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The SORD neuropathy has been identified as the most common autosomal recessive inherited neuropathy, occurring in thousands of patients worldwide. Fibroblast lines from 3 different patients containing the c.753delG; p.Ala253GlnfsTer27 SORD mutations were reprogrammed into induced Pluripotent Stem Cell (iPSC) lines. These iPSC lines demonstrate an apparent normal karyotype and have positive expression of pluripotency markers. These iPSC lines also stain positively for Ectoderm, Endoderm and Mesoderm markers following Embryoid body differentiation. These lines pose to serve as a valuable disease modeling resource for studying the SORD neuropathy, including studying disease phenotype and treatment efficacy.

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell–derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

Summary: Phosphoenolpyruvate carboxykinase (PCK) plays a critical role in cytosolic gluconeogenesis, and defects in PCK1 cause a fasting-aggravated metabolic disease with hypoglycemia and lactic acidosis. However, there are two genes encoding PCK, and the role of the mitochondrial resident PCK (encoded by PCK2) is unclear, since gluconeogenesis is cytosolic. We identified three patients in two families with biallelic variants in PCK2. One has compound heterozygous variants (p.Ser23Ter/p.Pro170Leu), and the other two (siblings) have homozygous p.Arg193Ter variation. All three patients have weakness and abnormal gait, an absence of PCK2 protein, and profound reduction in PCK2 activity in fibroblasts, but no obvious metabolic phenotype. Nerve conduction studies showed reduced conduction velocities with temporal dispersion and conduction block compatible with a demyelinating peripheral neuropathy. To validate the association between PCK2 variants and clinical disease, we generated a mouse knockout model of PCK2 deficiency. The animals present abnormal nerve conduction studies and peripheral nerve pathology, corroborating the human phenotype. In total, we conclude that biallelic variants in PCK2 cause a neurogenetic disorder featuring abnormal gait and peripheral neuropathy.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

Background and study aims Colonoscopy is effective in reducing the incidence of colorectal cancer, but interval cancers remain a concern and their occurrence mainly is thought to be due to poor detection of sessile serrated lesions (SSLs) and advanced neoplasia (AN). Currently there are no low-cost, easy-to-implement tools to improve detection of difficult-to-detect polyps. Our aims were to compare the detection rate for SSLs and AN between two groups of endoscopists at a large community practice, one of which received an intervention of a polyp detection poster displayed over the monitor in their endoscopy suite for 6 months. We compared preintervention and post-intervention detection rates in the intervention and control groups. Methods This was a convenience case control quality improvement project. For 6 months, a 2’ × 3’ poster of pictures of SSLs and advanced neoplasia was displayed over the monitor for 44 endoscopist in a large community gastroenterology practice in the Minneapolis/St.Paul area, while another 44 physicians performed colonoscopy in the usual fashion without the poster. The endpoints were improvement in detection rates for SSLs and AN preintervention and post-intervention between the control and intervention groups. Results During the study, 88 endoscopists performed 54,861 colonoscopies. At least one adenoma was detected in 41.3 % of patients, one or more SSLs in 11.4 %, and AN in 10.6 %. During the intervention period, the SSL detection rates were 10.9 % and 12.3 % for the control and intervention groups and for AN, the detection rates were 10.4 % and 10.75 % for the two groups, respectively. Exposure to the polyp detection poster significantly changed SSL detection for the intervention group relative to the control group (likelihood ratio test P

Amyloidosis has traditionally been of a few defined varieties, most commonly including light-chain amyloidosis (AL amyloidosis) and secondary amyloidosis due to chronic inflammation (AA amyloidosis). Apolipoprotein A-I/A-II cystatin C, gelsolin, lysozyme, fibrinogen alpha chain, beta 2 microglobulin, and transthyretin familial amyloidosis represent rarer but reported varieties. Ten years ago, the first reports linked leukocyte chemotactic factor 2 (LECT2) amyloidosis as a pathological agent identified as a novel class of amyloid-generating protein. Epidemiology suggested that this was a new cause of amyloidosis that is especially common in Hispanic patients and somewhat common among patients from the Middle East-North Africa (MENA) region. We report a case of splenic and renal LECT 2 amyloidosis in a 62-year- old Hispanic male with diabetes mellitus. After an unremarkable serological workup, LECT 2 amyloidosis was diagnosed on renal biopsy. The case presentation is reviewed as a typical presentation, and the literature is reviewed regarding this newly reported entity, resulting in infiltrative renal amyloidosis and chronic renal disease.

This prospective observational study quantified screen media use within the night-time pre-sleep period in a pediatric intensive care unit and postulated possible implications. Seventy-five patients between the ages of newborn to 19 years old were observed 5 evenings per week for 3 weeks. Trained observers documented the patient’s screen use, type of screen used, screen engagement, sleep state, light level, and parental presence. Patients in the ICU had on average 65 minutes of screen media use, per evening. The total screen media use averaged 59 minutes for the 0 to18-month age group; 83 minutes for the 18 to 24-month age group; 66 minutes for 2 to 6 year olds; 72 minutes for 6 to 13 year olds; and 74 minutes for those above 13. This research demonstrates that children are engaging in more screen time during the night hours than is recommended by the AAP.