugs which were used appropriately. Data regarding sex, age, at which the first seizure occurred, microcphaly, muscle tonicity, EEG findings, kind of treatment for controlling seizures and cognitive and motor development delay were collected from medical records. Development delay was defined as delay in acquiring cognitive ability and motor skills for age according to the Denver Scale II. Of 150 patients 72% were younger than 2 years old and 56.7% were male. About 35.3% were microcephalic while 76% had normal muscular tonicity. Only 2.7% had normal EEGs. About 37.3% showed a good response to anticonvulsive drugs and became seizure free, 13.3% showed a relative response to anticonvulsants but 49.3% did not respond. In the present study, 68% had cognitive developmental delay and 60.7% suffering motor delay. There was a significant difference in response to treatment between patients with cognitive and motor development delay. Cognitive developmental delay was more frequent in patients with refractory epilepsy, suggesting that early cognitive screening and introduction of rehabilitation programs are necessary for patients with refractory epilepsy

CNS involvement by novel influenza virus type A [H1N1], the first report from Iran

This is the first report of CNS involvement by the new influenza virus [influenza A [H1N1] in Iran. The patient was a 10-year-old boy with chief complaints of fever, malaise, and cranial nerve involvement, resulting in respiratory muscle paralysis and intubation. This shows that the new influenza virus, as well as the seasonal flu, can cause neurologic complications; however, the severity of the signs and symptoms is less and the disease may resolve without complications in the case of seasonal flu. Therefore, in each patient with neurological involvement and typical influenza signs and symptoms or a flu-like syndrome, diagnostic tests for H1N1 flu virus should be considered, especially during epidemics, and treatment with oseltamivir should be started

[Clinical survey of cerebrovascular disease in children]

Stroke is defined as the sudden occlusion or rupture of cerebral arteries or veins resulting in focal cerebral damage and clinical neurologic deficits. The risk factors for stroke in children are numerous and differ from those in adults. Identification of these factors can prevent subsequent strokes. The aim of this study is to determine the etiology of stroke in children. In this descriptive prospective study, children who were referred to pediatric neurology clinic in Mofid Children's Hospital due to acute hemiparesis during 2 years period [Sep 2003-Sep 2005] were evaluated and their diagnosis was cerebrovascular disorders, in the view of physical examination and brain imaging. The study group consisted of 40 children in age groups between 3 months to 14 years old. The most common age group at presentation was 2 to 5 years old. Occurrence was predominant during autumn and winter [70%]. The most common clinical presentations were acute hemiparesis [85%] and seizures [40%]. The other symptoms were as follow: 15% decreased level of consciousness, 12.5% fever, 7.5% VI nerve palsy, and 2.5% cerebellar signs. 20% of patients suffered from hemorrhagic and 80% had ischemic stroke. In 60% of the patients specific etiologic factors were identified and in the rest of the group, risk factors could be delineated. The most common etiologies were: 17.5% cardiac diseases or procedures and 10% hematologic disorders. Other etiologies included: 7.5% prothrombotic states, 7.5% CNS infection, 5% mitochondriopathy, 2.5% for each of the head trauma, migraine, serum lipid abnormality, hypertension and arteriovenus malformation. The most common risk factors consisted of 40% anemia and 20% infections. This study demonstrates that stroke in children is a multifactorial process. Identification of the underlying risk factors for cerebrovascular disorders is highly desirable because many of the risk factors can be prevented, resulting in reduction of the risk of subsequent f strokes

Case Report. Stroke in an infant; its association with Antiphospholipid antibody and acquired protein C and S deficiencies

We present the first reported case of antiphospholipid syndrome with stroke in an Iranian boy [7-month-old] who had two ischemic strokes within a period of 2 months. Serum anticardiolipid antibody was positive and the patient had low levels of protein S and C. This case emphasizes the importance of antiphospholipid antibody in children with unexplained ischemic stroke