Renal Focal Segmental Glomerulosclerosis Research Articles

SAT084 Maternally Inherited Diabetes With Deafness: A Rare And Challenging Diagnosis Of Diabetes

Abstract Disclosure: K. Cuan: None. I.R. Bass: None. Introduction: Maternally inherited diabetes with deafness (MIDD) is a rare mitochondrial disease with variable phenotypic expression characterized by a defect in insulin secretion and sensorineural hearing loss. Other potential features of MIDD include proximal myopathy, macular retinal dystrophy, and renal focal segmental glomerulosclerosis. Mitochondrial diseases are difficult to recognize given their heterogeneous presentation, however accurate diagnosis of MIDD is important as there are implications for management. DESCRIPTION: A 38-year-old adopted woman with previously diagnosed type 1 diabetes (T1DM), congenital deafness, and chronic kidney disease presented to our endocrinology clinic with concerns for difficulty controlling her blood glucose levels. She was diagnosed with T1DM at age 21 based on age and normal body habitus and was started on insulin. Due to insurance issues, she discontinued insulin use for several years and her diabetes was poorly controlled during that time, however, she never experienced diabetic ketoacidosis (DKA). Upon resuming insulin, she experienced multiple unpredictable episodes of hypoglycemia and subsequently self-discontinued insulin and presented 8 months later for further care. Past history was notable for muscle weakness with walking upstairs and vision loss in her left eye, which led to a diagnosis of retinopathy in her early twenties. Her family history was unavailable as she was adopted. Her physical exam was significant for a normal body mass index of 24. Labs showed a hemoglobin A1C of 10.8% and detectable c-peptide, 2.7 ng/mL (1.1-4.4 ng/mL) with a glucose of 192mg/dL. Glutamic acid decarboxylase, zinc transporter 8, IA-2 and islet-cell antibodies were all negative. Her creatinine was 1.23 ng/dL with a severely increased microalbumin to creatinine ratio (638, 0-29 mg/g). In view of her congenital deafness, non-diabetic retinopathy, absence of DKA while off insulin, negative antibody testing, and chronic kidney disease, mitochondrial diabetes was considered. She was referred to a geneticist for mitochondrial genome sequencing, of which the results are pending. Dietary modification and oral agents were recommended for her diabetes management, rather than insulin therapy. DISCUSSION: MIDD can be challenging to diagnose and patients may be incorrectly labeled as having type 1 diabetes. The presence of maternal transmission can aid in the diagnosis of MIDD, however, our patient was adopted and this information is unavailable. Additionally, retinal and renal features of MIDD can be misconstrued as microvascular complications of diabetes. In patients with deafness and poorly controlled diabetes with negative antibody testing, MIDD should be considered as an alternative diagnosis. MIDD can be managed with dietary modification, oral agents, and insulin if appropriate. Presentation: Saturday, June 17, 2023

R702C Mutation of the MYH9 Gene Provokes Impaired Platelet Formation, Renal Focal Segmental Glomerulosclerosis, and Hearing Disability In the Mice Model

AbstractAbstract 482R702C mutation of the MYH9 gene provokes impaired platelet formation, renal focal segmental glomerulosclerosis, and hearing disability in mice model.Several isoforms of class II myosins are required for cytokinesis, cell motility, cell polarity/chemotaxis, cell architecture, and development of nonmuscle cells. Among these, nonmuscle myosin heavy chain IIA (NMMHC-IIA) encoded by MYH9, is known to be associated with inherited human disease, MYH9 disorders, characterized by giant platelets, thrombocytopenia and characteristic Döhle body-like cytoplasmic granulocyte inclusion bodies. Also, these disorders frequently present with nephritis and sensorineural hearing disability. Particularly, recent studies using admixture mapping identified MYH9 as a major risk factor for focal and segmental glomerular sclerosis (FSGS) and nondiabetic kidney disease in African Americans. However, the function of NMMHCII-A, in the affected variable organs and how the gene is related to the disease have not been elucidated.In turn, our previous studies have shown that the MTH9+/− mice do not reproduce the clinical picture of MYH9 disorders and the MYH9−/− mice are lethal early during embryogenesis. Several MYH9 mutations are in most patients missense mutations occurring at a few codons and it is still ambiguous whether mutations determine haploinsufficiency or act through a dominant negative mechanism. We and other investigators indicated that human subjects with mutations in the motor domain, particularly at Arg 702 presented with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years. Here we generate and characterize mice expressing Arg702Cys (R702C) mutation. To introduce the mutation into exon 16 of MYH9 gene, a loxP-flanked PGK-neo selectable marker cassette was inserted into the intron upstream of exon 16, according with negative DT marker. Chimeric mice generated from two independent targeted 129SvJ ES cell clones were crossed with C57BL/6J mice to produce R702C heterozygotes. The loxP-neo cassette was removed by crossing the heterozygous mice with a CAG-Cre deleter mouse strain that constitutively expresses Cre recombinase to yield heterozygous knock in mice (R702C+/−).R702C+/− mice had markedly decreased platelet counts (53±31×109/L vs 1071.±321.7×109/L) and morphologically larger platelets than wild-type C57/BL6 mice. Although granulocyte inclusion bodies were mostly invisible or inconspicuous on May-Giemsa stained blood smears, immunofluorecence analysis indicated NMMHC-IIA proteins aggregated and accumulated in the granulocyte cytoplasm. Although the number of bone marrow megakaryocytes was comparable to wild-type mice, proplatelet formation of fetal liver-derived megakaryocytes from R702C+/− was impaired; the number of proplatelet-forming megakaryocytes was decreased and clusters of platelet-like particles were observed around megakaryocytes. The increased size and decreased number of proplatelet tips were also detected.To verify kidney function, spot urine samples free of fecal contamination were collected during 5–20 weeks (w) after birth. R702C+/− mice displayed a significant proteinuria dependent on age, whereas wild type mice had only trace amount (Figure). Examination of renal pathology of R702C+/− mice of 20w after birth revealed typical FSGS by light microscopy and podocyte foot process effacement by electron microscopy. Apparently, altered podocyte morphology at the foot process level resulted in a partial loss of glomerular filtration barrier.We further measured the auditory brainstem response (ABR) of 20w R702C+/− mice and studied whether they had hearing losses, Needle electrodes were inserted into the vertex of anesthetized mice, then ABR was obtained. The ABR thresholds in R702C+/− mice were significantly higher at all frequencies, indicating severe deafness.Our observations suggested that heterozygous expression of MYH9 R702C affected not only megakaryocyte proplatelet formation apparently resulting in macrothrombocytopenia, but also the function of the cells in other affected organs, where NMMHC-IIA is known to be exclusively expressed. [Display omitted] Disclosures:Naoe:Chugai Pharm. Co.: Research Funding; Zenyaku-Kogyo Co.: Research Funding; Kyowa-Kirin Co.: Research Funding; Dainippon-Sumitomo Pharm. Co.: Research Funding; Novartis Pharm. Co.: Research Funding; Janssen Pharm. Co.: Research Funding. Matsushita:Pfizer Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.