The First Report of Iranian Registry of Patients with Spinal Muscular Atrophy.

BACKGROUND: Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined. OBJECTIVE: To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA). METHODS: IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project. RESULTS: By October 1, 2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1, while the frequency of patients with higher copy numbers of SMN2, was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease. CONCLUSIONS: The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran.

The Cerebrospinal Fluid Concentration of Methyltetrahydrofolate and Serum Folate in Children with Developmental Delay, Regression, and/or Refractory Epilepsy.

BACKGROUND AND OBJECTIVES: Folate is an important vitamin with a significant role in cell metabolism processes, and its deficiency is associated with several diseases. In addition, cerebral folate deficiency is associated with neurodevelopmental disorders. Studying the association of serum and cerebral folate deficiency with childhood neurodevelopmental disorders such as refractory epilepsy, developmental delay, and regression can be an important step towards the improvement of symptoms of such disorders. MATERIALS AND METHODS: In this cross-sectional study, from February to October 2018, 60 children aged 6 months to 5 years; known cases of idiopathic refractory epilepsy; were selected randomly. After recording demographic, and clinical characteristics, cerebrospinal fluid (CSF) and blood samples were taken from the patients and sent to a laboratory for measurement of 5-methyltetrahydrofolate (5MTHF), folate, and homocysteine levels. RESULTS: Sixty patients completed the study, including 33 boys (55%) and 27 girls (45%). Mean ± SD of the studied population was 26.93 ± 19.97 months. Eighteen children (30%) had refractory epilepsy, 11 (18.3%) had developmental delay, 12 (20%) had refractory epilepsy and developmental delay, and 19 (31.7%) had refractory epilepsy and developmental regression. The results of brain magnetic resonance imaging (MRI) were normal in 47 (78.3%) children and atrophic in 13 (21.7%) children. Mean ± SD of serum level of homocysteine was 9.14 ± 8.58 µmol/L, that of folate was 11.60 ± 6.89 nmol/L, and that of 5MTHF was 69.23 ± 54.16 nmol/L. CONCLUSION: Measurement of serum folate, homocysteine, and CSF level of 5MTHF are of great importance in patients with developmental disabilities.

Schimke Immuno-osseous Dysplasia: A Case Report.

Schimke immuno-osseous dysplasia (SIOD) is a rare inherited disease characterized by steroid resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. Focal segmental glomerulosclerosis (FSGS) is the most frequent renal pathological finding associated with proteinuria in SIOD. In this case report, we describe a 4.5-year-old boy who presented with nephrotic syndrome and ventricular septal defect followed by tremor in the limbs after-cerebral infarction. It is emphasized that SIOD should be considered in children with wide range of presentation, from growth retardation, steroid resistant nephrotic syndrome, and bone, cardiac, and neurological abnormalities in the late childhood or even adolescence.

Early Onset Cerebral Infarction in Schimke Immuno-Osseous Dysplasia.

Schimke Immuno-osseous Dysplasia (SIOD) is a rare autosomal recessive disease caused by a biallelic mutation in SMARCAL1 gene. Typical findings in SIOD include spondylo-epiphyseal dysplasia, steroid resistance nephrotic syndrome, progressive renal failure, T-cell immunodeficiency, bone marrow failure, and cerebral infarction. In this case report, we describe a 9-yr-old girl who presented with failure to thrive in infancy. Nephrotic syndrome was diagnosed at the age of four years. She had three episodes of admission with cerebral stroke due to moyamoya syndrome. In the last admission at Namazi Hospital, Shiraz, southern Iran, in October 2016, she had new cerebral ischemia, developed seizure, and finally died.

Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature.

The IFAP syndrome is a rare X-linked recessive inheritance disorder with defect of the MBTPS2 gene defined by the triad of follicular ichthyosis, alopecia, and photophobia. A total of 40 cases has been reported, but no correlation with Hodgkin lymphoma has been reported yet. A 3.5-year-old boy was diagnosed with IFAP syndrome confirmed by Next Generation Sequencing. He was on regular follow-up when he developed prolonged fever and lymphadenopathy. His lymph node biopsy showed Hodgkin lymphoma with mixed cellularity subtype. This case is the first report on IFAP syndrome associated with malignancy. IFAP syndrome could be a risk factor in developing malignancy.

TSC1 Mutations in Keratoconus Patients With or Without Tuberous Sclerosis.

Purpose: To test candidate genes TSC1 and TSC2 in a family affected by tuberous sclerosis complex (TSC) where proband was also diagnosed with bilateral keratoconus (KC) and to test the hypothesis that defects in the same gene may lead to a nonsyndromic KC. Methods: Next-generation sequencing of TSC1 and TSC2 genes was performed in a proband affected by TSC and KC. Identified mutation was confirmed by Sanger DNA sequencing. Whole exome sequencing (WES) was performed in patients with nonsyndromic KC. Sanger DNA sequencing was used to confirm WES results and to screen additional patients. RT-PCR was used to investigate TSC1 expression in seven normal human corneas and eight corneas from patients with KC. Various in silico tools were employed to model functional consequences of identified mutations. Results: A heterozygous nonsense TSC1 mutation g.132902703C>T (c.2293C>T, p.Gln765Ter) was identified in a patient with TSC and KC. Two heterozygous missense TSC1 variants g.132896322A>T (c.3408A>T, p.Asp1136Glu) and g.132896452G>A (c.3278G>A, p.Arg1093Gln) were identified in three patients with nonsyndromic KC. Two mutations were not present in The Genome Aggregation (GnomAD), The Exome Aggregation (ExAC), and 1000 Genomes (1000G) databases, while the third one was present in GnomAD and 1000G with minor allele frequencies (MAF) of 0.00001 and 0.0002, respectively. We found TSC1 expressed in normal corneas and KC corneas, albeit with various levels. Conclusions: Here for the first time we found TSC1 gene to be involved in bilateral KC and TSC as well as with nonsyndromic KC, supporting the hypothesis that diverse germline mutations of the same gene can cause genetic disorders with overlapping clinical features.

Management of epilepsy in resource-limited areas: establishing an epilepsy surgery program in Iran.

Background Of about 40 million people with epilepsy, who live in developing countries, the majority do not receive appropriate treatment. Nonetheless, there are striking disparities among the so-called developing countries, however generally speaking, access to and availability of epilepsy management programs in developing countries are very limited and therefore, the issue of developing epilepsy centers in resource-limited settings in a large scale is very essential. The surgery for epilepsy, including temporal lobotomy, lesionectomy and corpus colostomy, for patients with medically-refractory seizures, defined as failure of adequate trials of two tolerated, appropriately chosen and using antiepileptic drug to achieve sustained freedom, from seizure has been proved to be feasible and cost-effective in developing countries. However, the success of epilepsy surgery depends upon the accurate identification of good surgical candidates based on the available resources and technologies without jeopardizing safety. In the current paper, we will share our experiences of establishing an epilepsy surgery program in Iran, despite all short-comings and limitations and try to provide some answers to those challenges, which helped us establish our program.

Corpus callosotomy is a valuable therapeutic option for patients with Lennox-Gastaut syndrome and medically refractory seizures.

PURPOSE: We present our experience with corpus callosotomy (CC) in a developing country with limited resources in patients with Lennox-Gastaut syndrome (LGS) and medically refractory seizures. METHODS: All patients with LGS who underwent CC for medically refractory epilepsy at Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran from May 2009 through March 2012 were reviewed in a retrospective study. Presurgical evaluation included clinical history, neurological examination, a 2-hour video-EEG recording, and 1.5-T MRI. Outcome was evaluated at 6, 12, and 24 months postoperatively. We considered the outcome as a success if the patients were either seizure-free or had more than 85% reduction in seizure frequency compared to their preoperative status. RESULTS: Eighteen patients (14 males and 4 females) had surgery. Overall, seizures in 11 patients (61.1%) responded favorably one year after surgery; this figure was 6 out of 9 patients (66.6%) two years after surgery. Seven patients (38.8%) were free of disabling seizures one year after CC; this figure was three out of nine patients (33.3%) two years after CC. Three patients (16.6%) were free of all seizure types one year after surgery. Ten patients (55.5%) had no postoperative complications of any kind. CONCLUSION: Corpus callosotomy is an effective palliative surgical procedure for patients with LGS with intractable seizures whose seizures are not amenable to focal resection. This is a feasible treatment option for patients, even for those in developing countries with limited resources.

A comparative study of celiac disease in children with migraine headache and a normal control group.

BACKGROUND/AIMS: Migraine headache is one of the most frequent types of headache in children in which multiple factors, including environmental and genetic, are involved. Celiac disease is an autoimmune-mediated disease with intolerance to gluten. The clinical spectrum of celiac disease is wide. Patients may present with malabsorption symptoms or extra-intestinal involvement, or can be totally asymptomatic. The association of migraine headache and celiac disease is not well known. The aim of this study was to assess the prevalence of celiac disease in children with migraine headache, in order to detect any relationship between them. METHODS: A total of 100 patients with migraine headache according to the International Headache Society criteria were enrolled in the study. 1500 children without history of headache or other medical diseases participating in another study for detection of the prevalence of celiac disease were selected in this study as a control group. Serum total IgA and anti-tissue transglutaminase IgA (anti-tTGA) antibodies were measured. In cases with positive serologic tests, duodenal biopsy was performed for confirmation of celiac disease. RESULTS: Two of 100 patients (2%) were found to have positive serologic tests for celiac disease, compared with 30 of 1500 children (2%) in the control group who had celiac disease. CONCLUSIONS: The results of this study showed that the prevalence of celiac disease was not higher in patients with migraine compared with the control group. Therefore, diagnostic tests for celiac disease are not necessary as a part of the management of migraine headache.