Comment on "A New Allelic Variant in the PANK2 Gene in a Patient with Incomplete HARP Syndrome".
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ABSTRACT:
SUBMITTER: Walker RH
PROVIDER: S-EPMC8490183 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Microscopic colitis (MC) is a chronic inflammatory bowel disease that has emerged in the last three decades as a leading cause of chronic watery diarrhoea. MC classically includes two main subtypes: lymphocytic colitis (LC) and collagenous colitis (CC). Other types of histopathological changes in the colonic mucosa have been described in patients with chronic diarrhoea, without fulfilling the conventional histopathological criteria for MC diagnosis. Whereas those unclassified alterations remained orphan for a long time, the use of the term incomplete MC (MCi) is nowadays universally accepted. However, it is still unresolved whether CC, LC and MCi should be considered as one clinical entity or if they represent three related conditions. In contrast to classical MC, the real epidemiological impact of MCi remains unknown, because only few epidemiological studies and case reports have been described. MCi presents clinical characteristics indistinguishable from complete MC with a good response to budesonide and cholestiramine. Although a number of medical treatments have been assayed in MC patients, currently, there is no causal treatment approach for MC and MCi, and only empirical strategies have been performed. Further studies are needed in order to identify their etiopathogenic mechanisms, and to better classify and treat MC.
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Project description:OBJECTIVE:Pantothenate kinase 2-associated neurodegeneration (PKAN) is a rare neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene. PKAN is associated with iron deposition in the basal ganglia and, occasionally, with the occurrence of misshaped erythrocytes (acanthocytes). The aim of this study was to assess residual activity of PANK2 in erythrocytes of PKAN patients and to correlate these data with the type of PANK2 mutations and the progression of neurodegeneration. METHODS:Residual PANK2 activities in erythrocytes of 14 PKAN patients and 14 related carriers were assessed by a radiometric assay. Clinical data on neurodegeneration included the Barry-Albright Dystonia Scale (BAD-Scale) besides further general patient features. A molecular visualization and analysis program was used to rationalize the influence of the PKAN causing mutations on a molecular level. RESULTS:Erythrocytes of PKAN patients had markedly reduced or no PANK2 activity. However, patients with at least one allele of the c.1583C > T (T528M) or the c.833G > T (R278L) variant exhibited 12-56% of residual PANK2 activity. In line, molecular modeling indicated only minor effects on enzyme structure for these point mutations. On average, these patients with c.1583C > T or c.833G > T variant had lower BAD scores corresponding to lower symptom severity than patients with other PANK2 point mutations. INTERPRETATION:Residual erythrocyte PANK2 activity could be a predictor for the progression of neurodegeneration in PKAN patients. Erythrocytes are an interesting patient-derived cell system with still underestimated diagnostic potential.
| S-EPMC7448160 | biostudies-literature
Project description:We investigated the presence of mutations in the pantothenate kinase (PANK2) gene in a 27-year-old male Chinese patient with atypical pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Automated DNA sequence analyses revealed compound heterozygous mutations in the exon 3 and 5. This patient had a 10-year history of PKAN characterized by a slight tremor of the right hand when writing at onset and a slow progressive rigidity of the neck and the right arm and resting tremor in upper extremities. Dysarthria, dysphagia, and dystonic-athetoid movements of the face and right fingers were marked. Magnetic resonance showed the typical "eye-of-the-tiger" sign.
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Project description:In a recent edition of this journal, Mannion and Braithwaite provide a succinct analysis of the emergence, and ultimately limited impact, of what they term the current 'Safety I' movement in healthcare. They describe the arc of this field from denial, through engagement via mechanisms and approaches imported from other industries, to the current situation where, despite 'best efforts,' error rates remain stubbornly recalcitrant. In examining the failure of system-wide efforts to produce sustained reductions in errors and adverse events, that article exposes the doxa, or what Bourdieu calls 'the taken for granted' which is central to this latest wave of patient safety movement. In this commentary, I would like to take focus on two key elements of Mannion and Braithwaite's argument: that harm is caused by misguided but otherwise well-intentioned actions and the 'embracing' of patient safety. I then conclude by briefly considering the implications of these for Safety II, particularly as envisaged by the authors as an evolutionary, and therefore linear progression, from Safety I.
| S-EPMC6186486 | biostudies-literature
Project description:Purpose:To present a new mutation in a patient with Papillorenal Syndrome (PAPRS). Observations:PAPRS is an autosomal dominant disease that involves ocular and renal abnormalities. We present a patient with PAPRS with a genetically diagnosed PAX2 and new pathogenic mutation. A complete ophthalmological, neurological, nephrological and Ears-Nose-Throat (ENT) examination were undertaken. The patient suffered from Focal Segmental Glomerulosclerosis (FSGS) and some typical ophthalmological signs of PAPRS, including optic nerve coloboma and optic disc pit (ODP) maculopathy associated with an abnormal retinal vessel distribution and numerous cilioretinal arteries in the right eye. The left eye showed similar vessel abnormalities although the optic disc had a normal morphology. Conclusions:A new mutation in the PAX2 gene was identified in a patient with ocular and renal abnormalities.
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Project description:BackgroundClassical Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder mainly caused by heterozygous COL5A1 or COL5A2 variants encoding type V collagen and rarely by the p.(Arg312Cys) missense substitution in COL1A1 encoding type I collagen. The current EDS nosology specifies that minimal suggestive criteria are marked skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility or at least three minor criteria comprising additional cutaneous and articular signs. To reach a final diagnosis, molecular testing is required. Herein, we report on a 3-year-old female who came to our attention with an inconclusive next generation sequencing (NGS) panel comprising all cEDS-associated genes.MethodsDespite the patient did not formally fulfill the nosological criteria because the skin was only slightly hyperextensible, we made a cEDS diagnosis, mainly for the presence of typical atrophic scars. We investigated COL5A1 intragenic deletions/duplications by Multiplex Ligation-dependent Probe Amplification (MLPA), excluded the recessive classical-like EDS type 2 by AEBP1 Sanger analysis, and retested COL5A1 with the Sanger method.ResultsMolecular analyses revealed the novel COL5A1 c.3369_3431dup p.(Glu1124_Gly1144dup) intermediate-sized duplication with a predicted dominant negative effect that was missed both by NGS and MLPA.ConclusionsThis report highlights that some cEDS patients might not display overt skin hyperextensibility and the importance of clinical expertise to make such a diagnosis in patients with an incomplete presentation. Our results also exemplify that NGS is not a fool-proof technology and that Sanger sequencing achieves the diagnostic goal when there is a sufficiently clear phenotypic indication.
| S-EPMC7549590 | biostudies-literature
Project description:Trichohepatoenteric syndrome is an autosomal recessive genetic disease with an estimated prevalence of 1:100,000. The mutation of the disease is placed either in SKIV2L or TTC37 genes. The onset of presentation is variable, but symptoms usually start with intractable diarrhea associated with woolly hair abnormality, immune dysfunction, and sometimes hepatic abnormality. This case is of a 10-month-old girl who was born at 37 + 2 weeks due to symmetrical intrauterine growth restriction (IUGR), with a low birth weight (1320 g). It was noticed during her stay in NICU that she had excessive diarrhea on day 8. Gastroenterology suggested starting an extensively-hydrolyzed formula, but no improvement noticed. The multidisciplinary teams decided to order whole-exome sequencing analysis after excluding diarrhea causes. The analysis detected a new variant mutation (c.1297C > T) p. (Arg433Cys). To our knowledge, this is the first time detected in a homozygous state in the SKIV2L gene, as this variant mutation has not been described in any previous literature. Our case was managed mainly by total parenteral nutrition. The patient responded to the treatment appropriately.
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Project description: Not available
| S-EPMC8222830 | biostudies-literature
Project description:BACKGROUND:Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome. CASE PRESENTATION:A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G?>?A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45. CONCLUSIONS:Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.
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Project description:Mutations in HepA-related protein (HARP, or SMARCAL1) cause Schimke immunoosseous dysplasia (SIOD). HARP has ATP-dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Here, we show that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity. Furthermore, chimeric proteins generated by fusing the 2HP domain of HARP with the SNF2 domain of BRG1 or HELLS show annealing helicase activity in vitro and, when targeted to replication forks, mimic the functions of HARP in vivo. We propose that the HARP domain endows HARP with this ATP-driven annealing helicase activity.
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