Annals of Indian Academy of Neurology
  Users Online: 5824 Home | About the Journal | InstructionsCurrent Issue | Back IssuesLogin      Print this page Email this page  Small font size Default font size Increase font size

Table of Contents
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1250-1252

Recurrent encephalopathy with metabolic acidosis and hypoglycemia: Do not forget fructose metabolism

1 Department of Neurology, Ramaiah Medical College, Bengaluru, Karnataka, India
2 Department of Pediatrics, Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission12-Sep-2022
Date of Decision19-Oct-2022
Date of Acceptance27-Oct-2022
Date of Web Publication22-Nov-2022

Correspondence Address:
Divya Nagabushana
Department of Neurology, Ramaiah Medical College, MSRIT Post, Mathikere, Bengaluru - 560 054, Karnataka
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.aian_768_22

Rights and Permissions


How to cite this article:
Hiremath PM, Nagabushana D, Patil S. Recurrent encephalopathy with metabolic acidosis and hypoglycemia: Do not forget fructose metabolism. Ann Indian Acad Neurol 2022;25:1250-2

How to cite this URL:
Hiremath PM, Nagabushana D, Patil S. Recurrent encephalopathy with metabolic acidosis and hypoglycemia: Do not forget fructose metabolism. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 27];25:1250-2. Available from:

To the Editor,

Fructose 1,6-bisphosphatase deficiency is a rare metabolic disorder with an incidence falling between 1:350000 and 1:900000 in Europe.[1] We report a novel mutation in a boy who had recurrent life-threatening metabolic crises.

A three-year-old boy presented with history of fever of three days duration, multiple episodes of vomiting, generalized seizures, and lethargy a day prior to admission. He had significant past history of similar illness and had been hospitalized a year earlier with a lower respiratory infection followed by vomiting and encephalopathy. He was found to have hypoglycemia, lactic acidemia, high anion gap metabolic acidosis, and hepatomegaly. Tandem mass spectrometry done to detect inborn errors of metabolism was normal. Post correction of metabolic acidosis and hypoglycemia, he had been discharged on oral vitamin supplements as the parents were unwilling to allow further evaluation. He was born to second-degree consanguineously married couple with a significant history of death of an older male sibling following acute seizures and encephalopathy at 18 months of life. In the present admission, the child was febrile and he had tachycardia with deep acidotic respiration. Abdominal examination revealed hepatomegaly. Rigidity of all limbs, brisk deep tendon reflexes, and extensor plantar responses were noted. Intermittent dystonic posturing of limbs was present.

Blood investigations revealed hypoglycemia, normal total leukocyte count (7900), normal CRP (1.5 mg/dL), elevated lactate level (5 mmol/L), high anion gap metabolic acidosis, hyperammonemia (143 micromol/L) and elevated liver enzymes (ALT 171 and AST 429 U/L). Ketone bodies (3+) were detected in the urine. Electroencephalography (EEG) showed generalized delta slowing of background. Magnetic resonance imaging (MRI) of the brain showed diffusion restriction in bilateral putamen and caudate nuclei [Figure 1]. Magnetic resonance spectroscopy (MRS) revealed nonspecific elevation of choline and creatine with normal N-acetyl-aspartate (NAA) levels. The recurrent episodic crisis of hypoglycemia, metabolic acidosis, and ketonuria were strongly indicative of a metabolic disorder. Tandem mass spectrometry was normal and urine gas chromatography/mass spectrometry (GC/MS) showed elevated glycerol-3-phosphate, glycerol, lactate, 3-hydroxybutyrate, 2-hydroxyisovalerate, and 4-hydroxyphenyl lactate. The child was started on intravenous dextrose and sodium bicarbonate infusion. Sodium benzoate was given during the first 24 hours and stopped after the ammonia level subsided. By day 5, the sensorium improved but the child had dysarthria, dysphagia, hypotonia, and sluggish reflexes. Nasogastric tube feeds were continued. The metabolic parameters normalized by the end of the first week. There was gradual improvement of the symptoms and the child regained normal power by two weeks.
Figure 1: MRI brain axial DW image (a) shows hyperintensity in bilateral putamen and caudate nuclei and diffusion restriction is noted in the corresponding ADC image (b)

Click here to view

The imaging findings of diffusion restriction in bilateral basal ganglia may be seen in many disorders such as hypoglycemia, hypoxic injury, propionic acidemia, glutaric aciduria, and mitochondrial diseases such as Leigh's disease or mitochondrial encephalopathy with lactic acidosis, and stroke-like episodes. The clinical, biochemical, and radiological findings pointed to a metabolic disorder with episodic hypoglycemic crisis such as organic acidemias, glycogen storage disorders, fatty acid oxidation defects, fructose intolerance, fructose 1,6-bisphosphatase deficiency and galactosemia.[2] The presence of lactic acidosis with bilateral basal ganglia involvement also raised the possibility of mitochondrial respiratory chain disorders and Krebs cycle disorder. After discussing with the family, whole exome sequencing (WES) was sent. Molecular analysis revealed homozygous missense variant c.494A>G (p.Tyr165Cys) on exon 4. The c.494A>G variant is novel and is predicted to be damaging by SIFT and PolyPhen-2 and is reported as pathogenic in VarSome. The molecular analysis of parents' DNA revealed heterozygous mutation c.494A>G (p.Tyr165Cys) on exon 4 in one allele each, making both of them carriers. The parents were counselled about the disease, autosomal recessive transmission, implications, and the risk in future pregnancy. The patient was advised frequent meals, to avoid fasting and foods with high fructose-to-glucose ratio (such as grapes, apples, cherries, and honey). Detailed instructions for the management of sick days were given. Currently, the child is on follow-up and has no neurological deficits. However, he has features of attention deficit hyperactivity disorder.

Fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate into fructose 6-phosphate.[3] Deficiency of this enzyme impairs the gluconeogenic pathway. The deficiency disorder has an autosomal recessive inheritance, caused due to either homozygous or compound heterozygous mutations of the FBP1 gene (OMIM: 611570) which is located on the long arm of chromosome 9 and consists of 8 exons.[3] Baker and Winegrad[4] first described the deficiency of hepatic fructose 1,6-bisphosphatase in 1970. Episodic hypoglycemia triggered by fasting or febrile illness is characteristically seen. Patients present in acute crisis with hyperventilation, apneic spells, convulsions and/or coma. Hypotonia and hepatomegaly may be seen. If untreated, continued catabolism leads to multiorgan failure with high morbidity and mortality. Hypoglycemia, ketonemia, ketonuria, elevated lactate, and high glycerol 3- phosphate in urine are classical metabolic findings. Pseudo-hypertriglyceridemia, hyperuricemia, increased free fatty acids, and elevated alanine are other features.[5] Tandem mass spectrometry (TMS) is usually normal and GC/MS will show elevated glycerol 3-phosphate. MRI brain is usually normal or shows nonspecific dilatation of the ventricles.[6] Our case had diffusion restriction in bilateral caudate and lentiform nuclei. This may have been secondary to cytotoxic edema following the hypoglycemia. Genetic analysis is the gold standard test to confirm the diagnosis of this easily treatable disorder which can lead to devastating complications, if undetected.

Fructose 1,6-bisphosphatase deficiency should be suspected in a child with hypoglycemia, metabolic acidosis with elevated lactate, and presence of urine ketones, especially with the background history of consanguinity and sibling death. Preventing hypoglycemia and sick day management with dextrose infusion is most important. Fructose, glycerol, and medicines containing sorbitol and sucrose should be avoided. Timely diagnosis and due precautions will ensure a normal life for a child with this diagnosis.

Author contributions

PH and DN contributed to the conception of the work, acquisition, and preparation of initial draft of the work. All the authors contributed to the analysis, interpretation of data, revised it critically, and approved the final version.

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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Santer R, du Moulin M, Shahinyan T, Vater I, Maier E, Muntau AC, et al. A summary of molecular genetic findings in fructose-1, 6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis. Orphanet J Rare Dis 2016;11:1-7.  Back to cited text no. 1
Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-Bisphosphatase Deficiency. 2019 Dec 5. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.  Back to cited text no. 2
El-Maghrabi MR, Lange AJ, Jiang W, Yamagata K, Stoffel M, Takeda J, et al. Human fructose-1, 6-bisphosphatase gene (FBP1): Exon-intron organization, localization to chromosome bands 9q22.2-q22.3, and mutation screening in subjects with fructose-1, 6-bisphosphatase deficiency. Genomics 1995;27:520-5.  Back to cited text no. 3
Baker L, Winegrad A. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1, 6-diphosphatase activity. Lancet 1970;296:13-6.  Back to cited text no. 4
Afroze B, Yunus Z, Steinmann B, Santer R. Transient pseudo-hypertriglyceridemia: A useful biochemical marker of fructose-1, 6-bisphosphatase deficiency. Eur J Pediatr 2013;172:1249-53.  Back to cited text no. 5
Li N, Chang G, Xu Y, Ding Y, Li G, Yu T, et al. Clinical and molecular characterization of patients with fructose 1,6-bisphosphatase deficiency. Int J Mol Sci 2017;18:857.  Back to cited text no. 6


  [Figure 1]


Print this article  Email this article


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (428 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

    Article Figures

 Article Access Statistics
    PDF Downloaded21    
    Comments [Add]    

Recommend this journal