Core myopathy in two siblings with a biallelic variant in the CACNA1S gene-A case series study.

Homozygous variants of Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation were previously identified as causes of periodic paralysis and congenital early-onset myopathy, while it could be manifested as a late-onset congenital core myopathy. Abstract: Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation has been linked to various neuromuscular conditions in recent years. Congenital myopathy with core-like features is one of the cardinal associations reported previously, causing severe respiratory insufficiency and death in neonates. Informed consent was received from the patients. Subsequently, peripheral blood leukocytes were utilized to extract genomic DNA. Moreover, exome enrichment was implemented through the Twist Human Core Exome Kit (Twist Bioscience) and exome sequenced using Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA). Sanger sequencing using BIG Dye Terminators confirmed the presence of the final variant. Finally, the candidate variants were classified based on the American College of Medical Genetics and Genomics (ACMG) guidelines. In this report, we describe two siblings, who presented with childhood and late-onset progressive muscle weakness, and had a homozygous variant in exon 2 of the CACNA1S gene defined as c.188C > A (p.Ala63Asp) (NM_000069.3). The SIFT, Polyphen2, CADD PHRED, and Mutation Taster analysis tools classified the variant as pathogenic/damaging. The muscle biopsy of the younger brother revealed intermyofibrillar network pattern disruption as cytoplasmic core-like lesions. The muscle magnetic resonance imaging (MRI) reported grade IIa and IIb fatty changes. Finally, the electromyography (EMG) findings suggested a myopathic change pattern. This report illustrates the clinical variability in CACNA1S-related myopathy by reviewing prior reports and adding newly found aspects, additionally expanding the gene defects associated with core myopathy.

Glioma Tumor Grading Using Radiomics on Conventional MRI: A Comparative Study of WHO 2021 and WHO 2016 Classification of Central Nervous Tumors.

BACKGROUND: Glioma grading transformed in World Health Organization (WHO) 2021 CNS tumor classification, integrating molecular markers. However, the impact of this change on radiomics-based machine learning (ML) classifiers remains unexplored. PURPOSE: To assess the performance of ML in classifying glioma tumor grades based on various WHO criteria. STUDY TYPE: Retrospective. SUBJECTS: A neuropathologist regraded gliomas of 237 patients into WHO 2016 and 2021 from 2007 criteria. FIELD STRENGTH/SEQUENCE: Multicentric 0.5 to 3 Tesla; pre- and post-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery. ASSESSMENT: Radiomic features were selected using random forest-recursive feature elimination. The synthetic minority over-sampling technique (SMOTE) was implemented for data augmentation. Stratified 10-fold cross-validation with and without SMOTE was used to evaluate 11 classifiers for 3-grade (2, 3, and 4; WHO 2016 and 2021) and 2-grade (low and high grade; WHO 2007 and 2021) classification. Additionally, we developed the models on data randomly divided into training and test sets (mixed-data analysis), or data divided based on the centers (independent-data analysis). STATISTICAL TESTS: We assessed ML classifiers using sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC). Top performances were compared with a t-test and categorical data with the chi-square test using a significance level of P < 0.05. RESULTS: In the mixed-data analysis, Stacking Classifier without SMOTE achieved the highest accuracy (0.86) and AUC (0.92) in 3-grade WHO 2021 grouping. The results of WHO 2021 were significantly better than WHO 2016 (P-value<0.0001). In the 2-grade analysis, ML achieved 1.00 in all metrics. In the independent-data analysis, ML classifiers showed strong discrimination between grade 2 and 4, despite lower performance metrics than the mixed analysis. DATA CONCLUSION: ML algorithms performed better in glioma tumor grading based on WHO 2021 criteria. Nonetheless, the clinical use of ML classifiers needs further investigation. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Co-occurrence of celiac disease and glycogen storage disease in a five-year-old patient with diabetes mellitus; a case report.

A patient presented with edema, ascites and jaundice. Histologic report was consistent with Celiac Disease. Liver biopsy commensurate with Glycogen storage disease III, which was confirmed by genetic testing. A gluten-free diet was initiated. After 2 months, ascites was relieved, hepatic function was improved, and hepatic size reduced.

Megaconial congenital muscular dystrophy due to CHKB gene variants, the first report of thirteen Iranian patients.

Megaconial congenital muscular dystrophy (OMIM: 602,541) related to CHKB gene mutation is a newly defined rare autosomal recessive disorder, with multisystem involvement presenting from the neonatal period to adolescence. Choline kinase beta, lipid transport enzyme, catalyzes the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, two major components of the mitochondrial membrane, on which respiratory enzyme activities are dependent. CHKB gene variants lead to loss-of-function of choline kinase b and lipid metabolism defects and mitochondrial structural changes. To date, many megaconial congenital muscular dystrophy cases due to CHKB gene variants have been reported worldwide. We describe thirteen Iranian megaconial congenital muscular dystrophy cases related to CHKB gene variants, including clinical presentations, laboratory and muscle biopsy findings, and novel CHKB gene variants. The most common symptoms and signs included intellectual disability, delayed gross-motor developmental milestones, language skills problems, muscle weakness, as well as autistic features, and behavioral problems. Muscle biopsy examination showed the striking finding of peripheral arrangements of large mitochondria in muscle fibers and central sarcoplasmic areas devoid of mitochondria. Eleven different CHKB gene variants including six novel variants were found in our patients. Despite the rarity of this disorder, recognition of the multisystem clinical presentations combined with characteristic findings of muscle histology can properly guide to genetic evaluation of CHKB gene.

Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy.

Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.

A case of diffuse leptomeningeal glioneuronal tumor in a 10-year-old boy: First report from Iran.

A 10-year-old boy who was referred due to acute hydrocephalus symptoms was diagnosed as the first case of pediatric DLGNT in Iran. The results suggested that using shunting for hydrocephaly and anti-seizure medicines, as well as chemotherapeutic agents, can be an effective treatment strategy for DLGNT. Although the patient was stable without a tumor recurrence for a limited follow-up period of 22 months, further studies are expected.

Neurological Complications of COVID-19: A Rare Case of Bilateral Blindness.

BACKGROUND: There are growing reports of the neurological involvement among patients with coronavirus disease 2019 (COVID-19). Headache, confusion, and anosmia after olfactory nerve disruption are the most prevalent presentation of the neurological involvement related to COVID-19. However, small numbers of the central nervous system involvement have been reported. CASE REPORT: A 49-year-old man was referred to our hospital with abrupt vision loss. Three weeks earlier he was admitted to the hospital based on his respiratory symptoms and was diagnosed with COVID-19 infection. Initial brain magnetic resonance imaging indicated diffuse restricted bilateral foci in both parietal and occipital lobes in favor of acute infarction. Diffuse weighted imaging demonstrated restricted bilateral hyperintense signals in parietal and occipital region. Occipital cortex biopsy showed brain tissue with focal infiltration of foamy macrophages mixed with reactive astrocytes and no plasma cell infiltration. Considering all of the evidence, post-COVID-19 encephalitis diagnosis was considered for the patient, and methyl prednisolone pulse therapy and intravenous immunoglobulin were initiated. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although there are growing reports of neurological involvement among patients, blindness is rarely observed as a complication of post-COVID-19 encephalitis. To our knowledge, this is the first case of post-COVID-19 encephalitis that presented with bilateral vision loss primarily. This case may raise physicians' awareness of neurological complications of COVID-19.

Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: Report of four patients.

Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired muscle disease presenting with subacute progression in adulthood. It can be accompanied by a monoclonal gammopathy of undetermined significance (MGUS). We describe clinical and histopathological findings of four SLONM patients with MGUS. In all patients, nemaline rod, inter-myofibrillary network disruption, atrophic changes, peripheral basophilic discoloration, vacuole without rim, and cytoplasmic body without inflammation were seen. Three out of four patients were treated with prednisolone in combination with IVIG monthly and had an appropriate response to the treatment. The optimal first-line treatment remains unclear in SLONM-MGUS, although corticosteroids plus IVIg is associated with favorable clinical response. These treatment modalities might be used as an optional treatment before autologous stem cell transplantation; however, further studies with a higher number of patients are required.

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.

Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.

A dermatopathic Juvenile Dermatomyositis; An Unexpected Case in Childhood.

Juvenile dermatomyositis (JDM) is a rare idiopathic inflammatory disease, which usually presents with skin rashes along with muscle weakness. We report a case of JDM in a 10- year-old girl with no skin manifestations presenting with progressive muscle weakness and fatigue. Further laboratory investigations, along with a muscle biopsy, confirmed the diagnosis of adermatopathic JDM. The patient was treated with intravenous immunoglobulin, corticosteroids, methotrexate, hydroxychloroquine, pamidronate, and rituximab. Following treatment, patients' symptoms subsided, and she gained normal muscular strength over a year.

Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report.

BACKGROUND: Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.1. Next Generation Sequencing (NGS) technology is the most effective method for identification of pathogenic variants with the ability to overcome some limitations which Sanger sequencing may encountered. There are few reports on this rare disease around the world and here in this study we first revealed genetic identification of two affected individuals in an Iranian family with a novel mutation. CASE PRESENTATION: The proband was a 5-year-old girl from consanguenous parents. She was first clinically suspicious of affected with limb-girdle muscular dystrophy (LGMD). Muscle biopsy studies and autozygosity mapping, using four short tandem repeat (STR) markers linked to 6 genes of the most prevalent forms of LGMD, ruled out calpainopathy, dysferlinopathy, and sarcoglycanopathis. DNA sample of the proband was sent for NGS. Whole exome sequencing (WES) revealed a novel mutation c.1295delA in exon 13 of MICU1 gene. This homozygous deletion creates a frameshift and a premature stop codon downstream of canonical EF4 calcium binding motif of MICU1. According to the American College of Medical Genetics and Genomics (ACMG) guidline for sequence interpretation, this variant was a pathogenic one. Sanger sequencing in all family members confirmed the results of the WES. CONCLUSIONS: This study was the first report of MPXPS in Iranian population which also revealed a novel mutation in the MICU1 gene.

Estrogen Receptor Expression in Glial Tumors of Iranian Patients: A Single Center Experience.

BACKGROUND & OBJECTIVE: Gliomas are the most common type of primary intracranial tumors in adults. The expression of estrogen receptors varies in different grades of glial tumors, and some studies have suggested that this expression might have a prognostic value. It seems that estrogen receptor expression negatively correlates with the histological grade of gliomas. In the present study, we aimed to determine the expression of estrogen receptor in different glial tumors in Iranian patients and to find a possible correlation between its expression and the grade of glial tumors. METHODS: The brain tumors pathology reports from 2014 to 2017 in the Pathology Department of Shohaday-e Tajrish Hospital in Tehran, Iran were evaluated and 104 different gliomas: 79 cases of astrocytoma and 25 cases of oligodendroglioma were selected. All the samples were re-evaluated by a neuropathologist in order to accurately determine the tumor grade. The immunohistochemistry was carried out to detect the expression of estrogen receptor alpha and beta on brain tumors. RESULTS: None of the samples expressed estrogen receptor alpha. In the case of estrogen receptor beta (ERß), all samples showed various degrees of positivity: 9% weak, 40% moderate, and 51% strong expressions. The level of ERß expression was found to be conversely correlated with tumor grade. CONCLUSION: Our study demonstrated that ERß is expressed in the majority (if not all) of the glial tumors and its expression was conversely related to the tumor grade. Because of well-tolerability and acceptable adverse effects, ER agonists might be considered as therapeutic agents for the patients with glial tumors.

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

Introduction: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central nervous system. These conditions are often under-appreciated among physicians. The first clinical manifestations of leukodystrophies are often nonspecific and can occur in different ages from neonatal to late adulthood periods. The diagnosis is, therefore, challenging in most cases.Area covered: Herein, the authors discuss different aspects of leukodystrophies. The authors used MEDLINE, EMBASE, and GOOGLE SCHOLAR to provide an extensive update about epidemiology, classifications, pathology, clinical findings, diagnostic tools, and treatments of leukodystrophies. Comprehensive evaluation of clinical findings, brain magnetic resonance imaging, and genetic studies play the key roles in the early diagnosis of individuals with leukodystrophies. No cure is available for most heritable white matter disorders but symptomatic treatments can significantly decrease the burden of events. New genetic methods and stem cell transplantation are also under investigation to further increase the quality and duration of life in affected population.Expert opinion: The improvements in molecular diagnostic tools allow us to identify the meticulous underlying etiology of leukodystrophies and result in higher diagnostic rates, new classifications of leukodystrophies based on genetic information, and replacement of symptomatic managements with more specific targeted therapies.Abbreviations: 4H: Hypomyelination, hypogonadotropic hypogonadism and hypodontia; AAV: Adeno-associated virus; AD: autosomal dominant; AGS: Aicardi-Goutieres syndrome; ALSP: Axonal spheroids and pigmented glia; APGBD: Adult polyglucosan body disease; AR: autosomal recessive; ASO: Antisense oligonucleotide therapy; AxD: Alexander disease; BAEP: Brainstem auditory evoked potentials; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CGH: Comparative genomic hybridization; ClC2: Chloride Ion Channel 2; CMTX: Charcot-Marie-Tooth disease, X-linked; CMV: Cytomegalovirus; CNS: central nervous system; CRISP/Cas9: Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9; gRNA: Guide RNA; CTX: Cerebrotendinous xanthomatosis; DNA: Deoxyribonucleic acid; DSB: Double strand breaks; DTI: Diffusion tensor imaging; FLAIR: Fluid attenuated inversion recovery; GAN: Giant axonal neuropathy; H-ABC: Hypomyelination with atrophy of basal ganglia and cerebellum; HBSL: Hypomyelination with brainstem and spinal cord involvement and leg spasticity; HCC: Hypomyelination with congenital cataracts; HEMS: Hypomyelination of early myelinated structures; HMG CoA: Hydroxy methylglutaryl CoA; HSCT: Hematopoietic stem cell transplant; iPSC: Induced pluripotent stem cells; KSS: Kearns-Sayre syndrome; L-2-HGA: L-2-hydroxy glutaric aciduria; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate; LCC: Leukoencephalopathy with calcifications and cysts; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate; MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: metachromatic leukodystrophy; MRI: magnetic resonance imaging; NCL: Neuronal ceroid lipofuscinosis; NGS: Next generation sequencing; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy-central-dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschprung disease; PMD: Pelizaeus-Merzbacher disease; PMDL: Pelizaeus-Merzbacher-like disease; RNA: Ribonucleic acid; TW: T-weighted; VWM: Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive.

The Art of Muscle Biopsy in the New Genetic Era: A Narrative Review.

Muscle biopsy has been practiced as a well-established part of paraclinical workup in patients with neuromuscular diseases since late 1960s. In this narrative review paper, the role of some pre and post muscle biopsy factors and their importance in achieving the best diagnostic results will be explained. Considering the new advances in diagnostic molecular techniques and the availability of local standard myopathology laboratory as well as the presence of a dedicated myopathologist, the indications of muscle biopsy in four major types of neuromuscular diseases will be shortly reviewed. Moreover, indications of muscle biopsy in four major types of neuromuscular diseases will be shortly discussed based on literature review of recent published diagnostic algorithms and our 11 years' experience of performing about 4000 muscle biopsies cases in the only standard referral diagnostic center for muscle biopsy in Iran. Although diagnostic algorithms of some muscle diseases have been changed based on recent advances in biochemical and molecular diagnostic techniques, still muscle biopsy continues to play a major role in the diagnosis and management of variety of neuromuscular disorders and has proved to be a preferable diagnostic procedure by some neuromuscular specialists for the cases who can benefit from rapid therapeutic management. The application of diagnostic algorithms should be practiced in accordance with geographic distribution of the diseases, the availability of diagnostic techniques and the presence of specialists in each center considering the local insurance coverage and the cost to be paid by the patient in every center.

Incontinentia Pigmenti Misdiagnosed as Neonatal Herpes Simplex Virus Infection.

Incontinentia pigmenti (IP) is an X-linked dominant neurocutaneous syndrome with ophthalmologic, neurologic, cutaneous, and dental manifestations and in most cases antenatally lethal in boys. Occasionally, typical IP may occur in boys due to Klinefelter syndrome or a genomic mosaicism. Skin lesions are observed in 4 stages: blistering, verrucous linear plaques, swirling macular hyperpigmentation, followed by linear hypopigmentation that develop during adolescence and early adulthood. Neonatal herpes simplex virus (HSV) infection can be manifested in 3 forms: localized, disseminated, and central nervous system (CNS) involvement. Timely diagnosis and treatment of neonatal HSV infection is critical. In this case report, we present a 12-day female newborn with a history of maternal genital HSV in second trimester and vesicular lesions on the upper and lower limbs that was appeared at first hours of life. She was admitted in the maternity hospital that was born and was treated by antibiotic and acyclovir for 11 days. Then, she readmitted for her distributed vesicular lesions. The results of blood and CSF for HSV PCR were negative. Eventually the diagnosis for incontinentia pigmenti was made by consultation with a dermatologist, and skin biopsy confirmed the diagnosis.

Distinct Clinical and Genetic Findings in Iranian Patients With Glycogen Storage Disease Type 3.

OBJECTIVES: Glycogen storage disease type 3 (GSD-III) is a rare inherited metabolic disorder caused by glycogen debranching enzyme deficiency. Various pathogenic mutations of the AGL gene lead to abnormal accumulation of glycogen in liver, skeletal, and cardiac muscles. Here, we report distinct clinical and genetic data of Iranian patients with GSD-III. METHODS: Clinical and laboratory data of 5 patients with GSD-III were recorded. Genetic investigation was performed to identify the causative mutations. RESULTS: Three patients had typical liver involvement in childhood and one was diagnosed 2 years after liver transplantation for cirrhosis of unknown etiology. Four patients had vacuolar myopathy with glycogen excess in muscle biopsy. All patients had novel homozygous mutations of the AGL gene namely c.378T>A, c.3295T>C, c.3777G>A, c.2002-2A>G, and c.1183C>T. CONCLUSIONS: This is the first comprehensive report of patients with GSD-III in Iran with 2 uncommon clinical presentations and 5 novel mutations in the AGL gene.

A Mitochondrial Disorder in a Middle Age Iranian Patient: Report of a Rare Case.

INTRODUCTION: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) can involve multiple systems and cause stroke-like episodes and status epilepticus. CASE PRESENTATION: A 48-year-old female with history of early fatigability, migraine-type headaches, and bilateral sensory-neural hearing loss presented 3 episodes of serial seizures. On admission she was affected by Wernicke aphasia and, then, right hemiparesis. Investigations showed elevated arterial lactate and ragged red fibers on muscle biopsy. CONCLUSION: Though more commonly diagnosed during childhood, some cases of adult-onset MELAS syndrome are reported. This syndrome should be considered in patients with stroke-like events in adults without cerebrovascular risk factors and difficult-to-treat seizures.

Primary Signet-Ring Cell Carcinoma of the Urinary Bladder Successfully Managed with Radical Cystectomy in a Young Patient.

Primary signet-ring cell adenocarcinoma of bladder is a rare neoplasm, usually seen in middle age adults. We report the case of an 18-year-old man who presented with intermittent gross hematuria. Computed tomography imaging showed multifilling defects in the bladder. The patient underwent a transurethral resection of the bladder tumor. Histological findings were consistent with poorly differentiated mixed mucinous and signet-ring cell adenocarcinoma. We ruled out other possible origins of tumor by gastrointestinal endoscopy and colonoscopy. The patient was treated with radical cystectomy with prostate and seminal vesicle sparing technique and orthotopic diversion using "W" ileum pouch with pelvic lymphadenectomy to the bifurcation of the aorta was done. Six-month follow-up of patient showed normal conditions without metastatic spread or any recurrence.