A Cause of Permanent Ketosis: GLUT-1 Deficiency

Abstract

GLUT-1-deficiency syndrome (GLUT1-DS; OMIM 606777) is a treatable metabolic disorder caused by a mutation of SLC2A1 gene. The functional deficiency of the GLUT1 protein leads to an impaired glucose transport into the brain, resulting in neurologic disorders.We report on a 6-month-old boy with preprandial malaises who was treated monthly by a sorcerer because of a permanent acetonemic odor. He subsequently developed pharmaco-resistant seizures with microcephaly and motor abnormalities. Metabolic explorations were unremarkable except for a fasting glucose test which revealed an abnormal increase of blood ketone bodies. At the age of 35 months, GLUT1-DS was diagnosed based on hypoglycorrhachia with a decreased CSF to blood glucose ratio, and subsequent direct sequencing of the SLC2A1 gene revealed a de novo heterozygous mutation, c.349A>T (p.Lys117X) on exon 4. It was noteworthy that the patient adapted to the deficient cerebral glucose transport by permanent ketone body production since early life. Excessive ketone body production in this patient provided an alternative energy substrate for his brain. We suggest a cerebral metabolic adaptation with upregulation of monocarboxylic acid transporter proteins (MCT1) at the blood-brain barrier provoked by neuroglycopenia and allowing ketone body utilization by the brain. This case illustrates that GLUT1-DS should be considered in the differential diagnosis of permanent ketosis.

Presumed Neuroglycopenia Caused by Severe Hypoglycemia in Horses

“…At that low glucose level, brain glucose concentration was reported to be close to zero . Measurement of glucose concentration in cerebrospinal fluid (CSF) might aid to investigate glucose concentration in the brain . Low glucose concentration in CSF is termed hypoglycorrhachia and is most commonly associated with infection (mainly bacterial meningitis) but other causes such as stroke, malignancy, neurosarcoidosis, and severe hypoglycemia are associated with low CSF glucose concentrations …”

“…However, there is variability among individuals manifesting neurologic dysfunction and EEG alterations associated with hypoglycemia . In addition to hypoglycemia, alterations in glucose transport, metabolism, and storage of glycogen can cause or contribute to low glucose concentrations in the brain . Hypoglycemia has been reported in horses and defined as a BG concentration below 75 mg/dL (< 4.2 mmol/L) .…”

Glucose Transporter 1 Deficiency: A Treatable Cause of Opsoclonus and Epileptic Myoclonus

“…Abnormal eye movements have been previously reported in this disease but only vaguely described as movement disorders [8], yet rarely specified as dyspraxia or opsoclonus [8,9]. Moreover, epileptic oscillatory eye movements mimicking opsoclonus have also been described in GLUT1DS [10], of which the spectrum of clinical phenotypes has been expanding M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 ( Table 1).…”

“…We also propose, alongside previous reports [11], that suspicion for GLUT1DS should be raised in infants with intractable epilepsy and an elusive pathology who respond to steroids. [1,6,8,9].…”

Hypoglycaemia, hypoglycorrhachia, neuroglycopenia and glycaemic thresholds

“…Although hypoglycaemia (blood glucose concentration <3.9 mmol/L [<70 mg/dL]) is the most common explanation for neuroglycopenia, it may also result from abnormal glucose transport, abnormal glycogen storage and abnormalities of metabolism (Aronoff et al 2004;Chenouard et al 2015).…”