Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.

Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A. Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy. Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.

Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy.

Inherited optic neuropathies (IONs) are rare genetic diseases characterized by progressive visual loss due the atrophy of optic nerves. The standard diagnostic workup involving next-generation sequencing panels has a diagnostic yield of about forty percent. In the other 60% of the patients with a clinical diagnosis of ION, the underlying genetic variants remain unknown. In this case study, we describe a potentially new disease-associated gene, NSUN3, for IONs. The proband was a young woman with consanguineous parents. She presented with bilateral optic atrophy and nystagmus at the age of seven years. Genetic testing revealed the homozygous variant c.349_352dup p.(Ala118Glufs*45) in NSUN3, with a segregation in the family compatible with autosomal recessive inheritance. Additional functional analysis showed decreased NSUN3 mRNA levels, slightly diminished mitochondrial complex IV levels, and decreased cell respiration rates in patient fibroblasts compared to healthy controls. In conclusion, pathogenic variants in NSUN3 can cause optic neuropathy. Trio whole-exome sequencing should be considered as a diagnostic strategy in ION cases where standard diagnostic analysis does not reveal disease-causing variants.

Characteristics of autosomal dominant WFS1-associated optic neuropathy and its comparability to OPA1-associated autosomal dominant optic atrophy.

This study aims to describe the ophthalmic characteristics of autosomal dominant (AD) WFS1-associated optic atrophy (AD WFS1-OA), and to explore phenotypic differences with dominant optic atrophy (DOA) caused by mutations in the OPA1-gene. WFS1-associated diseases, or 'wolframinopathies', exhibit a spectrum of ocular and systemic phenotypes, of which the autosomal recessive Wolfram syndrome has been the most extensively studied. AD mutations in WFS1 also cause various phenotypical changes including OA. The most common phenotype in AD WFS1-associated disease, the combination of OA and hearing loss (HL), clinically resembles the 'plus' phenotype of DOA. We performed a comprehensive medical record review across tertiary referral centers in the Netherlands and Belgium resulting in 22 patients with heterozygous WFS1 variants. Eighteen (82%) had HL in addition to OA. Diabetes mellitus was found in 7 (32%). Four patients had isolated OA. One patient had an unusual phenotype with anterior chamber abnormalities and malformations of the extremities. Compared to DOA, AD WFS1-OA patients had different color vision abnormalities (red-green vs blue-yellow in DOA), abnormal OPL lamination on macular OCT (absent in DOA), more generalized thinning of the retinal nerve fiber layer, and more reduced and delayed pattern reversal visual evoked potentials.

Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum.

Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including optic atrophy, hearing impairment, and diabetes mellitus. We summarize current literature, define the clinical characteristics, and investigate potential genotype phenotype correlations. A systematic literature search was conducted in electronic databases Pubmed/MEDLINE, EMBACE, and Cochrane Library. We included studies reporting patients with a clinical picture consisting at least 2 typical clinical manifestations of WSF1 disorders and heterozygous mutations in WFS1. In total, 86 patients from 35 studies were included. The most common phenotype consisted of the combination of optic atrophy (87%) and hearing impairment (94%). Diabetes mellitus was seen in 44% of the patients. Nineteen percent developed cataract. Patients with missense mutations in WFS1 had a lower number of clinical manifestations, less chance of developing diabetes insipidus, but a younger age at onset of hearing impairment compared to patients with nonsense mutations or deletions causing frameshift. There were no studies reporting decreased life expectancy. This review shows that, within the spectrum of WFS1-associated disorders or "wolframinopathies," autosomal dominantly inherited WFLS has a relatively mild phenotype compared to autosomal recessive WS. The clinical manifestations and their age at onset are associated with the specific underlying mutations in the WFS1 gene.

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer.

BACKGROUND: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. METHODS: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. RESULTS: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. CONCLUSION: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases.

Is Robotic Complete Mesocolic Excision Feasible for Transverse Colon Cancer?

Introduction: Laparoscopic complete mesocolic excision (CME) for transverse colon cancer is technically challenging. Robotic technology has been developed to reduce technical limitations of laparoscopy. Yet, no data are available on the role of robotic approach for CME of transverse colon cancer. The aim of this study is to evaluate the feasibility and short-term outcomes of robotic CME in this subset of colon cancer. Methods: A retrospective review of a prospectively maintained database of 29 consecutive patients undergoing robotic CME for transverse colon adenocarcinoma between December 2014 and December 2017 was performed. Data on demographics, tumor characteristics, postoperative 30-day complications, and oncologic outcomes were analyzed. Results: There were 21 (72%) men and 8 women with a mean age of 62.9 ± 15.6 years and a body mass index of 26.4 ± 4.8 kg/m2. Of the 29 robotic CME procedures, 12 patients underwent extended right colectomy, 10 extended left colectomy, 6 subtotal colectomy, and 1 total colectomy. The mean operative time was 321.7 ± 111.3 minutes and estimated blood loss was 106.9 ± 110.9 mL (median, 50; range, 10-400 mL). The intra- and postoperative complication rates were 7% and 24%, respectively. There were no conversions. The mean time to first bowel movement was 3.5 ± 1.3 and length of hospital stay was 7.1 ± 3.0 days. All the resections were R0. The mean number of harvested lymph nodes in extended and subtotal/total colectomy procedures was 36.6 ± 13.1 and 71.0 ± 30.3, respectively. The rate of mesocolic plane surgery was 79%. There were no statistically significant differences between the mesocolic and the intramesocolic/muscularis propria plane resections with respect to clinical characteristics, operative outcomes, and pathology results (P > .05). Conclusions: Robotic CME for transverse colon cancer is feasible and can be a procedure of choice to achieve a good surgical quality.