scholarly journals P.134 Infantile Onset Multisystem Neurologic, Endocrine and Pancreatic Disease: case series and review

2018 ◽  
Vol 45 (s2) ◽  
pp. S51-S51
Author(s):  
C Le ◽  
AN Prasad ◽  
D Debicki ◽  
A Andrade ◽  
AC Rupar ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Severe Disease ◽  
Case Series ◽  
Pancreatic Disease ◽  
Missense Mutations ◽  
First Case ◽  
Mutation Database ◽  
Disease Case ◽  
Ncbi Dbsnp ◽  
Clinical Phenotyping

Background: We report three brothers born to consanguineous parents of Syrian descent with a novel homozygous c.324G>A (p.W108*) mutation in PTRH2 that encodes mitochondrial peptidyl-tRNA hydrolase 2. Mutations in PTRH2 have recently been identified in the autosomal recessive condition, Infantile Onset Multisystem Neurologic, Endocrine and Pancreatic Disease (IMNEPD). To our knowledge, this is the first case of IMNEPD described in a Canadian centre. Methods: Clinical phenotyping enabled a targeted approach in which all exons of PTRH2 were sequenced. We identified a novel mutation and compared our patients with those recently described. Results: We identified a homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). This G to A mutation results in a premature stop at codon 108 that produces a truncated protein, removing most of the amino acids at the enzymatic active site. This mutation is not listed in the human Gene Mutation Database Cardiff, NCBI dbSNP, 1000 Genomes, Exome Variant Server or ClinVar and is a rare variant listed in gnomAD. Conclusions: In IMNEPD, nonsense mutations in PTRH2 appear to cause severe disease with postnatal microcephaly, neurodevelopmental regression, and ataxia with additional features of seizures, peripheral neuropathy, and pancreatic dysfunction, whereas missense mutations may produce a milder phenotype. The spectrum exhibited by our patients suggests variable expressivity with PTRH2 mutations.

scholarly journals Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review

2019 ◽  
Vol 46 (04) ◽  
pp. 459-463 ◽  
Author(s):  
Christine Le ◽  
Asuri N. Prasad ◽  
C. Anthony Rupar ◽  
Derek Debicki ◽  
Andrea Andrade ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Pancreatic Insufficiency ◽  
Epileptic Seizures ◽  
Pancreatic Disease ◽  
Language Delay ◽  
The Core ◽  
Disease Case ◽  
Clinical Phenotyping ◽  
Targeted Approach ◽  
Homozygous Nonsense Mutation

ABSTRACT:We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss. Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy. Clinical phenotyping enabled a targeted approach to the investigation and identification of a novel homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). We compare our patients with those recently described and review the current literature for IMNEPD.

Clinical findings in five Turkish patients with citrin deficiency and identification of a novel mutation on SLC25A13

2020 ◽  
Vol 33 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Melis Demir Köse ◽  
Mehtap Kagnici ◽  
Taha Reşit Özdemir ◽  
Cahit Barış Erdur ◽  
Gülin Erdemir ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Genetic Disorder ◽  
Laboratory Data ◽  
Clinical Manifestations ◽  
Case Series ◽  
Clinical Findings ◽  
First Case ◽  
Age Related ◽  
Citrin Deficiency ◽  
Turkish Patients

AbstractBackgroundCitrin deficiency (CD) is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. Three clinical manifestations have been described until today.Case presentationWe reported 5 CD patients from two families. Four patients were male and one patient was female. Two of them have NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency); three of them have CTLN2 (adult-onset type II citrullinemia). Both NICCD patients showed typical clinical and biochemical changes with a diagnosis confirmed by mutations in the SLC25A13 gene. We detected a previously unreported homozygous novel mutation c.478delC (L160Wfs*36 ) on the SLC25A13 gene. All of the CTLN2 patients were siblings. Proband was a 15-year-old mentally retarded and autistic male who had admitted to our emergency with disorientation. Laboratory data showed hyperammonemia and citrullinemia.ConclusionsTwo different profiles of age-related CD have been depicted with this article. It has been aimed to underline that the CD can be observed in different forms not only in neonatals or little infants but also in adolescents. This article is the first case series that covers both NICCD and CTLN2 cases together and that has been published in Turkey. Considering the fact that especially the majority of CTLN2 cases have been identified in Asian countries, our article has vital importance in terms of defining phenotypic features of the disease.

scholarly journals Novel mutation in carnitine palmitoyltransferase 1A detected through newborn screening for a presymptomatic case in China：A case report and literature review

2020 ◽  
Author(s):  
Haining Fang ◽  
Yi Gan ◽  
Fei Yu
Keyword(s):  
Newborn Screening ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Carnitine Palmitoyltransferase ◽  
Free Carnitine ◽  
Dimensional Structure ◽  
Acid Oxidation ◽  
Missense Mutations ◽  
First Case ◽  
Mitochondrial Fatty Acid

Abstract Background：Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder that results in hypoketotic hypoglycemia and hepatic encephalopathy. It is caused by mutation in CPT1A. To date, only two symptomatic cases of CPT1A deficiency have been reported in China.Case presentation: A newborn male, without any disease-related clinical manifestations, was diagnosed with CPT1A deficiency through newborn screening. Increased free carnitine levels and a significantly increased C0/(C16+C18) ratio were detected at 3 days of age, and subsequently, mutations in CPT1A were found by gene sequence analysis. The patient was advised a low-fat, high-protein diet and followed up regularly. During three-years of follow-up since, the patient showed normal growth velocity and developmental milestones. Whole-exome sequencing identified two mutations, c.2201T >C (p.F734S) and c.1318G>A (p.A440T), in the patient. The c.2201T >C mutation, which has been reported previously, was inherited from his father, while the c.1318G>A, a novel mutation, was inherited from his mother. The amino acid residues encoded by original sequences are highly conserved across different species. These mutations slightly altered the three-dimensional structure of the protein, as analyzed by molecular modeling, suggesting that they may be pathogenic.Conclusion: This is the first case of CPT1A deficiency detected through newborn screening based on diagnostic levels of free carnitine, in China. We identified two missense mutations, c.2201T >C and novel c.1318G>A, in the patient. Our findings have expanded the gene spectrum of this rare condition and provided a basis for family genetic counseling and prenatal diagnosis.

scholarly journals Identification of Novel Nucleotide Changes in INHBB Gene by Mutation Screening in Females with Ovarian Dysgenesis: A Case Report

2021 ◽  
Author(s):  
Pooja Chauhan ◽  
Anjali Rani ◽  
Amit Kumar Rai
Keyword(s):  
In Silico ◽  
Novel Mutation ◽  
Mutation Screening ◽  
Follicle Stimulating Hormone ◽  
Primary Amenorrhea ◽  
Missense Mutations ◽  
Clinical Genetic ◽  
Ovarian Dysgenesis ◽  
First Case ◽  
Stimulating Hormone

Background: Inhibin and activin regulate the follicle stimulating hormone level by their antagonistic actions and thus have been considered as strong candidate genes in the etiology of ovarian dysgenesis. In the present study, two cases of primary amenorrhea with poorly developed secondary sexual characteristics were reported. The purpose of the study was to identify mutations in candidate gene. Case Presentation: In this paper, clinical, genetic, biochemical, and molecular findings in female patients with primary amenorrhea were reported. Whole blood culture and G-banding for karyotyping, sequencing, and in silico analysis were performed following the standard protocol. Both cases were cytogenetically characterized as normal females with 46,XX, chromosome constitution. Hormonal assay revealed high level of follicle stimulating hormone and luteinizing hormone. DNA sequence analysis of inhibin identified two novel heterozygous missense mutations of c.975T>A and c.1156G>A which were translated into p.I310N and p.D386N, respectively. These identified positions were highly conserved across species during evolution. In silico prediction tools, intramolecular hydrogen bonding pattern and hydrophobicity analysis, revealed deleterious effect of p.I310N and neutral effect of p.D386N mutation. Conclusion: Our observation suggested that identified novel mutation in the first case might be the reason for ovarian dysgenesis and provides additional support to the previously reported genotype-phenotype correlations.

Clinical Features and Surgical Outcomes of Patients With Moyamoya Disease and the Homozygous RNF213 p.R4810K Variant

2019 ◽  
Vol 34 (13) ◽  
pp. 793-800 ◽  
Author(s):  
Qian Zhang ◽  
Peicong Ge ◽  
Yonggang Ma ◽  
Dong Zhang ◽  
Rong Wang ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Surgical Outcomes ◽  
Carotid Arteries ◽  
Susceptibility Gene ◽  
Case Series ◽  
External Carotid ◽  
First Case ◽  
Disease Case ◽  
Indirect Revascularization

The ring-finger protein 213 ( RNF213) gene is a major susceptibility gene for moyamoya disease. The homozygote of the p.R4810K variant on RNF213 exhibits an early onset age and severe form of moyamoya disease. We report 4 unrelated pediatric moyamoya disease cases with the homozygous p.R4810K variant and the long-term surgical outcomes. Published reports on surgical outcome of moyamoya disease case with the homozygous p.R4810K variant were reviewed. Cerebral angiography revealed classic angiographic findings of moyamoya disease in 7 hemispheres of the 4 children. All patients underwent successful indirect revascularization. Abundant collateral blood flow from the external carotid arteries to the internal carotid arteries was observed in all bypass procedures by angiography. Improvements in symptoms and cerebral blood volume were observed in all patients at long-term follow-up. This report is the first case series in the literature on the surgical management of these patients. These cases highlight the effectiveness of indirect revascularization for moyamoya disease patients with the homozygous p.R4810K variant. Early diagnosis and treatment are crucial to avoid irreversible neurologic deficits in these patients.

scholarly journals Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients With RAG1/2 Mutations: First Cases Series From Mexico and Description of Two Novel Mutations.

2021 ◽  
Author(s):  
Mario Ernesto Cruz-Munoz ◽  
Saul Oswaldo Lugo-Reyes ◽  
Nina Pastor ◽  
Edith González-Serrano ◽  
Marco Yamazaki-Nakashimada ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Severe Combined Immunodeficiency ◽  
Clinical Manifestations ◽  
Case Series ◽  
Missense Mutations ◽  
Antigen Receptors ◽  
Novel Mutations ◽  
Nonsense Mutations ◽  
First Case ◽  
Immunological Phenotype

Abstract Mutations in Recombinase Activating Genes 1 and 2 (RAG1/2) results in human severe combined immunodeficiency (SCID). The products of these genes, are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Nonsense mutations in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with missense mutations may develop leaky SCID or Omenn syndrome (OS). A group of non-previously recognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two previously unidentified variants as causative of pathological manifestations associated to immunodeficiency. This study represents the first case series of RAG1 or RAG2 deficient patients from Mexico and Latin America.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1815
Author(s):  
Jan Boeckhaus ◽  
Oliver Gross
Keyword(s):  
Glomerular Filtration ◽  
Alport Syndrome ◽  
Large Scale ◽  
Case Series ◽  
Hereditary Diseases ◽  
Glomerular Filtration Barrier ◽  
Early Effect ◽  
Filtration Barrier ◽  
First Case ◽  
Sodium Glucose Cotransporter

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

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