Disruption of PIKFYVE causes congenital cataract in human and zebrafish

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. However, the molecular mechanisms underlying the pathogenesis of congenital cataract remain incompletely defined. Through whole-exome sequencing of a Chinese family with congenital cataract, we identified a potential pathological variant (p.G1943E) in PIKFYVE, which is located in the PIP kinase domain of the PIKFYVE protein. We demonstrated that heterozygous/homozygous disruption of PIKFYVE kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKFYVE activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and pinpointed the potential application of Baf-A1 for the treatment of congenital cataract caused by PIKFYVE deficiency.

Genetic Causes of Oculocutaneous Albinism in Pakistani Population

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

Varied Presentation of Oral Verrucous Carcinoma in a Tertiary Hospital of Dhaka City

Introduction: Ackerman’s tumor or Verrucous carcinoma is a distinguished clinic-pathological variant of squamous cell carcinoma, presenting with multiple clinical presentations. This study provides a contemporary survey of morphological presentation of oral verrucous carcinoma (OVC) in the oral cavity with site of predilection and possible etiological factors. Method: An observational studywas conducted from January 2014 to June 2016.A suspected patient diagnosed clinically and histologically as OVC at the Dhaka Dental College Hospital (DDCH) was enrolled in this study. Results: In this study total 15 number of patients male were 53.3% and female were 47%. The morphological presentation of the study was proliferative and verrucous, each of which comprises 40.0% of cases. The tumor's primary site was the buccal mucosa 46.67% and history ofbetel quid chewing was 46.9%. Conclusion: The study concluded that it is very difficult to distinguishing clinically between verrucous carcinoma and other exophytic lesions of the oral cavity. OVC presents with different morphological presentation such as proliferative and verrucous types. Buccal mucosa is the site of predilection. J Bangladesh Coll Phys Surg 2021; 39(2): 80-86

Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar immune microenvironment as compared to conventional UC.

477 Background:Plasmacytoid urothelial carcinoma (UC) is a rare pathological variant of UC with low chemotherapeutic sensitivity and dismal outcomes. The molecular and immune profiles of such tumors remain poorly investigated. Herein, we investigated the phenotypical features of a cohort of plasmacytoid UC (n = 32) by comparison to a control group of conventional high-grade UC with matched clinicopathological characteristics (n = 30). Methods: Histopathological analysis included the following antibodies: p63, GATA3, CK5/6, CK20 and HER2. In addition, the density of intra-tumor CD8+ lymphocytes, and PD-L1 expression in tumor (TC) and immune cells (IC) were evaluated. Clinical data were collected. Results: Plasmacytoid UC expressed GATA3 (97% vs 86% p = 0.18), CK20 (59% vs 36% p = 0.08) markers and showed a significantly higher rate of HER2 overexpression (2+ and 3+ score: 25% vs 0%, p < 0.01) compared to controls. A significantly lower expression of CK5/6 (22% vs 56%, p < 0.05) and p63 (41% vs 80%, p < 0.05) was observed in plasmacytoid UC compared to controls. The density of tumor-infiltrating CD8+ cells was similar between plasmacytoid and conventional UC (p = 0.5). PD-L1 expression on IC was similar compared to conventional UC (p = 0.3). Overall survival at 5 years was significantly lower among patients with plasmacytoid UC compared to patients with conventional UC (p = 0.02). Conclusions: Together, our study demonstrated that plasmacytoid UC belong to the luminal subtype and display a rather inflamed microenvironment similar to conventional UC. These data support the inclusion of plasmacytoid variant of UC in clinical trials evaluating immune checkpoint inhibitors monotherapy or combination immunotherapeutic strategies.

Hypophosphatasia screening in pediatric age based on records

Introduction: hypophosphatasia (HPP) is a congenital disease, characterized by a defect in bone and dentary mineralization, secondary to a deficiency in the biosynthesis of non-specific tissue isoenzyme of alkaline phosphatase (TNSALP), resulting in decreased levels of alkaline phosphatase (ALP) activity and the extracellular accumulation of its substrates. Our goal was to establish the interest of screening the hospital databases of pediatric patients with low levels of ALP for the diagnosis of HPP. Materials and methods: during the period from September 2016 to September 2017, 23231 patients were tested for ALP, 1752 of them showed low levels of ALP. Based on the clinic, basal disease and that in previous analyses they did not present ALT norm values, 14 cases were selected: 8 cases associated with early puberty, 1 case of low size, 1 case of liver disease and myasthenia and 1 case of teething problems. ALPL gene was studied in those cases. Results: the latter case was of an 8-year-old male with a pathological variant of HPP: c.343_348dupACCGCC (p.Thr115_Ala116dup) in exon 5 in dominant heterozygous, inherited from his mother. At the substrate level the levels of pyridoxal-5-phosphate were above 50μg/L. Conclusion: the diagnostic strategy with a high index of clinical suspicion of HPP should include the observation of low levels of serum ALP activity. Our study shows that HPP is an underdiagnosed disease.An appropriate protocol to detect HPP in a clinical setting in tertiary care hospitals is required.

A Child Who Suddenly Freezes While Trying to Cross Crosswalks—Unique Clinical Manifestation of Paroxysmal Kinesigenic Dyskinesia: A Case Report

(1) Background: We report the case of a patient with a unique clinical presentation of inability to cross crosswalks due to paroxysmal kinesigenic dyskinesia (PKD). (2) Case presentation: A 14-year-old boy presented with the inability to move his right leg at gait initiation from the standing position. This episode lasted for approximately 20–30 s and manifested 1–3 times a day. The difficulty in gait initiation usually occurred when the patient tried to cross crosswalks when the traffic light turned from red to blue. His right arm stiffened occasionally while trying to write with a pencil and eat food with a spoon or chopsticks. Other neurological manifestations and pain were absent during these episodes. No neurological symptoms were observed between the attacks. Brain magnetic resonance imaging did not reveal any abnormalities. A next-generation sequencing study revealed a pathological variant in the proline-rich transmembrane protein 2 (PRRT2) gene. The patient was diagnosed with PKD. His symptoms disappeared completely after treatment with carbamazepine (100 mg/day). (3) Conclusions: The symptoms of PKD can be successfully controlled using antiepileptic medications. Therefore, clinicians should be aware of the clinical manifestations of PKD to provide appropriate treatment.

Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.