ABCC8 p.Ala113Val
| Predicted by SNAP2: | C: N (57%), D: D (66%), E: D (71%), F: D (75%), G: N (87%), H: D (66%), I: N (57%), K: D (71%), L: D (59%), M: D (63%), N: D (66%), P: D (71%), Q: D (63%), R: D (63%), S: N (82%), T: N (87%), V: D (63%), W: D (75%), Y: D (63%), |
| Predicted by PROVEAN: | C: N, D: D, E: D, F: D, G: N, H: D, I: D, K: N, L: N, M: N, N: N, P: D, Q: N, R: D, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Noninvasive diagnosis of focal hyperinsulinism of ... Diabetes. 2006 Jan;55(1):13-8. Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H
Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography.
Diabetes. 2006 Jan;55(1):13-8., [PMID:16380471]
Abstract [show]
Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the beta-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. We evaluated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months). To reduce bias in PET image interpretation, quantitative means for evaluation of pancreatic [(18)F]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [(18)F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [(18)F]-DOPA in the pancreas (SUV ratio <1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [(18)F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI.
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100 In one of these (case no. 7), a pancreatic biopsy with diffuse-type pathol- TABLE 1 Clinical and genetic characteristics of the patients, together with the findings in PET scan, pancreatic catheterization, surgery, and histology Patient Age at diagnosis/PET ABCC8 mutation Response to medication Glucose need (mg/kg/min) PET PVS/PACS Surgery/histology 1 Neonatal/6 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 12.3 focal/head focal/head focal resection/posterior neck PAD: focus 6.8 afb; 4 mm 2 4 months/13 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 9.5 focal/body focal/body focal resection/body PAD: focus 5 afb; 4 mm 3 Neonatal/6 months G1469V (4408Gb0e;T) (Paternal) Dzxafa;, Octr af9; 12.7 focal/head focal/head focal resection/head PAD: focus 8 afb; 5 mm 4 Neonatal/3.5 years V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 12.7 diffuse diffuse* ND 5 Neonatal/6 months A113V (338Cb0e;T) (Paternal) Dzxafa;, Octr af9; 12.7 diffuse diffuse Near-total pancreatectomy PAD: diffuse histology 6 Neonatal/5 years No mutations Dzx af9; 6.5 diffuse diffuse* ND 7 3 months/4 years No mutations Dzx af9; 6.5 diffuse ND Pancreas biopsy PAD: diffuse histology 8 Neonatal/9 months G92D (275Gb0e;A) Dzxafa;, Octr af9; 10.3 diffuse ND Near-total pancreatectomy PAD: diffuse histology 9 Neonatal/1 month V187D (561Tb0e;A) (Paternal) Dzxafa;, Octrafa; 20 focal/head ND focal resection/uncinate process PAD: focus 8 afb; 4 mm 10 Neonatal/2 months No mutations Dzx partial, Octr af9; 6.2 diffuse ND ND 11 5 months/13 months V187D (561Tb0e;A) (Paternal) Dzxafa;, Octr af9; 6.4 diffuse diffuse ND 12 Neonatal/1.5 months G474A (de novo) Dzxafa;, Octr af9; 15.9 diffuse ND Near-total pancreatectomy PAD diffuse; 13 Neonatal/3 months C418R (1252Tb0e;C) (Maternal) Dzxafa;, Octr af9; 26 focal/body ND focal resection/body PAD: focus 10 afb; 6 mm 14 Neonatal/6 months A113V (338Cb0e;T) (Paternal) Dzxafa;, Octr af9; 13 diffuse ND ND The glucose need refers to the glucose infusion rate that was required to maintain normoglycemia at the time of the PET scan.
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ABCC8 p.Ala113Val 16380471:100:943
status: NEWX
ABCC8 p.Ala113Val 16380471:100:1981
status: NEW[hide] Clinical and histological heterogeneity of congeni... Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8. Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S, Hussain K
Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8., [PMID:25201519]
Abstract [show]
CONTEXT: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
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70 (c.1629-2A>C) Walker B *R177W *M209I *I284del E292K T294M G312C COOH COOH NH2 M1 M2 6 1 TMD0 TMD1 TMD2 2 3 4 5 7 8 9 10 11 12 13 14 15 16 17 p.*391Rext*94 *T62M R1494W Q954X G111R A113V *V601I *A1153T D1031N L1171X A1263T V185fs Intracellular NH2 NBD2 NBD1 Cell membrane Figure 1 Paternal mutations mapped onto the SUR1 and Kir6.2 protein.
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ABCC8 p.Ala113Val 25201519:70:180
status: NEW74 Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome ABCC8 1 40, 3150 Male 52 2.4 4.3 L1431F/N (c.4291COT/N) Yes - On Dzx at 6.4 years 2 40, 4000 Male 2 2.4 1.9 p.?/N (c.2697C4AOT/N) Yes - Off Dzx at 2 years 3 40, 5010 Female !1 2.6 8.6 E1507K/N (c.4519GOA/N) Yes - On Dzx at 2.3 years 4 40, 5600 Male !1 2.0 7.5 A1508P/N (c.4522GOC/N) Yes - On Dzx at 12 years 5 37, 4820 Male !1 2.0 9.0 A1153T/N (c.3457GOA/N) Yes - On Dzx at 4 years 6 38, 3630 Female 72 3.1 !2 A1153T/N (c.3457GOA/N) Yes - On Dzx at 2 years 8 35, 2820 Male !1 1.2 12.9 A1185V/N (c.3554COT/N) Yes - Off Dzx at 8 months 9 36, 4450 Male !1 2 28.5 p.?/N (c.3992-9GOA/N) Yes - Off Dzx after 4.5 months 10 41, 2780 Female !1 1 9.3 D1472N/N (c.4414GOA/N) Yes - Off Dzx after 10 months 11 38, 3750 Male !1 2.6 5.90 V601I/N (c.1801GOA/N) Yes - Off Dzx after 14 months 13 40, 4160 Female !1 2.4 14.8 V185fs/N (c.554delT/N) No Diffuse Off octreotide at 5 years 14 37, 3090 Male !1 0.6 12.4 p.?/N (c.3992-9GOA/N) No Focal On octreotide at 9.5 years 15 40, 3600 Male !1 2.7 6.7 H627fs/N (c.1879delC/N) No Diffuse Off octreotide at 18 months 16 40, 4700 Female !1 2.0 !2 E1507K/N (c.4519GOA/N) NA - No treatment required 17 40, 4200 Male !1 1.0 !2 D1031N/N (c.3091GOA/N) NA - No treatment required 18 41, 4850 Male !1 1.2 10.1 M1V/N (c.1AOG/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 19 38, 2400 Male !1 2.1 16.3 D1194V; R1437Q/N (c.3581AOT; c.4310GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 20 40, 4580 Female !1 1.1 103 A1493T/N (c.4477GOA/N) Yes a No Diffuse Near-total pancreatectomy (95%) 21 40, 4600 Male !1 1.2 22.5 K890fs/N (c.2669_2675del/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 22 40, 4335 Male !1 2.6 3.4 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 23 40, 3030 Male !1 1.8 15.6 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 24 40, 2770 Male !1 2.2 3.4 p.?/N (c.580-1GOC/N) No Indeterminate (PVS) Partial pancreatectomy - focal lesion on histology 25 41, 4290 Male 2 2.3 4.32 E128K/N (c.382GOA/N) No Focal Hypoglycaemia resolved after removal of focal lesion 27 40, 5095 Male !1 2.0 10.5 L1171X/N (c.3512delT/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 29 37, 3560 Male !1 1.6 21.8 p.?/N (c.1629-2AOC/N) No Focal Hypoglycaemia resolved after removal of focal lesion 30 40, 2750 Male !1 1.5 16.4 G111R/N (c.331GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 31 37, 3340 Male !1 2.1 15 H627fs/N (c.1879delC/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 32 41, 4950 Male !1 1.2 11.95 R934X/N (c.2800COT/N) No Focal Hypoglycaemia resolved after removal of focal lesion 33 40, 3080 Female 12 1.5 4.6 S12X/N (c.35COA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 34 39, 3600 Male !1 2.5 8 R1494W/N (c.4480COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 37 36, 3410 Male !1 0.9 17.42 R1494W/N (c.4480COT/N) No Focal Partial pancreatectomy Table 1 Continued Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome 38 39, 4900 Female !1 1.4 23.61 A113V/N (c.338COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 39 36, 3210 Male !1 0.6 114 Mosaic Q54X (c.160COT) No Diffuse Near-total pancreatectomy (95%) 40 41, 4300 Female !1 2.1 17 Q954X/N (c.2860COT/N) No Diffuse Near-total pancreatectomy (95%) 41 36, 2730 Male !1 ?
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ABCC8 p.Ala113Val 25201519:74:3388
status: NEW