Recurrent p.H119Y variant in MAP2K1 expands the phenotypic spectrum of MAP2K1-related RASopathy.

We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy.

Atypical Diabetes: What Have We Learned and What Does the Future Hold?

As our understanding of the pathophysiology of diabetes evolves, we increasingly recognize that many patients may have a form of diabetes that does not neatly fit with a diagnosis of either type 1 or type 2 diabetes. The discovery and description of these forms of "atypical diabetes" have led to major contributions to our collective understanding of the basic biology that drives insulin secretion, insulin resistance, and islet autoimmunity. These discoveries now pave the way to a better classification of diabetes based on distinct endotypes. In this review, we highlight the key biological and clinical insights that can be gained from studying known forms of atypical diabetes. Additionally, we provide a framework for identification of patients with atypical diabetes based on their clinical, metabolic, and molecular features. Helpful clinical and genetic resources for evaluating patients suspected of having atypical diabetes are provided. Therefore, appreciating the various endotypes associated with atypical diabetes will enhance diagnostic accuracy and facilitate targeted treatment decisions.

Identification of a novel hepatocyte nuclear factor-1 alpha (HNF1A) variant in maturity onset diabetes of the young type 3 (HNF1A-MODY).

Summary: We identified an adolescent young woman with new-onset diabetes. Due to suspicious family history, she underwent genetic testing for common monogenic diabetes (MODY) genes. We discovered that she and her father carry a novel variant of uncertain significance in the HNF1A gene. She was successfully transitioned from insulin to a sulfonylurea with excellent glycemic control. Based on her family history and successful response to sulfonylurea, we propose that this is a novel pathogenic variant in HNF1A. This case highlights the utility of genetic testing for MODY, which has the potential to help affected patients control their diabetes without insulin. Learning points: HNF1A mutations are a common cause of monogenic diabetes in patients presenting with early-onset diabetes and significant family history. Genetic testing in suspected patients allows for the identification of mutations causing monogenic diabetes. First-degree relatives of the affected individual should be considered for genetic testing. The use of sulfonylurea agents in patients with HNF1A-MODY can reduce dependence on insulin therapy and provide successful glycemic control.

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1ß, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Monogenic and syndromic diabetes due to endoplasmic reticulum stress.

The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly, dysregulation of ER homeostasis leads to ß-cell dysfunction in type 1 and type 2 diabetes that ultimately culminates in cell death. The ER is therefore an emerging target for understanding the mechanisms of diabetes mellitus that captures the complex etiologies of this multifactorial class of metabolic disorders. Our strategy for developing ER-targeted diagnostics and therapeutics is to focus on monogenic forms of diabetes related to ER dysregulation in an effort to understand the exact contribution of ER stress to ß-cell death. In this manner, we can develop personalized genetic medicine for ERstress-related diabetic disorders, such as Wolfram syndrome. In this article, we describe the phenotypes and molecular pathogenesis of ERstress-related monogenic forms of diabetes.

Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly.

Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels. Studies were undertaken to determine a potential genetic etiology for IMPA. The proband and her family members underwent whole exome sequencing. Functional studies were undertaken to validate the pathogenicity of candidate variant alleles. Whole exome sequencing identified monoallelic, predicted deleterious variants in genes that mediate fibroblast growth factor 21 (FGF21) signaling, FGFR1 and KLB, which were inherited in trans from each parent. FGF21 has multiple metabolic functions but no known role in human insulin resistance syndromes. Analysis of the function of the FGFR1 and KLB variants in vitro showed greatly attenuated ERK phosphorylation in response to FGF21, but not FGF2, suggesting that these variants act synergistically to inhibit endocrine FGF21 signaling but not canonical FGF2 signaling. Therefore, digenic variants in FGFR1 and KLB provide a potential explanation for the subject's severe insulin resistance and may represent a novel category of insulin resistance syndromes related to FGF21.

Severe bilateral adrenal hemorrhages in a newborn complicated by persistent adrenal insufficiency.

Bilateral adrenal hemorrhages rarely occur during the neonatal period and are often associated with traumatic vaginal deliveries. However, the adrenal gland has highly regenerative capabilities and adrenal insufficiency typically resolves over time. We evaluated a newborn female after experiencing fetal macrosomia and a traumatic vaginal delivery. She developed acidosis and acute renal injury. Large adrenal hemorrhages were noted bilaterally on ultrasound, and she was diagnosed with adrenal insufficiency based on characteristic electrolyte changes and a low cortisol (4.2 µg/dL). On follow-up testing, this patient was unable to be weaned off of hydrocortisone or fludrocortisone despite resolution of hemorrhages on ultrasound. Providers should consider bilateral adrenal hemorrhage when evaluating critically ill neonates after a traumatic delivery. In extreme cases, this may be a persistent process. LEARNING POINTS: Risk factors for adrenal hemorrhage include fetal macrosomia, traumatic vaginal delivery and critical acidemia.Signs of adrenal hemorrhage include jaundice, flank mass, skin discoloration or scrotal hematoma.Adrenal insufficiency often is a transient process when related to adrenal hemorrhage.Severe adrenal hemorrhages can occur in the absence of symptoms.Though rare, persistent adrenal insufficiency may occur in extremely severe cases of bilateral adrenal hemorrhage.Consider adrenal hemorrhage when evaluating a neonate for shock in the absence of an infectious etiology.

Propagation of the [PIN+] prion by fragments of Rnq1 fused to GFP.

Prions are viewed as enigmatic infectious entities whose genetic properties are enciphered solely in an array of self-propagating protein aggregate conformations. Rnq1, a yeast protein with yet unknown function, forms a prion named [PIN+] for its ability to facilitate the de novo induction of another prion, [PSI+]. Here we investigate a set of RNQ1 truncations that were designed to cover major Rnq1 sequence elements similar to those important for the propagation of other yeast prions: a region rich in asparagines and glutamines and several types of oligopeptide repeats. Proteins encoded by these RNQ1 truncations were tested for their ability to (a) join (decorate) pre-existing [PIN+] aggregates made of wild-type Rnq1 and (b) maintain the heritable aggregated state in the absence of wild-type RNQ1. While the possible involvement of particular sequence elements in the propagation of [PIN+] is discussed, the major result is that the efficiency of transmission of [PIN+] from wild-type Rnq1 to a fragment decreased with the fragment's length.