A Family Case Report of Niemman Pick C with New Mutation and Different Presentations

How to Cite this Article: Shalbafan B. A Family Case Report of Niemman Pick C with New Mutation and Different Presentations. Iran J Child Neurol. 2015 Autumn;9:4(Suppl.1): 20-21. Pls see pdf.

Alexander and Canavan Disease

How to Cite This Article: Shalbafan B. Alexander and Canavan Disease. Iran J Child Neurol. Autumn 2014;8;4(Suppl.1):20-21

Leber Hereditary Optic Neuropathy

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Perspective Chapter: Red Flags for Syndromic Epilepsy

Despite the high frequency of seizures and propensity to develop status epilepticus (SE) most cases do not develop a long-term predisposition to seizures. So, investigating a patient with refractory epilepsy or unexplained status epilepticus is important to consider the possibility of treatable diseases i.e. treatable types of inborn error of metabolism, paraneoplasia, infections, and TLE due to temporal lobe encephalocele and IIH. Epilepsy syndrome (ES) refers to a cluster of features that should be paying attention to its red flags to narrow the wide differential diagnosis

Cell and Molecular Mechanisms of Retinal Ganglion Cell Degeneration in Glaucoma

AbstractGlaucoma is an eye disorder in which intraocular pressure is elevated and retinal ganglion cells therefore degenerate. It is a multifaceted ailment with multiple cell types and pathways involved, all working together and giving rise to optic nerve degeneration. Current drugs used in the treatment of glaucoma all work by lowering intraocular pressure and only slowing the progression of the optic nerve damage. No drugs have yet been shown to effectively target retinal ganglion cells and help regain the lost vision. It is of great importance to understand the cellular and molecular processes involved in glaucomatous neurodegeneration to be able to identify potential targets of treatment. The current review attempts to provide insight into these processes. First, an overview of the disease is provided and then, cell types other than retinal ganglion cells (RGCs) that contribute to the neurodegeneration process (including lamina cribrosa cells, astrocytes, oligodendrocytes, andmicroglia) and cellular and molecular events in the RGCs leading to their degeneration and death (such as mitochondrial dysfunction, axonal transport disruption, calcium dyshomeostasis, oxidative stress, apoptosis, and endothelial reticulum stress) are explained.Keywords: Glaucoma; Retinal Ganglion Cell; Neurodegeneration; Apoptosis; Cellular Components;Signaling Pathways

The First Reported Case of Ocular Syphilis in an Iranian Patient

Purpose: To report the first case of ocular syphilis in an Iranian patient and discuss its diagnostic challenges. Case Report: A man in his mid-70s presented with progressive bilateral visual and auditory decline. He had previously lived in a Southeast Asian country for 10 years. Prior steroid therapies entailed no inflammation subsidence. His visual acuity at presentation was light perception OU. Funduscopic findings included severe vitritis, severe optic atrophy, diffuse retinal vascular occlusion, and diffuse retinal atrophy OU. Angiography demonstrated diffuse areas of retinal and choriocapillaris atrophy with no active choroiditis. Scaly cutaneous lesions were noted on his palms and soles – atypical findings of secondary syphilis. Serum analysis revealed an underlying syphilis infection. The cerebrospinal fluid sample was reactive to anti-syphilis antibodies, securing a neurosyphilis diagnosis. Two weeks of antibiotic therapy resulted in cutaneous lesions resolution and relative visual improvement despite extensive baseline retinal atrophic damage. Conclusion: Ocular syphilis can mimic numerous ocular inflammatory scenarios. In cases of ocular inflammation that is unresponsive to steroids, reconsidering alternative diagnoses, especially infections with the highest clinical relevance, is necessary. We stress the importance of acquiring patients’ sexual history, regardless of cultural barriers and the rarity of the entity in some regions

Whole exome sequencing revealed a novel dystrophin-related protein-2 (DRP2) deletion in an Iranian family with symptoms of polyneuropathy

Objective(s): Charcot-Marie Tooth disease (CMT) is one of the main inherited causes of motor and sensory neuropathies with variable expressivity and age-of onset. Although more than 70 genes have been identified for CMT, more studies are needed to discover other genes involved in CMT. Introduction of whole exome sequencing (WES) to capture all the exons may help to find these genes.Materials and Methods: Here, we tried to find the genetic cause of the neuropathy in two Iranian brothers using WES. Blood sample was collected from probands and their family members to extract the genomic DNA. The extracted DNA from one of the affected case was subjected for WES. The variant calls were filtered  to reveal the pathogenic variant. Presence of the candidate mutation was confirmed using Sanger sequencing. The pathogenic potential of the variant was examined using in silico software. Using ClustalW multiple alignment, the presence of variant in conserved domain of protein was investigated. The parent and another affected boy were also checked for presence of the variant using PCR-sequencing. Results: The obtained data presented a novel TTC del mutation in CDS 738 of dystrophin related protein 2 (DRP2) gene, which was validated by sequencing. The variant was located in a conserved domain of DRP2 protein and predicted as pathogenic. Two affected boys were hemizygous for the mutation and received the mutation from mother. Conclusion: Here, we provided the evidence for the contribution of DRP2 in CMT. Also, the symptoms shed light on molecular aspect of this genetically heterogeneous disease

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking

Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course

Experimental <em>in Vitro</em> and <em>in Vivo</em> Models of Demyelinating Disorders

Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in Demyelinating disorders. The development of new in vitro and in vivo models or variations of existing models will contribute to a better understanding of these diseases and their treatment. Experimental models help to extrapolate information on treatment response. Indeed, the choice of the experimental model strongly depends on the research question and the availability of technical equipment. In this chapter, the current in vitro and in vivo experimental models to examine pathological mechanisms involved in inflammation, demyelination, and neuronal degeneration, as well as remyelination and repair in demyelination disorders are discussed. We will also point out the pathological hallmarks of demyelinating disorders, and discuss which pathological aspects of the disorders can be best studied in the various animal models available