
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.67291
Endocrinology/Diabetes/Metabolism
Genetics
Pediatrics
Infantile Fructose-1,6-Bisphosphatase Deficiency Masquerading as Mitochondriopathy
Muacevic Alexander
Adler John R
Chandrasekhar Varshini 1
Yelkur Pallavi 1
K Vidhyasagar 1
1 Paediatrics, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
Varshini Chandrasekhar varshuchandrasekhar@gmail.com
20 8 2024
8 2024
16 8 e6729122 7 2024
20 8 2024
Copyright © 2024, Chandrasekhar et al.
2024
Chandrasekhar et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/280974-infantile-fructose-16-bisphosphatase-deficiency-masquerading-as-mitochondriopathy
Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is a rare autosomal recessive disorder of gluconeogenesis. Affected children present with severe hypoglycemia and lactic acidosis in infancy. We report a case of a female child, aged one year and six months, born out of a third-degree consanguineous marriage, who initially presented with sudden-onset vomiting episodes and failure to thrive. Despite a clinical suspicion of mitochondrial disorder, biochemical investigations revealed elevated levels of alanine, glycine, lactic acid, pyruvic acid, 3-hydroxy isovaleric acid, fumaric acid, and 4-hydroxy phenylacetic acid. Clinical exome sequencing confirmed homozygous inheritance of a mutated FBP1 gene, establishing the diagnosis of FBP1 deficiency. Differential diagnoses included mitochondrial disorders and transaldolase deficiency, but comprehensive genetic testing excluded these conditions. Management focused on dietary adjustments to avoid simple sugars and increase complex carbohydrates during illness. This case underscores the complexity of diagnosing rare metabolic disorders and highlights the pivotal role of genetic testing in accurate diagnosis and management.

mitochondriopathy
genetic testing
hypoglycemia
metabolic acidosis
fructose
==== Body
pmcIntroduction

Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is an autosomal recessive disorder of fructose metabolism caused by mutations in the FBP1 gene, which encodes the crucial enzyme FBP1. This enzyme is essential for regulating fructose metabolism [1]. The condition leads to severe, recurring episodes of hypoglycemia and lactic acidosis, typically triggered by infections, the introduction of complementary feeding, fever, fasting, reduced intake, vomiting, or high fructose consumption. Symptoms often manifest in early childhood and include hyperventilation, apneic spells, seizures, and coma. Nearly half of affected infants may present with hypoglycemia shortly after birth due to low glycogen reserves [2].

Individuals who experience recurring episodes of lactic acidosis and ketotic hypoglycemia and exhibit specific urinary organic acid profiles (such as peaks in glycerol and glycerol-3-phosphate) should be considered at high risk for FBP1 deficiency. Diagnosis is typically confirmed by identifying two pathogenic variants in the FBP1 gene through genetic testing, which is preferred for its accessibility and reliability [3]. Alternatively, reduced FBP1 enzyme activity in the liver or mononuclear white blood cells can be measured. Key diagnostic features include hypoglycemia, high anion-gap metabolic acidosis, lactic acidemia, potential ketosis, and pseudo-hypertriglyceridemia due to elevated glycerol levels. Hyperuricemia and occasionally elevated free fatty acids may also be observed. These signs warrant further investigation as they could indicate FBP1 deficiency. If not diagnosed and treated promptly, affected children may progress from recurrent hypoglycemic episodes to seizures, coma, and potentially death [4,5].

Mutations in this gene were initially reported in 1970 [4], causing reduced or absent activity of fructose-1,6-diphosphatase in the liver. These genetic alterations prevent the conversion of fructose-1,6-diphosphate to fructose-6-phosphate, impacting gluconeogenesis [5]. While the condition is typically fatal in newborns, early diagnosis and rigorous management significantly improve the long-term outlook for this condition, underscoring the critical role of promptly confirming the molecular diagnosis [6,7].

Case presentation

A female child aged one year and six months, the first child of a third-degree consanguineous marriage, presented with sudden-onset vomiting episodes. Her mother had an uncomplicated pregnancy and delivered her at full term via normal vaginal delivery, weighing 3.5 kg. The child experienced neonatal hyperbilirubinemia on day three of life, requiring two days of phototherapy in the neonatal intensive care unit before discharge from the hospital. Until 12 months of age, she had no complaints but then started experiencing recurrent, sudden-onset vomiting episodes and hypoglycemia, leading to dehydration and requiring hospitalization.

The child is developmentally normal and has received vaccinations according to the national immunization schedule. There was no significant family history of similar complaints among any family members on both the paternal and maternal sides. No prior workup was done on the parents, as they also did not have any similar complaints. Anthropometric measurements indicated failure to thrive based on weight, height, and weight-for-height ratio, all falling below the third standard deviation as per WHO growth charts. The general examination was found to be normal with no gross dysmorphic features; in addition, on the abdomen examination, there was no palpable hepatomegaly. When other systems were examined, they revealed findings within normal parameters.

A complete blood count, renal function test, and liver function test showed normal results. The C-reactive protein test was found to be negative, and sterile blood and urine cultures were obtained. Abdominal ultrasound indicated normal liver and spleen sizes without organ enlargement. Echocardiography revealed no cardiac abnormalities. Blood gas analysis revealed high anion-gap metabolic acidosis (Table 1), which was disproportionate to the vomiting episodes.

Table 1 Arterial blood gas (ABG) analysis

Components of Blood Gas	Blood Gas Values	Reference Values	
pH	7.107	7.35-7.45	
pCO2 (carbon dioxide)	30 mmHg	35-45 mmHg	
pO2 (oxygen)	49.8 mmHg	80-100 mmHg	
HCO3 (bicarbonate)	15.9 mmol/L	22-26 mmol/L	
Anion gap	19.2	10-12	
Lactate	7.1 mmol/L	0.5-1 mmol/L	

Specialized biochemical tests conducted on the child's blood sample revealed markedly elevated levels of total carnitine, free carnitine, and acylcarnitine. This investigation was done using tandem mass spectrometry. Additionally, the ratio of free to acylcarnitine was found to be increased, as detailed in Table 2. In light of these findings, a thorough evaluation was initiated to explore potential underlying conditions, including carnitine deficiency, an inborn error of fatty acid beta-oxidation, and organic acidurias.

Table 2 Carnitine/acylcarnitine profile

Investigation	Actual Value (μmol/L)	Normal Range (μmol/L)	
Total carnitine	114.95	20-87.7	
Free carnitine	91.41	24.7-66.6	
Acylcarnitine	23.54	4-28	
Free/acyl ratio	3.88	>2.0	

In addition to the above parameters analyzed, Table 3 reveals a derangement in amino acid and free fatty acid profile. The analysis shows elevated levels of alanine and glycine, with both exceeding their normal ranges. Non-esterified fatty acids (NEFA) are also higher than expected, although beta-hydroxybutyrate (BHB) is within the normal range. As a result, mitochondrial disorder was suspected due to initial findings of elevated carnitine and amino acid levels resulting in the initiation of supplementation with coenzyme Q and riboflavin.

Table 3 Amino acid and free fatty acid profile

Investigations	Actual Value (μmol/L)	Normal Range (μmol/L)	
Alanine	2322.47	600.0	
Glycine	1486.82	900.0	
Non-esterified fatty acid	0.731	0.133-0.455	
Beta-hydroxybutyrate	0.107	0.02-1.0	
Non-esterified fatty acid/beta-hydroxybutyrate	6.83	0.5-5.0	

Organic acid analysis was performed by using both liquid and gas chromatography methods to rule out organic acidurias, as detailed in Table 4. The results showed elevated levels of several organic acids, including lactic acid, pyruvic acid, 3-hydroxyisovaleric acid, fumaric acid, and 4-hydroxyphenylacetic acid, suggesting a possible co-existing organic acid defect in the child. Additionally, the levels of biotinidase enzyme, Gal-1-Put enzyme, and total galactose levels were identified by making use of mass spectrometry, and all were found to be within normal ranges.

Table 4 Organic acid analysis

Biochemical Parameter	Actual Value	Normal Range	
Lactic acid	9.266 mmol/L	2 mmol/L	
Pyruvic acid	11.234 mmol/L	0.08-0.16 mmol/L	
3-hydroxyisovaleric acid	15.417 mmol/L	0.42-8.5 mmol/L	
Urea	18.553 mg/dL	5-18 mg/dL	
Fumaric acid	22.106 nmol/mg	0-16 nmol/mg	
4-hydroxy phenylacetic acid	35.615 mmol/mol creatinine	0-29 mmol/mol creatinine	

Table 5 details the positive findings from clinical exome sequencing, which was conducted to identify the biochemical defect contributing to the child's clinical symptoms and abnormal lab results. This analysis aimed to rule out inborn errors of metabolism and storage disorders. Using the IDT xGen Exome Research Panel v2.0 (Coralville, Iowa) for clinical whole-exome sequencing, a homozygous pathogenic variant in the FBP1 gene (ENST00000415431.5) was identified. Specifically, the variant c.611_614del (p.Lys204ArgfsTer72) was found, with autosomal recessive inheritance. This mutation causes a frameshift, resulting in a premature stop codon at position 72 and the production of a truncated FBP1 enzyme. The truncated protein is typically nonfunctional or lacks the essential catalytic activity required for gluconeogenesis.

Table 5 Clinical exome sequencing showing FBP1 gene mutation

OMIM: Online Mendelian Inheritance in Man

Gene (Transcript)	Location	Variant	Zygosity	Disease (OMIM)	Inheritance	Classification	
FBP1 (-) (ENST00000415431.5)	Exon 6	c.611_614del (p.Lys204ArgfsTer72)	Homozygous	Fructose-1,6-bisphosphatase deficiency	Autosomal recessive	Pathogenic	

Upon diagnosing FBP1 deficiency, a specific dietary plan was recommended for the patient. The plan emphasized frequent meals to prevent fasting and included incorporating more uncooked starches, such as rice powder, into her diet. She was advised to avoid simple sugars, such as table sugar, fruit juices, toffees, and chocolates, and instead focus on consuming complex carbohydrates and increasing vegetable intake. During follow-up visits, her growth and development were closely monitored, showing normal progress with normalized metabolic parameters. Her abdominal examination remained normal, with no indications of hepatomegaly or splenomegaly. The parents were instructed to maintain regular follow-ups and adhere strictly to the dietary guidelines. Additionally, they were informed about the child's prognosis and received genetic counseling, which included discussing the potential inheritance of the defect in future offspring.

Discussion

Fructose bisphosphatase regulates gluconeogenesis by converting fructose-1,6-biphosphate into fructose-6-phosphate and inorganic phosphate. This condition is inherited in an autosomal recessive pattern and causes severe, recurrent episodes of life-threatening hypoglycemia and metabolic acidosis in children, often appearing in infancy, as seen in our case [8]. This genetic mutation leads to a lack of fructose-1,6-diphosphatase activity, impairing gluconeogenesis in the liver and causing the accumulation of gluconeogenic precursors from dietary intake, such as fructose, lactate, glycerol, alanine, and other amino acids [9].

It was found in another case study that a novel maternal mutation (c.977(exon7)T>C) in the FBP1 gene was identified in two siblings: a two-year-old female and a newborn male. Clinical suspicion for FBP1 deficiency should be heightened in cases presenting with acute infection onset, severe metabolic acidosis, and hypoglycemia. Early genetic sequencing can confirm the diagnosis, facilitating timely intervention and sustained dietary management to prevent mortality, support growth, and improve the quality of life for affected children [10].

Due to the disease's nonspecific clinical features, differential diagnoses such as glycogen storage diseases (GSDs) and mitochondrial diseases (MDs) should be considered at first and ruled out before confirming enzymatic defects such as FBP1 deficiency, as these conditions also present with similar symptoms of hypoglycemia and hyperlactatemia [11]. In another case series, three cases of fructose intolerance were documented, with manifestations including hypoglycemia, recurrent metabolic acidosis, abdominal distension, and hepatomegaly. Genetic testing revealed mutations in the FBP1 gene in two patients and one mutation in the ALDO-B gene [12].

Gluconeogenesis primarily occurs in the liver and kidneys, and some of these conditions lead to the accumulation of toxic metabolites, which can result in end-organ damage leading to hepatomegaly as one of the presentations [13,14]. In our case, the child presented with recurrent episodes of vomiting, hypoglycemia, and metabolic acidosis, without features of abdominal distension or hepatomegaly. While hypoglycemia episodes are uncommon in neonates due to lower glycogen stores, they typically occur more frequently in older infants [15]. In a case reported by Madhusudan et al., they described a 2.5-year-old boy with normal development who experienced recurrent hypoglycemic seizures. Laboratory analyses during critical episodes showed ketosis, lactic acidosis, hyperuricemia, and elevated triglycerides. Initially provisionally diagnosed with GSD type 1; subsequent evaluations did not reveal the typical physical features associated with this condition [1].

Historically, the definitive diagnosis of FBP1 deficiency relied on enzymatic activity assays conducted on liver biopsy samples or cultured leukocytes [16,17]. However, molecular analysis of the FBP1 gene has now largely supplanted these methods. The FBP1 gene is located on chromosome 9q22.2-q22.3 and encodes the enzyme (P09467; NM_000507; transcript id ENST00000375326.8), spanning seven coding exons over 31 kilobases, interspersed with six introns. Initial research on homozygous and heterozygous mutations in the FBP1 gene was pioneered in the Japanese population, with subsequent studies identifying specific mutations common to various regions [7].

In studies conducted in India and Pakistan by Ijaz et al., a DNA nucleotide change (c.611_614delAAAA) resulting in a predicted protein change (p.Lys204ArgfsTer72) was observed [7]. Afroze et al. in 2013 identified another DNA nucleotide change (c.841G>A) leading to a predicted protein change (p.Glu281Lys), observed in populations from India, Pakistan, and Saudi Arabia [3]. These recent advancements in genetic testing are helping us identify various mutations across different countries resulting in the presentation of this condition across children of various age groups and ethnicities.

Conclusions

FBP1 deficiency is a spectrum disorder that should be considered in children presenting with symptoms such as failure to thrive, recurrent hypoglycemia, and/or metabolic acidosis. These children may experience hypoglycemia when consuming fructose-rich diets. Differential diagnoses include other gluconeogenesis disorders such as GSD type 1, pyruvate carboxylase deficiency, and phosphoenolpyruvate carboxykinase deficiency, as well as mitochondrial disorders, all of which present with ketotic hypoglycemia and lactic acidosis. It is essential to exclude these conditions before diagnosing FBP1 deficiency, which usually does not cause end-organ damage.

This case study illustrates a comprehensive approach to diagnosing and managing a female child, aged one year and six months, with FBP1 deficiency, identified via clinical exome sequencing as a pathogenic homozygous variant in the FBP1 gene. Her symptoms, including sudden-onset vomiting, hypoglycemia, and abnormal metabolic markers, were effectively managed with a specific dietary plan designed to prevent fasting and regulate carbohydrate intake. Ongoing follow-ups confirmed normalized metabolic parameters and growth. The treatment focuses on dietary management to prevent hypoglycemia, emphasizing the restriction of fructose and sorbitol and careful food intake monitoring.

The Departments of Biochemistry and Radiology are acknowledged with deep appreciation for their pivotal contributions to this case report. Their expert analyses and collaborative efforts have greatly enriched the work. The biochemical insights were crucial for understanding the molecular mechanisms, while the radiological evaluations provided essential perspectives that enhanced the investigation. Their exceptional support is sincerely appreciated.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K

Acquisition, analysis, or interpretation of data:  Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K

Drafting of the manuscript:  Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K

Critical review of the manuscript for important intellectual content:  Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K

Supervision:  Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K
==== Refs
References

1 Fructose 1,6 bisphosphatase deficiency mimicking glycogen storage disease as recurrent hypoglycemia Indian Pediatr Case Rep Madhusudan M Manoj S Sankar J 127 129 1 2021
2 Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up J Inherit Metab Dis Gorce M Lebigot E Arion A 215 222 45 2022 34687058
3 Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency Eur J Pediatr Afroze B Yunus Z Steinmann B Santer R 1249 1253 172 2013 23881342
4 Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity Lancet Baker L Winegrad AI 13 16 4 1970
5 Clinical and molecular characterization of patients with fructose 1,6-bisphosphatase deficiency Int J Mol Sci Li N Chang G Xu Y 857 18 2017 28420223
6 Exon 2 deletion represents a common mutation in Turkish patients with fructose-1,6-bisphosphatase deficiency Metab Brain Dis Kılıç M Kasapkara ÇS Yılmaz DY Özgül RK 1487 1491 34 2019 31278438
7 Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families J Pediatr Endocrinol Metab Ijaz S Zahoor MY Imran M 1203 1210 30 2017 29016355
8 Investigation of inborn errors of metabolism in unexpected infant deaths Lancet Emery JL Howat AJ Variend S 29 31 2 1988 2898629
9 Clinical and molecular characterization of Indian patients with fructose-1, 6-bisphosphatase deficiency: identification of a frequent variant (E281K) Ann Hum Genet Bhai P Bijarnia-Mahay S Puri RD 309 317 82 2018 29774539
10 A patient with glycogen storage disease type 0 and a novel sequence variant in GYS2: a case report and literature review J Int Med Res Arko JJ Debeljak M Tansek MZ Battelino T Groselj U 48 2020
11 UQCRC2 mutation in a patient with mitochondrial complex III deficiency causing recurrent liver failure, lactic acidosis and hypoglycemia J Hum Genet Gaignard P Eyer D Lebigot E Oliveira C Therond P Boutron A Slama A 729 731 62 2017 28275242
12 Fructose metabolism defects in Indian children—uncommon or under-reported? A case series Cent Eur J Paediatr Mirza N Maheshwari A 137 19 2023
13 Estimation of gluconeogenesis in newborn infants Am J Physiol Endocrinol Metab Kalhan SC Parimi P Van Beek R Gilfillan C Saker F Gruca L Sauer PJ 0 7 281 2001
14 Disorders of gluconeogenesis J Inherit Metab Dis van den Berghe G 470 477 19 1996 8884571
15 Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: clinical and molecular findings in Malaysian patients Pediatr Neonatol Moey LH Abdul Azize NA Yakob Y Leong HY Keng WT Chen BC Ngu LH 397 403 59 2018 29203193
16 Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 6-phosphate, AMP, and magnesium Proc Natl Acad Sci U S A Ke HM Zhang YP Lipscomb WN 5243 5247 87 1990 2164670
17 Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency Am J Hum Genet Kikawa Y Inuzuka M Jin BY 852 861 61 1997 9382095
