|Year : 2021 | Volume
| Issue : 2 | Page : 127-129
Fructose 1,6 bisphosphatase deficiency mimicking glycogen storage disease as recurrent hypoglycemia
Manoj Madhusudan, Janani Sankar, Venkateswari Ramesh
Department of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India
|Date of Submission||04-Apr-2021|
|Date of Decision||21-Apr-2021|
|Date of Acceptance||14-May-2021|
|Date of Web Publication||31-May-2021|
Dr. Manoj Madhusudan
Department of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital, 12/A, Nageshwara Road, Josier Street, Nungambakkam, Chennai - 600 034, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Fructose 1,6 Bisphosphatase (FBPase) deficiency is a rare and treatable cause of ketotic hypoglycemia in children. Affected children present in the postneonatal period with recurrent episodes of early morning hypoglycemia typically triggered by an infection. We present a child with recurrent hypoglycemic seizures who was initially considered as glycogen storage disease (GSD) type 1, but on further evaluation, was diagnosed with FBPase deficiency. Clinical Description: A 2.5-year-old developmentally normal boy presented with the second episode of hypoglycemic seizure. He had a similar episode following a fasting time of 10 h at 2 years of age. Critical sample analysis revealed ketosis, lactic acidosis, hyperuricemia, and raised triglycerides. He was diagnosed with probable GSD type 1. At 2.5 years of age, he had another episode of hypoglycemic seizures following a similar fasting spell, and critical sample evaluation revealed similar findings. However, he did not have the classical cherubic facies associated with GSD type 1, and a repeat ultrasound abdomen showed normal-sized liver. Management: The clinical presentation and critical sample evaluation were suggestive of gluconeogenesis defect. However, the child did not have any other end-organ involvement. Hence, a possibility of FBPase deficiency was considered. The genetic testing confirmed compound heterozygous mutations involving the FBP1 gene. Conclusion: Fructose 1,6 bisphosphonate deficiency is a close mimicker of GSD 1.
Keywords: Fructose 1,6 bisphosphatase deficiency, gluconeogenesis defect, glycogen storage disease 1, recurrent hypoglycemia
|How to cite this article:|
Madhusudan M, Sankar J, Ramesh V. Fructose 1,6 bisphosphatase deficiency mimicking glycogen storage disease as recurrent hypoglycemia. Indian Pediatr Case Rep 2021;1:127-9
|How to cite this URL:|
Madhusudan M, Sankar J, Ramesh V. Fructose 1,6 bisphosphatase deficiency mimicking glycogen storage disease as recurrent hypoglycemia. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 21];1:127-9. Available from: http://www.ipcares.org/text.asp?2021/1/2/127/317364
Hypoglycemia in children is a heterozygous condition with different possible etiologies. Thorough clinical examination with analysis of critical samples is essential to clinch the diagnosis. Despite this, there is considerable overlap in clinical presentation between the various etiologies that pose challenges in making an accurate diagnosis. We present a child with recurrent ketotic hypoglycemia, initially suspected to have glycogen storage disease (GSD) type 1, where genetic evaluation revealed fructose 1,6 bisphosphatase (FBPase) deficiency.
| Clinical Description|| |
Two and half-year-old developmentally normal boy, firstborn to nonconsanguineous marriage, was admitted and evaluated elsewhere for early morning hypoglycemic seizure at the age of 2 years. Critical sample analysis revealed elevated lactate, uric acid, and triglycerides with 2+ urine ketones. Ultrasound abdomen showed enlarged liver with altered liver echotexture. He was diagnosed with probable GSD type 1, and his parents were counseled regarding the same. Further evaluation was not done as parents could not come following COVID 19 pandemic-associated lockdown.
Management and outcome
Six months later, he presented to our hospital with a second episode of early morning hypoglycemic seizures following approximately 10 h of fasting. A dietary history revealed that he was on exclusive breast feeds till 6 months of age following which weaning was started. He was a strict vegetarian with a preference for sweets and fruits and had his regular meal the night earlier with an extra half apple. On examination, his anthropometric measurements were normal and he did not have the cherubic facies typically observed in GSD. There was no hepatomegaly, and his external genitalia was normal. Critical sample evaluation revealed similar findings: ketosis, lactic acidosis, hyperuricemia, and normal A repeat ultrasound abdomen revealed a normal-sized liver without any altered echoes. The occurrence of recurrent early morning hypoglycemia with ketosis, lactic acidosis, and hyperuricemia suggested a disorder of gluconeogenesis, the most common of which is GSD type 1. However, without the classic cherubic facies, hepatomegaly, or any other end-organ involvement, the possibility of FBPase deficiency was considered. A molecular genetic evaluation revealed a compound heterozygous missense mutation of the FBP1 gene (c. 841G>A p. Glu281 Lys and c.472C>T p. Arg158Trp) gene, which was reported as pathogenic for FBPase deficiency. Parents were counseled to avoid a fructose-rich diet and advised to undergo sanger sequencing for risk stratification for the next pregnancy.
| Discussion|| |
In otherwise healthy children, dietary glucose utilization takes over 3–4 h after a feed. Any starvation beyond this causes a fall in insulin levels and a rise in counter-regulatory hormones such as glucagon, cortisol, and growth hormone. This causes a switch from glycolysis to glycogenolysis and gluconeogenesis, which maintains glucose levels in the serum. Thus, GSDs and disorders of gluconeogenesis present during the postneonatal period when infants are exposed to prolonged fasting of 3–6 h.
Gluconeogenesis is the reverse reaction to glycolysis which involves the synthesis of glucose from the various substrate (pyruvate, lactate, glycerol, and gluconeogenic amino acids). Disorders of gluconeogenesis include GSD type 1, pyruvate carboxylase deficiency, phospho-enol-pyruvate carboxykinase deficiency, and FBPase deficiency. Gluconeogenesis mainly occurs in the liver and kidneys, and some of these disorders result in the accumulation of toxic metabolites resulting in liver and kidney injury.
FBPase is a critical enzyme in gluconeogenesis. It catalyzes the conversion of fructose 1,6 bisphosphate to fructose-6-phosphate. FBPase deficiency is a rare autosomal recessive disease with an estimated incidence between 1/350,000 and 1/900,000. Children present with recurrent hypoglycemia with lactic acidosis, triggered by prolonged fasting or an intercurrent illness. These children develop hypoglycemia following a fructose-rich diet. This is because of the accumulation of fructose-1-phosphate in the liver, which inhibits glycogen phosphorylase. Hypoglycemic episodes can rarely present in the neonatal period, as neonates have lower glycogen stores, but commonly occur in older infants. These episodes are associated with hyperventilation, tachycardia, and seizures. Our child had a normal neonatal period and infancy, with the first symptoms occurring at 2 years. Like other gluconeogenetic defects, critical sample evaluation reveals ketosis, lactic acidosis, hyperuricemia, pseudo hypertriglyceridemia (due to elevated glycerol) with appropriately suppressed insulin and elevated levels of counter-regulatory hormones. Treatment is tailored to the prevention of hypoglycemia. This includes dietary restriction of fructose and sorbitol and intake of uncooked starch to maintain fasting sugar levels. This is especially important during intercurrent illness as the overall intake is reduced. Dietary restrictions include a reduction in the number of fruits such as apples, apricots, bananas, processed dates, grapes, and raisins. All commercially available ready-to-eat foods such as jams, jellies, hard-boiled candies, chocolates, sweetened yogurt, bakery items, breakfast cereals, energy drinks, and bottled juices/sodas should be avoided as well. Medications in syrup formulation should be avoided as there have been case reports of hypoglycemic episodes triggered by fructose-sweetened syrups. Differential diagnoses include gluconeogenesis defects such as GSD-1, pyruvate carboxylase, and phosphor enoyl pyruvate carboxykinase deficiency as well as mitochondrial disorders, all of which will present with ketotic hypoglycemia and lactic acidosis. Unlike those diseases, children with FBPase deficiency do not have end-organ involvement. Previous case reports have also noted its similarity in presentation between with GSD 1,. Children with FBP1 deficiency can have mild transient hepatomegaly during the metabolic crisis, in contrast to GSD1 where they present with huge firm hepatomegaly. With proper prevention and management of hypoglycemic episodes, these children tend to have normal growth and development.
To conclude, FBPase deficiency can mimic GSD type 1 and should be considered in any child who presents with recurrent ketotic hypoglycemia with lactic acidosis. It is a benign disease without any end-organ involvement, and children have normal growth. Management typically involves long-term dietary modification. The long-term prognosis of FBPase deficiency is excellent, and preventive long-term dietary modification is recommended.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kalhan SC, Parimi P, Van Beek R, et al.
Estimation of gluconeogenesis in newborn infants. Am J Physiol Endocrinol Metab 2001;281:E991-7.
van den Berghe G. Disorders of gluconeogenesis. J Inherit Metab Dis 1996;19:470-7.
Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-bisphosphatase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al.
, editors. Gene Reviews®. Seattle, WA: University of Washington; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK550349
. [Last accessed on 2021 Jan 19].
Moey LH, Abdul Azize NA, Yakob Y, et al.
Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: Clinical and molecular findings in Malaysian patients. Pediatr Neonatol 2018;59:397-403.
Pinto A, Alfadhel M, Akroyd R, et al.
International practices in the dietary management of fructose 1-6 biphosphatase deficiency. Orphanet J Rare Dis 2018;13:21.
De Prà M, Laudanna E. Baker-Winegrad disease (hepatomegaly, hypoglycemia during fasting, hyperlactacidemic metabolic acidosis, hepatic fructose-1-6-diphosphatase deficiency). Presentation of the 1st
Italian case and pathogenetic hypothesis. Minerva Pediatr 1978;30:1973-86.
Sharma AG, Kanwal SK, Chhapola V, et al
. Novel fructose bisphosphatase 1 gene mutation presenting as recurrent episodes of vomiting in an Indian child. J Postgrad Med 2018;64:180-2.
] [Full text]
Kamate M, Jambagi M, Gowda P, et al.
Fructose-1,6-diphosphatase deficiency: A treatable neuro metabolic disorder. BMJ Case Rep 2014;2014:bcr2013201553.