Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation.

AIM: Congenital hyperinsulinism (CHI) and glycogen storage disease (glycogenosis) are both causing hypoglycemia during infancy, but with different additional clinical features and therapeutic approach. We aimed to identify a genetic cause in a child with an ambiguous phenotype. METHODS AND RESULTS: We present a child with hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in erythrocytes, increased liver transaminases, and increased echogenicity on liver ultrasonography. As both parents of the proband were referred as healthy, we raised a clinical suspicion on glycogenosis with recessive inheritance. However, whole exome sequencing revealed no mutation in genes causing glycogenosis, but a novel heterozygous variant LRG_483t1: c.427-1G>A in the HNF4A gene was identified. Aberrant splicing resulting in in-frame deletion c.429_476del, p.(T144_I159del) was confirmed by sequencing of HNF4A transcripts reverse-transcribed from whole blood RNA. The same variant was found in five of eight tested family relatives (one of them already had diabetes, two had prediabetes). With regard to the results of DNA analysis, we added diazoxide to the therapy. Consequently, the frequency and severity of hypoglycemia in the proband decreased. We have also recommended sulfonylurea treatment after diabetes onset in adult mutation carriers. CONCLUSIONS: We have identified a novel HNF4A gene mutation in our patient with CHI and glycogenosis-like phenotype. The proband and her family members benefited from the genetic testing by WES method and consequently personalized therapy. Nevertheless, the HNF4A gene testing may be considered in selected CHI cases with glycogenosis-like phenotype prior WES analysis.

The significance of electron microscopic examination of gingiva in cases of Hunter syndrome and hereditary gingival fibromatosis.

INTRODUCTION: Electron microscopy has been for decades a basic morphological method still used in diagnostic protocols of some pathological conditions affecting the ultrastructure of cells and extracellular matrix. The aim of this study was an ultrastructural description of gingiva of patients with Hunter syndrome and hereditary gingival fibromatosis. PATIENTS AND METHODS: Gingival biopsies were obtained during surgical periodontal treatment from a 9-year-old boy with Hunter disease (with enzyme replacement therapy with recombinant human idursulphase) and a 15-year-old girl with hereditary gingival fibromatosis. Gingival samples obtained from the upper anterior region were processed and examined with transmission electron microscope. RESULTS: In the case of Hunter syndrome due to the genetic lack of one lysosomal enzyme, an intercellular accumulation of glycosaminoglycans occurs. Within the gingiva of a patient with Hunter syndrome we observed membrane-bound storage vesicles in the cytoplasm of fibroblasts, endothelial cells of capillaries, surface epithelial cells, mast cells, and macrophages. Despite a long-term enzyme replacement therapy which improves clinical manifestations of Hunter syndrome, on the cellular level we still found marked accumulations of glycosaminoglycans in the cytoplasm of different cells as well as in the extracellular matrix. Hereditary gingival fibromatosis is a benign, slowly progressive and non-inflammatory gingival enlargement with a predominance of randomly oriented collagen fibrils in the gingival lamina propria. Some of these fibrils exhibited loops. Another unusual ultrastructural finding is the presence of empty perinuclear space in the cytoplasm of epithelial cells. The origin and significance of these non-membrane bound spaces are unknown. CONCLUSION: In both genetically determined diseases, the electron microscopic examination may be useful, and physicians get relevant information about the progress of illness.

Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease.

PURPOSE: Fabry disease, a genetic deficiency of alpha-galactosidase A, is characterized by pathogenic cellular accumulation of globotriaosylceramide. During clinical trials, recombinant human alpha-galactosidase A (agalsidase beta; Fabrazyme, Genzyme Corporation, Cambridge, MA), infused intravenously at 1.0 mg/kg every 2 weeks for 6 months, cleared or reduced globotriaosylceramide in renal, cardiac, and dermal microvascular endothelia and other cells, with results sustained for up to 5 years in most patients evaluated. This study explored whether a lower dose could maintain globotriaosylceramide clearance achieved with 1.0 mg/kg. METHODS: Cellular globotriaosylceramide levels were assessed histologically in kidney and skin biopsies from 21 adult Fabry males treated for 6 months at 1.0 mg/kg/2 weeks followed by 18 months at 0.3 mg/kg/2 weeks. RESULTS: In kidney interstitial capillary endothelium, the primary endpoint, globotriaosylceramide clearance was achieved in 100% of patients with 1.0 mg/kg and maintained in 90% with 0.3 mg/kg. In seven other renal cell types and superficial dermal capillary endothelium, globotriaosylceramide reduction or clearance was maintained with 0.3 mg/kg in approximately 70% of patients. CONCLUSIONS: A lower dose of agalsidase beta may be sufficient in some, but not all, patients with Fabry disease to maintain the cellular globotriaosylceramide clearance achieved with 1.0 mg/kg/2 weeks. Long-term clinical effects of transitioning to the lower dose have not been evaluated.