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Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family.
Pappalardo, J, Heath Jeffery, RC, Thompson, JA, Charng, J, Chelva, ES, Constable, IJ, McLaren, TL, Lamey, TM, De Roach, JN, Chen, FK
Ophthalmic genetics. 2021;(1):62-70
Abstract
BACKGROUND Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP. MATERIALS AND METHODS An observational case series of four family members with adRP. They were examined clinically, with multi-modal retinal imaging and electroretinography (ERG) to ascertain phenotype. Disease progression rate was measured using optical coherence tomography (OCT) and fundus autofluorescence (FAF). A retinal dystrophy panel was used for the proband and cascade testing with targeted Sanger sequencing was conducted in other available family members. RESULTS The proband presented at 36 years of age with profoundly reduced full-field ERG responses despite a sector RP phenotype. This progressed to a classic RP pattern over several decades leaving a small residual island of central visual field. The horizontal span of the residual outer nuclear layer and the area of hyperautofluorescent ring contracted at a rate of 8-11% and 9-14% per year, respectively. DNA sequencing confirmed the segregation of SAG c.440 G > T mutation with disease. CONCLUSION SAG adRP presents with a reduced full-field ERG response consistent with a rod-cone dystrophy in mid-life despite a sector RP phenotype. Centripetal progression of the disease into the macula can be tracked by OCT and FAF imaging.
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A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis.
Vahidnezhad, H, Youssefian, L, Saeidian, AH, Mansoori, B, Jazayeri, A, Azizpour, A, Hesari, KK, Yousefi, M, Zeinali, S, Jouanguy, E, et al
The Journal of investigative dermatology. 2019;(5):1195-1198
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SLC25A13 c.1610_1612delinsAT mutation in an Indian patient and literature review of 79 cases of citrin deficiency for genotype-phenotype associations.
Radha Rama Devi, A, Naushad, SM
Gene. 2018;:190-195
Abstract
Here, we report SLC25A13 c.1610_1612delinsAT mutation from India in a 13-year old boy who presented with recurrent episodes of delirium and hyperammonemia. This is the second case with this mutation; the first case was of Pakistani origin. The boy responded to diet modification, sodium benzoate and arginine supplementation. Furthermore, we have aimed to establish genotype-phenotype correlation of 79 cases of citrin deficiency (46 males and 33 females) reported in 24 studies from all over the world. Inverse association was observed between age of onset and jaundice (r = -0.73). Late age of onset was associated with delirium (r = 0.61), aggressive behaviour (r = 0.67), altered sensorium (r = 0.67) and tremors (r = 0.65). The most common mutations associated with citrin deficiency were c.851_854del4, IVS16ins3kb, 1638-1660dup with a frequency of 42.41%, 16.46% and 6.33%, respectively. The c.851_854del4 mutation showed positive association with alpha feto protein (r = 0.40), ammonia (r = 0.50) and tyrosine (r = 0.40) while showing inverse association with threonine (r = -0.55). The IVS16ins3kb mutation was associated with high total (r = 0.65) and conjugated bilirubin (r = 0.54) along with high aspartate transaminase (r = 0.49) while citrulline levels are lower (r = -0.36). To conclude, all cases of intrahepatic cholestasis and neuropsychiatric abnormalities should be evaluated for citrin deficiency. However, the ethnic group-specific mutation frequencies should be considered in implementing screening.
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Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition.
Canna, SW, Girard, C, Malle, L, de Jesus, A, Romberg, N, Kelsen, J, Surrey, LF, Russo, P, Sleight, A, Schiffrin, E, et al
The Journal of allergy and clinical immunology. 2017;(5):1698-1701
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Abstract
NLRC4-inflammasome hyperactivity causes infantile-onset Macrophage Activation Syndrome and enterocolitis with extraordinary serum IL-18 elevation (NLRC4-MAS). Herein, we report a critically ill infant with severe, refractory NLRC4-MAS who showed sustained response to treatment with experimental IL-18 inhibition.
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A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature.
Frosk, P, Chodirker, B, Simard, L, El-Matary, W, Hanlon-Dearman, A, Schwartzentruber, J, Majewski, J, , , Rockman-Greenberg, C
BMC medical genetics. 2015;:28
Abstract
BACKGROUND Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene. CASE PRESENTATION Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant. CONCLUSIONS CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome.
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Calponin expression in laryngeal myoepithelial carcinoma and its prognostic implications: a case report and literature review.
Mao, YJ, Luo, XM, Zhou, SH, Zheng, ZJ
The Journal of international medical research. 2010;(2):711-9
Abstract
A case report of laryngeal myoepithelial carcinoma (MEC) is presented and the literature concerning prognostic factors in MEC is reviewed. A 61-year old man was admitted to hospital with hoarseness and progressive dyspnoea. On examination, both vocal cords were fixed in the midline with a glottic fissure of only 3 mm. No tumour was seen, but the subglottis was not completely visible. A computed tomography scan showed a soft mass below the right vocal cord obstructing two-thirds of the larynx. On suspension laryngoscopy, a dull mass (1.5 x 1.5 cm) was seen below the right vocal cord, which was malignant on frozen biopsy. A total laryngectomy was performed and the patient received radiotherapy. He died of recurrence 25 months later. The tumour was positive for cytokeratin 14, S-100 protein and calponin. MEC of the larynx is extremely rare. The clinical behaviour of MEC is variable and prognostic factors have been poorly analysed. Calponin expression may be a prognostic factor, but other factors also affect the outcome in MEC.
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[Identification and diagnosis of three novel mutations in SLC25A13 gene of neonatal intrahepatic cholestasis caused by citrin deficiency].
Song, YZ, Sheng, JS, Ushikai, M, Hwu, WL, Zhang, CH, Kobayashi, K
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2008;(6):411-5
Abstract
OBJECTIVE Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is a novel autosomal recessive disease caused by mutations in the gene SLC25A13 that encodes for citrin, a liver-type aspartate/glutamate carrier located in the mitochondrial inner membrane. SLC25A13 was cloned in 1999 by Kobayashi et al at Kagoshima University in Japan, and until now, most of the NICCD patients reported in the world were Japanese. Most of the Chinese NICCD patients diagnosed by genetic analysis had the same SLC25A13 mutations as Japanese, however, in some cases, known mutations were not detected. This research aimed to identify novel SLC25A13 mutations in Chinese NICCD patients and to explore the experimental conditions for their genetic diagnosis. METHODS Genomic DNA was extracted from blood samples of 3 NICCD patients from Taiwan (P757), Guangdong (P1194) and Hebei province (P1443) of China, respectively, and all the 18 exons and their flanking sequences of SLC25A13 gene were sequenced. Furthermore, the identified novel mutations were diagnosed by amplification with PCR, digestion with corresponding restriction endonuclease, and agarose gel electrophoresis. RESULTS Three novel mutations identified in SLC25A13 gene of the 3 NICCD patients were an abnormal splicing IVS7-2A > G (P757), a missense A541D (c.1622C > A, P1194) and a nonsense R319X (c.955C > T, P1443). The PCR-restriction fragment length polymorphism (RFLP) procedures for their genetic diagnosis were also established, with specific fragments on electrophoresis after digestion of the PCR products with three different restriction endonucleases Msp I, Hpy188I and Taq I, respectively. CONCLUSIONS So far as we know, the three novel mutations in SLC25A13 gene of Chinese NICCD patients were first identified, suggesting that SLC25A13 mutation distributed in Chinese population is somewhat different from that in Japanese. Moreover, the PCR-RFLP diagnostic procedures established in this research provide valuable tools not only for the genetic diagnosis of NICCD but also for further molecular epidemiologic investigations in Chinese population.
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A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome.
Hur, DJ, Raymond, GV, Kahler, SG, Riegert-Johnson, DL, Cohen, BA, Boyadjiev, SA
American journal of medical genetics. Part A. 2005;(1):36-40
Abstract
Keutel syndrome (KS) [OMIM 245150] is a rare autosomal recessive condition, characterized by abnormal cartilage calcification. Mutations in the matrix Gla protein gene (MGP) have been previously reported in three unrelated KS families. MGP is an extracellular matrix protein that acts as a calcification inhibitor by repressing bone morphogenetic protein 2 (BMP2). Loss-of-function mutations of MGP result in abnormal calcification of the soft tissues, a cardinal feature of KS. We report the fourth MGP mutation (IVS2 + 1G > A) in a consanguineous Arab family, which results in the loss of the consensus donor splice site at the exon 2-intron 2 junction. In addition to the typical manifestations, we observed abnormalities in the white matter of the brain, optic nerve atrophy, and mid-dermal elastolysis in the affected individuals of this family. This report broadens the clinical phenotype observed in patients with KS. The effect of the IVS2 + 1G > A mutation is consistent with the previously reported loss-of-function mutations of MGP.