Serum Copper and Zinc Levels Among Iranian Vitiligo Patients.

Introduction: Vitiligo is a chronic skin disease, which its etiopathogenesis is not fully understood. Numerous studies have suggested that oxidative stress may play a role in the pathophysiology of vitiligo. There are controversial reports as to the changes of serum trace elements, copper (Cu) and zinc (Zn) levels in vitiligo patients. Objectives: We evaluated the alterations in the level of serum Cu and Zn among a group of Iranian vitiligo patients. Methods: The levels of serum Cu and Zn were compared between 117 vitiligo patients and 137 healthy controls using atomic absorption spectrophotometry. Results: The mean Cu and Zn levels in the cases (113.57 ± 59.43 and 95.01 ± 58.95 µg/dl, respectively) were significantly lower than those of the controls (138.90 ± 38.14 and 121.83 ± 33.80 µg/dl, respectively) (P = 0.00). We also observed significantly lower serum Cu and Zn concentrations in young (< 50 years) than the elderly (≥ 50 years) patients (P = 0.00). The mean Cu and Zn levels in the patients with generalized vitiligo (111.63±54.18 and 93.11±59.33 µg/dl, respectively) were significantly lower than patients with localized vitiligo (120.74 ±71.64 and 98.69±58.63 µg/dl, respectively) and those in the control (P = 0.00). The serum Cu/Zn ratio obtained in the young and male patients was higher than those in their matched controls (P = 0.01). Conclusions: The current study has shown that the disturbance of serum Cu and Zn levels is associated with vitiligo, and may play an important role in the disease development of Iranian patients.

New Report of a Different Clinical Presentation of CD151 Splicing Mutation (c.351+2T>C): Could TSPAN11 be Considered as a Potential Modifier Gene for CD151?

CD151, a member of the tetraspanin family, is essential for normal development of skin and kidney. To date, only 2 pathogenic variants of the CD151 gene have been identified in a related disorder with recessive inheritance. Here, in the third study of CD151 mutations, we report 3 affected siblings presenting variable degrees of renal and dermal symptoms. Whole exome sequencing (WES) was performed on the proband, followed by data analysis and in silico assessments. Confirmation of the mutation in the other patients were carried out using Sanger sequencing. The consequence of the CD151 mutation was investigated by RNA extraction and Sanger sequencing of PCR products from cDNA. Multiple computational tools were applied for protein alignment, homology modeling, and molecular interaction analysis. WES revealed the variant c.351+2T>C, NM_139029 (GRCh37) in CD151, and this was confirmed by Sanger sequencing in all patients. This variant is the result of a substitution of nucleotide T with C that changes the position +2 of the donor splice site in intron 5, leading to total loss of exon 5 from the transcript. The mentioned variant was not found in population allele frequency databases, and prediction tools concurred in its damaging effect on the protein. Based on the criteria from ACMG guidelines, this variant is pathogenic. Interestingly, in terms of clinical findings, symptoms and severity of the disease in the patients in this study were different compared to the previous report of the mutation and the disease. In addition, in silico analysis in this study appears to suggest a candidate protein, Tetraspanin-11 (TSPAN11), that could partially modify CD151 functions. This study supports the pathogenic effect of the CD151 variant c.351+2T>C, highlights the extensive variable expressivity amongst patients, reinforces the contribution of genomic content to clinical characteristics of CD151 mutations, and accentuates the importance of modifier genes.

Use of expanded carrier screening for retrospective diagnosis of two deceased siblings with Van Maldergem syndrome 2: case report.

Van Maldergem syndrome (VMLDS) is a recessive disease which affects multiple organs including the face, ear, and limb extremities. It can be caused by pathogenic variants in either the gene DCHS1 or FAT4. Diagnosis of VMLDS is complicated, especially regarding its similarity of symptoms to Hennekam syndrome, another disorder caused by FAT4 variants. Reported patients are two infantile siblings with multiple congenital anomalies, who deceased without clinical diagnosis. Whole exome sequencing was exploited for expanded carrier screening (ECS) of their parents, which revealed a novel splicing variant in the gene FAT4, NM_024582.6: c.7018+1G>A. In silico analysis of the variant indicates loss of canonical donor splice site of intron 6. This variant is classified as pathogenic based on ACMG criteria. Reverse phenotyping of patients resulted in likely diagnosis of VMLDS2. This study reaffirms the possibility of using ECS, leading to the genetic diagnosis of a rare disease with complicated clinical features.

Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19.

Introduction Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19 . MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.

Preparation and evaluation of rhenium-188-pamidronate as a palliative treatment in bone metastasis.

OBJECTIVE: Rhenium-188-hydroxyethylidene diphosphonate (188Re-HEDP) as a first generation bisphosphonate has been widely used for bone seeking radiopharmaceutical in cases of metastatic bone disease. No study has been yet reported on preparing a complex of 188Re with pamidronate (3-aminohydroxypropylidene-1,1-bisphosphonic acid) (PMA) as a second generation bisphosphonate. Based on this fact, it was hypothesized that a bone-seeking 188Re-PMA radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. METHODS: Pamidronate was labeled with 188ReO4- eluted from the alumina based 188W/188Re generator. Labeling was optimized, and radiochemical analysis was performed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). Biodistribution of this radioconjugate was evaluated and verified further in mice. RESULTS: 188Re-PMA was prepared successfully in a high labeling yield (˃95%) corresponding to a specific activity of 124MBq/µmol and good in vitro stability, but it is likely to consist of multiple species. In biodistribution studies selective uptake and retention of activity in the skeletal system (0.81±0.25% ID/g and 0.57±0.16 at 4 and 48h in bone post injection respectively) followed by clearance in the soft tissues were observed. CONCLUSION: These results show that due to its biological capabilities it would be advantageous to use 188Re-PMA for bone pain palliation therapy.