Khalid Hussain - Academia.edu (original) (raw)
Papers by Khalid Hussain
Journal of Pediatrics, 2005
Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclea... more Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclear. We report a case of a novel splice site mutation in the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) gene associated with hyperinsulinism. This mutation resulted in a nearly complete absence of immunoreactive protein and a decrease in fibroblast SCHAD activity. (J Pediatr 2005;146:706-8)
Diabetes, 2008
OBJECTIVE-Insulin gene (INS) mutations have recently been described as a cause of permanent neona... more OBJECTIVE-Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.
Journal of Medical Genetics, 2009
Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of ... more Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic b-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period. Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from b-cells.
Hormone Research, 2006
... External Resources 2. Glaser B, Thornton PS, Otonkoski T, Junien C: Genetics of neonatal hype... more ... External Resources 2. Glaser B, Thornton PS, Otonkoski T, Junien C: Genetics of neonatal hyperinsulinism. ... External Resources 15. Suchi M, Thornton PS, Adzick NS, et al: Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. ...
Seminars in Fetal & Neonatal Medicine, 2005
Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a... more Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a heterogeneous disease with respect to clinical presentation, molecular biology, genetic aetiology and response to medical therapy. The clinical heterogeneity may range from severe life-threatening disease to very mild clinical symptoms. Recent advances have begun to clarify the molecular pathophysiology of this disease, but despite these advances treatment options remain difficult and there are many long-term complications. So far mutations in five different genes have been identified in patients with congenital hyperinsulinism. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). Two histological subtypes of the disease - diffuse and focal - have been described. The preoperative histological differentiation of these two subtypes is now mandatory as surgical management will be radically different. The ability to distinguish diffuse from focal lesions has profound implications for therapeutic approaches, prognosis and genetic counselling.
Archives of Disease in Childhood-fetal and Neonatal Edition, 2000
Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatr... more Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without diYculty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It oVers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment. (Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107)
Journal of Clinical Investigation, 2001
A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic con... more A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid β-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the β cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.
Diabetes, 2001
Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea ... more Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.
Journal of Pediatrics, 2005
Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclea... more Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclear. We report a case of a novel splice site mutation in the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) gene associated with hyperinsulinism. This mutation resulted in a nearly complete absence of immunoreactive protein and a decrease in fibroblast SCHAD activity. (J Pediatr 2005;146:706-8)
Diabetes, 2008
OBJECTIVE-Insulin gene (INS) mutations have recently been described as a cause of permanent neona... more OBJECTIVE-Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.
Journal of Medical Genetics, 2009
Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of ... more Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic b-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period. Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from b-cells.
Hormone Research, 2006
... External Resources 2. Glaser B, Thornton PS, Otonkoski T, Junien C: Genetics of neonatal hype... more ... External Resources 2. Glaser B, Thornton PS, Otonkoski T, Junien C: Genetics of neonatal hyperinsulinism. ... External Resources 15. Suchi M, Thornton PS, Adzick NS, et al: Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. ...
Seminars in Fetal & Neonatal Medicine, 2005
Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a... more Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a heterogeneous disease with respect to clinical presentation, molecular biology, genetic aetiology and response to medical therapy. The clinical heterogeneity may range from severe life-threatening disease to very mild clinical symptoms. Recent advances have begun to clarify the molecular pathophysiology of this disease, but despite these advances treatment options remain difficult and there are many long-term complications. So far mutations in five different genes have been identified in patients with congenital hyperinsulinism. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). Two histological subtypes of the disease - diffuse and focal - have been described. The preoperative histological differentiation of these two subtypes is now mandatory as surgical management will be radically different. The ability to distinguish diffuse from focal lesions has profound implications for therapeutic approaches, prognosis and genetic counselling.
Archives of Disease in Childhood-fetal and Neonatal Edition, 2000
Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatr... more Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without diYculty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It oVers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment. (Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107)
Journal of Clinical Investigation, 2001
A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic con... more A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid β-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the β cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.
Diabetes, 2001
Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea ... more Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.