An improved diagnostic method for taurodontism and a comparative study on its effectiveness evaluation.

OBJECTIVE: The two commonly used diagnostic methods for taurodontism are susceptible to aging changes, mastication wear and other factors. Therefore, this study proposed an improved diagnostic method for taurodontism, and compared it with the previous two methods as a supplement for taurodontism diagnosis. METHODS: The included patients were aged 10-89 years and admitted to the Department of Stomatology of Hebei Eye Hospital from June 1, 2022 to May 31, 2023. Eighty cone-beam computed tomography images were divided equally into 4 groups: 10-29, 30-49, 50-69, and 70-89 years old. The right mandibular first molars were selected as measurement objects. Firstly, |BD| and taurodontism index (TI)-related parameters were measured using Shifman and Chanannel's method and crown-body(CB) and root (R) lengths was measured by Seow and Lai's method. The improved method used the length from the cementoenamel junction(CEJ) to the root bifurcation point(body, B)and the root length(root, R)as the measurement objects. Finally, TI, CB/R ratios, and B/R ratios were calculated according to the formulas given below. One-way ANOVA analysis was mainly used to compare the differences in the values, indices and ratios of taurodontism among different age groups (p<0.05). RESULTS: With the increase of age, |BD| and TI values decreased significantly (p<0.01). The CB/R ratios of 70-89 years group were significantly lower than those of the other three groups (p<0.01). Ratios derived from the improved method were significantly lower in the 70-89 years than in 10-29 years group (p<0.05). CONCLUSIONS: The |BD| and TI parameters proposed by Shifman and channel are significantly influenced by age. The measurements of Seow and Lai (CB/R ratios) were less affected by age compared with those of the former. The improved method(B/R ratios) was least affected by age, which would reduce error and bias in the measurement of taurodontism and obtain more objective results in older patients.

Clinical features and genetic analysis of 15 Chinese children with dent disease.

OBJECTIVE:  The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease. METHODS:  We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. RESULTS:  All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). CONCLUSION:  Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

A qualitative study to explore the burden of disease in activated phosphoinositide 3-kinase delta syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers. METHODS: Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. RESULTS: Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications. CONCLUSIONS: APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians.

Genetic analysis of a child with severe intellectual disability caused by a novel variant in the FERM domain of the FRMPD4 protein.

Intellectual developmental disorder, X-linked 104 (XLID104), caused by the FRMPD4 gene variant, is a rare X-linked genetic disease that primarily manifests as intellectual disability (ID) and language delay, and may be accompanied by behavioural abnormalities. Currently, only 11 patients from four families have been reported to carry FRMPD4 gene variants. Here, we report a rare case of a Chinese patient with XLID104 who was presented with severe ID and language impairment. Genetic testing results showed that the patient had a novel hemizygous variant on FRMPD4 inherited from the heterozygous variant NM_001368397: c.1772A>C (p.Glu591Ala) carried by his mother. To our knowledge, this variant has not been reported previously. Western blot results for the recombinant plasmid constructed in vitro indicated that the expression of the mutant protein may be reduced. Using molecular dynamics simulations, we predicted that the mutant protein may affect the interaction of the FRMPD4 protein with DLG4. In this study, we expand the spectrum of FRMPD4 variants and suggest that the clinical awareness of the genetic diagnosis of nonsyndromic ID should be strengthened.

Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior.

The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI influences X-linked disease penetrance: maternal transmission of the fragile X mental retardation 1 (Fmr1)-knockout (KO) allele confers 55% of total brain cells with mutant X-active, which is sufficient for behavioral penetrance, while 40% produced from paternal transmission is tolerated. Local XCI mosaicism within affected maternal Fmr1-KO mice further specifies sensorimotor versus social anxiety phenotypes depending on which distinct brain circuitry is most affected, with only a 50%-55% mutant X-active threshold determining penetrance. Thus, our results define a model of X-linked disease penetrance in females whereby distributed XCI among single cells populating brain circuitries can regulate the behavioral penetrance of an X-linked mutation.

ERG Responses in Albinism, Idiopathic Infantile Nystagmus, and Controls.

Purpose: Our primary aim was to compare adult full-field ERG (ffERG) responses in albinism, idiopathic infantile nystagmus (IIN), and controls. A secondary aim was to investigate the effect of within-subject changes in nystagmus eye movements on ffERG responses. Methods: Dilated Ganzfeld flash ffERG responses were recorded using DTL electrodes under conditions of dark (standard and dim flash) and light adaptation in 68 participants with albinism, 43 with IIN, and 24 controls. For the primary aim, the effect of group and age on ffERG responses was investigated. For the secondary aim, null region characteristics were determined using eye movements recorded prior to ffERG recordings. ffERG responses were recorded near and away from the null regions of 18 participants also measuring the success rate of recordings. Results: For the primary aim, age-adjusted photopic a- and b-wave amplitudes were consistently smaller in IIN compared with controls (P < 0.0001), with responses in both groups decreasing with age. In contrast, photopic a-wave amplitudes increased with age in albinism (P = 0.0035). For the secondary aim, more intense nystagmus significantly reduced the success rate of measurable responses. Within-subject changes in nystagmus intensity generated small, borderline significant differences in photopic b-wave peak times and a-and b-wave amplitudes under scotopic conditions with standard flash. Conclusions: Age-adjusted photopic ffERG responses are significantly reduced in IIN adding to the growing body of evidence of retinal abnormalities in IIN. Differences between photopic responses in albinism and controls depend on age. Success at obtaining ffERG responses could be improved by recording responses at the null region.

A rare co-occurrence of phosphorylase kinase deficiency (GSD type IXd) and alpha-glycosidase deficiency (GSD Type II) in a 53-year-old man presenting with an atypical glycogen storage disease phenotype.

Glycogen Storage Disease (GSD) IXd, caused by PHKA1 gene mutations, is an X-linked rare disorder that can be asymptomatic or associated with exercise intolerance. GSD type II is an autosomal recessive disorder caused by mutations in the GAA gene that lead to severe cardiac and skeletal muscle myopathy. We report the first case of co-occurrence of type IXd and type II GSDs in a 53-year-old man with an atypical glycogen storage disease presentation consisting in myalgia in the lower limbs at both rest and after exercise and increased levels of transaminases from the age of 16. At the age of 43, the patient presented a steppage gait, inability to run and walk on his heels, hypotrophy of the pectoral and proximal muscles, reflexes not elicitable, and CK levels 3.6 times the upper reference limit. Next Generation Sequencing (NGS) identified one variant in the PHKA1 gene, c.1360A > G p.Ile454Val (exon 14) inherited by his mother, and two heterozygous variants in the GAA gene, c.784G > A (exon 4) and c.956-6T > C (exon 6). A review of GSD IXd cases reported to date in the literature is also provided.

Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses.

PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

IgA nephropathy in a child with X-linked agammaglobulinemia: a case report.

BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are at an increased risk of developing autoimmune diseases. However, renal involvement are rare in cases of XLA. CASE PRESENTATION: In this report, we discussed a specific case involving a 6-year-old boy with XLA who experienced recurrent upper respiratory tract infections since the age of one. He presented with symptoms of hematuria and proteinuria, and renal pathology confirmed the presence of immunoglobulin (Ig) A nephropathy. Treatment comprised glucocorticoids, mycophenolate mofetil, and intermittent intravenous immunoglobulin replacement therapy. Consequently, there was a remission of proteinuria and a partial improvement in hematuria. CONCLUSIONS: In this study, we describe the first case of IgA nephropathy associated with XLA. This is an interesting phenotype found in XLA, and it provides valuable insights into the process of autoimmunity and the regulation of immune function in individuals with XLA. Based on our findings, we recommend the evaluation of immunoglobulin levels in patients diagnosed with IgA nephropathy.

Clinical and genetic studies for a cohort of patients with congenital stationary night blindness.

BACKGROUND: Congenital stationary night blindness (CSNB) is an inherited retinal disorder. Most of patients have myopia. This study aims to describe the clinical and genetic characteristics of fifty-nine patients with CSNB and investigate myopic progression under genetic cause. RESULTS: Sixty-five variants were detected in the 59 CSNB patients, including 32 novel and 33 reported variants. The most frequently involved genes were NYX, CACNA1F, and TRPM1. Myopia (96.61%, 57/59) was the most common clinical finding, followed by nystagmus (62.71%, 37/59), strabismus (52.54%, 31/59), and nyctalopia (49.15%, 29/59). An average SE of -7.73 ± 3.37 D progressed to -9.14 ± 2.09 D in NYX patients with myopia, from - 2.24 ± 1.53 D to -4.42 ± 1.43 D in those with CACNA1F, and from - 5.21 ± 2.89 D to -9.24 ± 3.16 D in those with TRPM1 during the 3-year follow-up; the TRPM1 group showed the most rapid progression. CONCLUSIONS: High myopia and strabismus are distinct clinical features of CSNB that are helpful for diagnosis. The novel variants identified in this study will further expand the knowledge of variants in CSNB and help explore the molecular mechanisms of CSNB.

Increased Proteolytic Activity of Serratia marcescens Clinical Isolate HU1848 Is Associated with Higher eepR Expression.

Serratia marcescens is a global opportunistic pathogen. In vitro cytotoxicity of this bacterium is mainly related to metalloprotease serralysin (PrtS) activity. Proteolytic capability varies among the different isolates. Here, we characterized protease production and transcriptional regulators at 37°C of two S. marcescens isolates from bronchial expectorations, HU1848 and SmUNAM836. As a reference strain the insect pathogen S. marcescens Db10 was included. Zymography of supernatant cultures revealed a single (SmUNAM836) or double proteolytic zones (HU1848 and Db10). Mass spectrometry confirmed the identity of PrtS and the serralysin-like protease SlpB from supernatant samples. Elevated proteolytic activity and prtS expression were evidenced in the HU1848 strain through azocasein degradation and qRT-PCR, respectively. Evaluation of transcriptional regulators revealed higher eepR expression in HU1848, whereas cpxR and hexS transcriptional levels were similar between studied strains. Higher eepR expression in HU1848 was further confirmed through an in vivo transcriptional assay. Moreover, two putative CpxR binding motifs were identified within the eepR regulatory region. EMSA validated the interaction of CpxR with both motifs. The evaluation of eepR transcription in a cpxR deletion strain indicated that CpxR negatively regulates eepR. Sequence conservation suggests that regulation of eepR by CpxR is common along S. marcescens species. Overall, our data incorporates CpxR to the complex regulatory mechanisms governing eepR expression and associates the increased proteolytic activity of the HU1848 strain with higher eepR transcription. Based on the global impact of EepR in secondary metabolites production, our work contributes to understanding virulence factors variances across S. marcescens isolates.

Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.

Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy-A Case Report.

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype-phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors.

Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury.

The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the L1 gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis. Clinicians have observed that recovery post-traumatic brain injury (TBI) varies among the population. This variability may be explained by the genetic differences present in the general population. In this study, we utilized a novel mouse model of L1 syndrome with a mutation at aspartic acid position 201 in the extracellular domain of L1 (L1-201). We assessed the impact of this specific single nucleotide polymorphism (SNP) localized to the X-chromosome L1 gene on recovery outcomes following TBI by comparing the L1-201 mouse mutants with their wild-type littermates. We demonstrate that male L1-201 mice exhibit significantly worse learning and memory outcomes in the Morris water maze after lateral fluid percussion (LFP) injury compared to male wild-type mice and a trend to worse motor function on the rotarod. However, no significant changes were observed in markers for inflammatory responses or apoptosis after TBI.