Brain Glucose Supply and the Syndrome of Infantile Neuroglycopenia

ORIGINAL CONTRIBUTION Brain Glucose Supply and the Syndrome of Infantile Neuroglycopenia Juan M. Pascual, MD, PhD; Dong Wang, MD; Veronica Hinton, PhD; Kristin Engelstad, BS; Chitra M. Saxena, MPH; Ronald L. Van Heertum, MD; Darryl C. De Vivo, MD Objective: To describe neuroglycopenia as a specific syn- abnormalities and reduced thalamocortical glucose up- drome caused by insufficient glucose availability during take despite subsequent supply of energetic substrate. brain development. Conclusions: When neuroglycopenia—the lack of ad- Design: Neurologic examinations, neuropsychologic equate glucose supply to the nervous system—occurs in tests, biochemical methods, and functional imaging. the developing brain, thalamic and cortical metabolism mature aberrantly, causing epilepsy associated with other Participants: Patients afflicted by genetic mutation of characteristic neurologic and behavioral disturbances, a the cerebral glucose transporter type 1 and a patient af- pattern also reflected in functional images, as if there were flicted by persistent infantile hypoglycemia (hyperinsu- a temporal window during which glucose were crucial linism) matched to her healthy twin. for brain development. When maturation is complete, glucose merely serves as a fuel, and then, when deficient, it Results: The hallmark of the phenotype is the combina- only causes unrelated disturbances. tion of infantile epilepsy and cerebellar and pyramidal tract dysfunction, together with permanent neuropsychologic Arch Neurol. 2007;64:507-513 IVING ORGANISMS HARNESS fects of both substrate-mediated modula- and exchange energy via the tion and of mutation-induced intrage- formation and breakdown of nomic changes on the development of the bonds found in certain com- nervous system are unknown in most neu- pounds. Not all substances rometabolic diseases, partly because they Lwith the potential to restore high-energy need not act exclusively and partly be- bonds are efficient fuels, because only a cause of oversimplified gene/protein func- few are recognized by cells. Thus, energy tion paradigms that do not describe metabolism accurately. CME course available at Brain energy serves 2 purposes: devel- www.archneurol.com opment and activity maintenance. After birth, brain metabolism relies predomi- metabolism is inextricably dependent on nantly on glycolysis, which is stimulated Author Affiliations: Colleen at an accelerated rate. During childhood, Giblin Research Laboratories, molecular recognition. Most energetic Neurological Institute of New compounds function as molecular sig- the cerebral uptake of glucose increases, exceeding that of the newborn by 3-fold York (Drs Pascual, Wang, and nals in addition to fuels, because they regu- and that of the adult by 2-fold.2,3 In the De Vivo, and Ms Engelstad), late their own metabolism, acting di- adult, the cerebral metabolic rate for glu- Departments of Neurology rectly on enzymes and genes. Therefore, (Drs Pascual, Wang, and cose stabilizes and, at this time, can be as- De Vivo, and Ms Engelstad) and disorders of energy metabolism cause sec- sumed to mainly reflect maintenance con- Pediatrics (Drs Pascual and ondary genetic dysregulation, similar to the sumption. The large difference between the De Vivo), Department of way deficiencies of transcription or tro- highest (child) and lowest (neonate) glu- Radiology, Kreitchman PET phic factors alter gene expression. An ad- cose consumption includes expenditures Center (Ms Saxena and ditional mechanism, of not only meta- in development. Dr Van Heertum), and bolic disorders but of all genetic diseases, Department of Neurology, Numerous energy-consuming pro- Sergievsky Center (Dr Hinton), involves widespread effects exerted by a cesses are limited or preferentially circum- College of Physicians and mutant gene on the rest of the genome at scribed to infancy and childhood, but Surgeons, Columbia University, the pretranslational level, regardless of the among them the formation and consoli- New York, New York. function of the gene product.1 The ef- dation of neural circuits—which include (REPRINTED) ARCH NEUROL / VOL 64, APR 2007 WWW.ARCHNEUROL.COM 507 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 the division and movement of neurons and precursors, leptic encephalopathy that was refractory to anticonvulsants. and the generation and pruning of synapses—are asso- From age 3 to 15 months, head circumference growth had ciated with a high energetic demand.4 This energy must decelerated from the 50th percentile to 2 cm below the third ultimately be derived from glucose. There are two in- percentile, where she remained all of her life. Studies before stances where the cerebral access of glucose is compro- the participant aged 15 months included a computed tomography scan of the head; electroencephalography; and examina- mised for a sufficiently prolonged period of time to im- tion of visual- and auditory-evoked potentials; urine oligosac- pact development: one is mutation of the glucose charides and amino acids; blood gases, pH, ammonia, lactate, 5 transporter type 1 (GLUT1) of the blood-brain barrier, pyruvate, amino acids, organic acids, lysosomal hydrolases; and the other is chronic congenital (or early infantile) and cerebrospinal fluid lactate, pyruvate, and amino acids. All hypoglycemia. Neither resembles acute hypoglycemia, study results were normal. At age 15 months, a routine blood which causes a different type of encephalopathy domi- chemistry survey obtained while fasting during a hospital nated by cellular injury. admission for further evaluation revealed a blood glucose of 15 The classic phenotype of GLUT1 deficiency is mg/dL (0.83 mmol/L). Additional blood glucose determina- known6-10; most patients who are GLUT1 deficient mani- tions confirmed hypoglycemia. During a brief (6-hour) fast, fest encephalopathy dominated by hyperexcitability (epi- blood glucose concentration fell from 92 to 32 mg/dL (5.1 to 1.8 mmol/L). At the end of the fast, a glucagon stimulation test lepsy) and abnormalities of cognition and motor con- resulted in a marked glycemia response peaking at 134 mg/dL trol that respond to a ketogenic diet to a varying degree. (7.4 mmol/L), suggesting hyperinsulinism. Diazoxide and In particular, seizures are typically controllable with this ephedrine failed to control glycemia and the patient ultimately diet, whereas other patients experience a transient im- necessitated a nasogastric glucose drip to prevent seizures provement in neurologic performance after a carbohy- associated with hypoglycemia. Several additional maneuvers drate load. Independent of these interventions, most pa- also suggested hyperinsulinism: a ketogenic diet failed to gen- tients exhibit a persistent, residual encephalopathy erate ketone bodies despite decreasing glucose levels, and a characterized by the constellation of motor and lan- leucine load failed to alter glycemia. Insulin levels were more guage dysfunction and mental retardation together with often normal than elevated. A subtotal pancreatectomy (85%) thalamocortical hypometabolism and accentuated basal revealed a pancreatic tail adenoma and islet cell material throughout the body of the organ, consistent with nesidioblas- ganglia metabolism as detected by 18F-2-deoxyglucose 11 tosis. On discharge several weeks later, the patient’s neurologic positron emission tomography (PET). This peculiar performance was vastly improved with residual psychomotor imaging pattern appears to be imprinted on the brain in abnormalities; language had not yet developed. Muscle tone infancy and remains essentially immutable, indicating that and reflexes were increased, and plantar responses were flexor. deficiency of GLUT1 causes an abnormal neural matu- Prominent ataxia limited standing to brief periods of time. Gly- rational and functional pattern during the earlier devel- cemic levels were normal or high normal (Ͻ130 mg/dL [Ͻ7.2 opmental interval. mmol/L]). Seizures all but ceased, and rare residual convul- We set out to elucidate whether this aberrant pattern sions subsided during the next few years. Electroencephalogra- was caused by the genetic deficit of GLUT1 (ie, by vir- phy results were normal under normoglycemic conditions. At tue of the mutation of the glucose carrier irrespective of age 26 years, the patient’s brain magnetic resonance imaging results were normal. its function as a transporter) or whether it was simply Participant 2, a 16-year-old adolescent boy, had GLUT1 de- the consequence of diminished brain glucose availabil- ficiency. His early development was characterized by frequent ity during a specific developmental interval despite a nor- generalized seizures that were refractory to anticonvulsants since mal GLUT1 gene. The clinical, neuropsychologic, and PET age 18 months. Additional features were ataxia, dysarthria, and study of twins with normal GLUT1 expression, one of difficulties with limb action due to pyramidal tract dysfunc- whom was afflicted by chronic congenital hypoglyce- tion. Sitting was accomplished at 1 year of age and ambulation mia, supported the latter mechanism, indicating that glu- was achieved at 2 years. Head circumference growth deceler- cose, rather than GLUT1, is required for the develop- ated and remained at the third percentile. Additional seizures ment of normal excitability in certain cerebral regions consisting of loss of postural tone became prominent after 3 during a critical developmental interval. years of

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