Download Seminars in

Seminars in Neonatology (2004) 9, 49–58
Seminars in
NEONATOLOGY
www.elsevierhealth.com/journals/siny
REVIEW ARTICLE
Neonatal hypoglycaemia: aetiologies
Pascale de Lonlay *, Irina Giurgea, Guy Touati, Jean-Marie Saudubray
Department of Paediatrics, Hôpital Necker — Enfants Malades, 149 rue de Sèvres, 75743 Paris cedex 15,
France
KEYWORDS
Hypoglycaemia;
Hyperinsulinism;
Gluconeogenesis;
Fatty acid disorder;
Growth hormone;
Glucagon;
Cortisol;
Insulin-like growth
factor 1;
Glucose transporter
disorders
Summary Diagnosis of glucose status requires knowledge of the homeostatic mechanisms that maintain the blood glucose concentration between the narrow range of 2.5
and 7.5 mmol/l during periods of eating or fasting. Hypoglycaemia occurring within
the first few hours after eating is suggestive of hyperinsulinism. Most glucose is
subsequently converted into glycogen in the liver, and hypoglycaemia occurring
during this phase is suggestive of glycogenosis. During fasting, gluconeogenesis
progressively replaces glycogen as the major source of blood glucose, and hypoglycaemia occurring during this period is suggestive of impaired gluconeogenesis or fatty
acid disorders. Growth hormone, glucagon, cortisol and insulin-like growth factor 1
deficiencies may also play a role. Other causes of hypoglycaemia have also been
identified recently, namely glucose transporter disorders, respiratory chain disorders
and congenital disorders of glycosylation.
© 2003 Elsevier Ltd. All rights reserved.
Classification of congenital
hypoglycaemias
Glucose is of essential, fundamental importance for
brain metabolism.1 The major source of glucose to
the brain is the blood supply, so if the blood glucose
content becomes deficient, this may lead to a
severe encephalopathy. A prompt diagnosis is
essential for the management of hypoglycaemia.
This requires knowledge of the homeostatic mechanisms that maintain blood glucose concentration
between the relatively narrow range of 2.5 and
7.5 mmol/l during periods of eating or fasting.2
Within the last decade, many new insights and facts
have increased our understanding of causes and
mechanisms of genetic hypoglycaemia.3
During feeding, the liver builds up energy stores
in the form of glycogen and triglyceride, the latter
* Correspondence to: P. de Lonlay, Department of
Paediatrics, Hôpital Necker-Enfants Malades, 149 rue de
Sèvres, 75743 Paris cedex 15, France. Tel.: +33-144494852;
fax: +33-144494850
E-mail address: [email protected]
being exported to adipose tissue. During fasting, it
releases glucose and ketone bodies. The maintenance of a normal blood glucose level is dependent
upon: (1) functionally intact hepatic glycogenolytic
and gluconeogenic enzyme systems; (2) an adequate supply of endogenous gluconeogenic substrates (amino acids, glycerol and lactate); (3) an
adequate energy supply provided by B-oxidation of
fatty acids to synthesize glucose and ketone bodies,
the latter being exported to peripheral tissues and
used preferentially to glucose as an alternative
fuel; and (4) a normal endocrine system for integrating and modulating these processes. The major
signals controlling the transition between fed and
fasted states are glucose, insulin and glucagon.
These directly or indirectly influence the enzymes
that regulate liver carbohydrate and fatty acid
metabolism, and thereby orient metabolic fluxes
towards either energy storage or substrate
release.3,4
Based on the origin of glucose in blood, it is
possible to divide the timing of glucose homeostasis
into five phases. In the first phase (absorptive and
1084-2756/04/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2003.08.002
50
postphase), blood glucose is derived principally
from exogenous carbohydrate (glucose ingestion).
The concentrations of insulin and glucose are
elevated, and glucagon is depressed. Glucose in
excess of the fuel needs is stored as glycogen in
liver and muscle, or is converted to lipid. This is the
only phase in which the liver is a net user of
glucose, and gluconeogenesis is of little consequence for glucose homeostasis. Hypoglycaemia
occurring during this phase is suggestive of hyperinsulinism. In the second phase, for 3–4 h after
glucose ingestion (postabsorptive phase and early
starvation), insulin returns to basal levels, glucagon
increases and the liver produces glucose, derived
principally from stored glycogen. The major user of
glucose during this phase is the brain, which oxidizes glucose exclusively. Other obligate glycolysers, such as red blood cells and the renal medulla,
also use glucose during this period. Muscles and
adipose tissue, however, use glucose at a slower
rate than phase. The glycogen present in the liver
after an overnight fast (90 g in adults, 20–25 g in a
10-kg infant) is only sufficient to meet the requirements of peripheral tissues for half a day. Hypoglycaemia occurring during this phase is suggestive of
glycogenosis. Phase 3 (early/intermediate starvation) begins after 12–16 h of fast. In this third
phase, gluconeogenesis progressively replaces glycogen as the major source of blood glucose. It is
during this phase, when glycogen stores are
depleted and the brain has not yet begun to utilize
ketone bodies in significant quantities, that the
demand for gluconeogenesis is at its peak, and
susceptibility to hypoglycaemia because of
impaired gluconeogenesis is greatest. It must be
stressed that this period starts immediately after
the overnight physiological fast. Hypoglycaemia
occurring during this fasting period is suggestive of
impaired gluconeogenesis. Fatty acids are essential
for gluconeogenesis, which requires energy. In
phase 4 (long fasting period), fatty acid disorders
are described in which hypoglycaemia is associated
with multivisceral failure by acute ATP deficiency.
Growth hormone (GH), glucagon, cortisol and
insulin-like growth factor 1 (IGF1) deficiencies also
play a role and summarize phase 5 in which the
endocrine system is effective, whatever the eating
and fasting periods.
Causes of hypoglycaemia
Table 1 lists the causes of genetic hypoglycaemia.
In our experience, hyperinsulinism and fatty acid
oxidation (FAO) disorders are the most frequent
causes of genetic hypoglycaemia. Conversely,
P. de Lonlay et al.
patients with glycogenosis and endocrine disorders
(mostly GH deficiency and adrenal disorders) are
not specifically referred to our ward and thus are
probably under-represented. Among the rare disorders, ketogenesis and ketolytic defects, glycogen
synthetase deficiency, and mitochondrial respiratory chain defects represent interesting and original
mechanisms of hypoglycaemia. Hyperinsulinism is a
heterogeneous disorder of primary origin, or occurs
secondary to fatty acid deficiency, congenital disorders of glycosylation or glutamate dehydrogenase
deficiency. The principal differential diagnosis is
facticious hypoglycaemia secondary to Munchausen
by proxy syndrome, which mimics unusual genetic
hypoglycaemia. The following paragraphs will focus
on the most frequent aspects of congenital hyperinsulinism, FAO disorders and some other rare
enzymatic and glucose transporter disorders
(mostly non-ketotic hypoglycaemias).
Hyperinsulinism
The diagnostic criteria for congenital hyperinsulinism (CI) include fasting and postprandial hypoglycaemia (<2 mmol/l) with hyperinsulianemia
(plasma insulin concentrations >3 mU/l), requiring
high rates of intravenous glucose infusion (>10 mg/
kg/min) to maintain blood glucose >3 mmol/l, a
positive response to the subcutaneous or intramuscular administration of glucagon (plasma glucose
concentration increases by 2–3 mmol/l following
0.5 mg glucagon) and persistent hypoglycaemia
throughout the first month of life.5,6 In the absence
of clearly abnormal insulin levels during hypoglycaemia, a 4–6 h fasting test searching for inappropriately low plasma levels of ketone bodies, free
fatty acids and branched chain amino acids may be
helpful. However, during the neonatal period, diagnosis is usually clear, mostly based on the severity
of hypoglycaemia occurring within 72 h of birth and
glucagon responsiveness. The majority of newborns
are macrosomic at birth. Hypoglycaemia is always
severe, revealed by seizures in about half of all
cases, with further brain damage. The rates of
intravenous glucose required to prevent hypoglycaemia are elevated, with a mean at 17 mg/kg min
in our series. Blood glucose concentrations increase
by 2–3 mmol/l in response to subcutaneous or
intramuscular administration of glucagon (0.5 mg).
A mild hepatomegaly is common and does not
exclude the diagnosis of hyperinsulinism.
The clinical presentation (hypoglycaemia) is
similar whatever the histological lesions and the
genetic causes. Most often, no other symptoms are
associated with hypoglycaemia. Facial dysmorphism with high forehead, large and bulbous nose
Neonatal hypoglycaemia: aetiologies
Table 1
51
Genetic hypoglycaemias
Diagnosis
Postprandial period
Hyperinsulinism
SUR1
Kir6.2
GLUD1
GK
SCHAD
CDG
Usher Ic (contiguous gene syndrome)
BWS
Perlman's syndrome
Sotos' syndrome
A few hours after meal
Glycogenosis (I and III)
Glycogen synthetase
Respiratory chain disorders
Fasting period
Fructose biphosphatase (neoglucogenesis defect)
FAO disorders
Ketogenesis and ketolytic defects
Functional hypoglycaemia
Respiratory chain disorders
Fanconi Bickel
Endocrinological causes
Growth hormone deficiency (GH, IGF1)
Adrenal steroid disorders
Other
GLUT1 (only in CSF)
Molecular study
Molecular study
Enzymatic and molecular study
Enzymatic and molecular study
Enzymatic and molecular study
Western blot of glycosylated protein
Molecular study
No diagnosis
Molecular study
Enzymatic and molecular study
Enzymatic and molecular study
Enzymatic study
Enzymatic and molecular study
Enzymatic and molecular study
Enzymatic and molecular study
Enzymatic study
Molecular study
CSF, cerebrospinal fluid; FAO, fatty acid oxidation; SCHAD, short-chain l-3-hydroxyacyl-CoA dehydrogenase; CDG, congenital
disorders of glycosylation; GLUT, glucose transporter; IGF1, insulin-like growth factor 1; GH, growth hormone.
with short columella, smooth philtrum and thin
upper lip are frequently observed in all types of
hyperinsulinism. However, a few cases of syndromic hyperinsulinism have also been described, such
as hyperinsulinism associated with Usher's syndrome type Ic or congenital disorders of glycosylation type Ia or Ib. A few patients with Beckwith–
Widemann's syndrome, Perlman's syndrome and
Sotos' syndrome have also been described.
Hyperinsulinaemic hypoglycaemia is due to
insulin hypersecretion by the islets of Langerhans.
Insulin is the only hormone to lower plasma glucose
concentration. It does so by inhibiting glucose
release from hepatic glycogen, and increasing glucose uptake in muscle cells. This explains the two
main characteristic findings of neonatal CI: the high
glucose requirement to correct hypoglycaemia and
the responsiveness of hypoglycaemia to exogenous
glucagon. Several pathways are involved in the
regulation of insulin secretion by the pancreatic
B-cells, and this helps to explain the effectiveness
of different medical treatments, such as diazoxide,
somatostatin, calcium-channel inhibitors and
protein-restricted diet (Fig. 1).7,8 Glucose and
amino acids stimulate insulin secretion through
their metabolism. Glucokinase, the enzyme that
initiates glucose metabolism in B-cells, has a high
Km for glucose. Thus, the circulating concentrations
of glucose directly determine the rate of glucose
oxidation. High blood glucose levels increase glucose oxidation and, subsequently, the ATP/ADP
ratio, which activates a plasma membrane protein,
the sulphonylurea receptor (SUR), and closes an
ATP-dependent potassium channel (KATP channel).
This leads to depolarization of the B-cell membrane, an influx of extracellular calcium, and the
release of insulin from storage granules. Leucine,
one of the most potent amino acids to stimulate
insulin secretion, acts indirectly as a positive allosteric affector of glutamate dehydrogenase to
increase the rate of oxidation of glutamate.
Increased glutamate dehydrogenase activity is
responsible for hyperammonaemia, an increased
alpha ketoglutarate level and, consequently,
increased Krebs cycle activity and B-cell ATP/ADP
ratio, with subsequent exaggerated insulin release.
Sulphonylureas, such as tolbutamide, stimulate
insulin secretion by binding directly to SURs.
52
P. de Lonlay et al.
Figure 1 Insulin metabolism. Several pathways are involved in the regulation of glucose, including insulin secretion by pancreatic
B-cells, explaining the modality of effectiveness of medical treatments as diazoxide, somatostatin and a protein-restricted diet.
Glucose and other fuels, such as amino acids, stimulate insulin secretion through their metabolism to raise the intracellular ATP/ADP
ratio. Glucokinase, the enzyme that initiates B-cell glucose metabolism, has a high Km for glucose, and, thus, the circulating
concentrations of glucose directly determine the rate of glucose oxidation and subsequent release of insulin. Increases in the ATP/ADP
ratio activate a plasma membrane protein, the sulphonylurea receptor (SUR), to cause closure of a potassium channel (KATP channel).
This, in turn, leads to depolarization of the membrane, an influx of extracellular calcium, and the release of insulin from storage
granules. Leucine, one of the most potent amino acids in stimulating insulin secretion, acts indirectly as a positive allosteric affector
of glutamate dehydrogenase to increase the rate of oxidation of glutamate. Increased glutamate dehydrogenase activity is responsible
for increased alpha ketoglutarate level, increased Krebs cycle activity and B-cell ATP/ADP ratio, and subsequently leads to
exaggerated insulin release.
Diazoxide inhibits insulin secretion by binding to
SURs.
Insulin secretion in response to tolbutamide has
recently been suggested to separate focal forms
(tolbutamide responsive) from diffuse forms (tolbutamide insensitive). Tolbutamide triggers insulin
secretion in focal forms, but not in diffuse forms.
This hypothesis has not been confirmed in our
experience (submitted for publication).
Patients who are treated surgically have to be
classified according to histological criteria.9–11 The
focal form is defined as a focal adenomatous hyperplasia. The lesion measures 2.5–7.5 mm in diameter, differing from true adult-type pancreatic
adenoma which is clearly limited with a different
topographic distribution. Diffuse CI shows abnormal
B-cell nuclei in all sections of the pancreas. In the
absence of any distinctive clinical feature, and
because pre-operative classical radiology of the
pancreas, including echotomography, computed
tomography scan and nuclear magnetic resonance,
is not efficient to screen the focal forms, pancreatic venous catheterization12,13 and pancreatic
arteriography are the only pre-operative proce-
dures currently available for locating the site of
insulin secretion. They are not performed before
the age of 1 month, to exclude patients with transient forms, or in patients with hyperammonaemia
who are likely to have diffuse hyperinsulinism.
The estimated incidence of CI is 1/50 000 live
births, but the incidence may be high as 1/2500 in
countries with substantial inbreeding. The two histological forms that can be found in both neonatal
and infancy-onset hyperinsulinism correspond with
distinct molecular entities.12,13. Focal islet-cell
hyperplasia is associated with hemi- or homozygosity of a paternally inherited mutation of the SUR1 or
the inward-rectifying potassium channel (Kir6.2)
genes on chromosome 11p15 and loss of the
maternal allele in the hyperplastic islets
neonates.14,15 The loss of the 11p15 maternal allele
leads to an unbalanced expression of 11p15
imprinted genes, namely growth factor and suppressor tumour genes. Focal lesion is probably a
sporadic event, as suggested by the somatic molecular abnormality in the pancreas and by discordant identical twins. However, the co-existence of a
focal and a diffuse lesion in the same family cannot
Neonatal hypoglycaemia: aetiologies
be excluded. Diffuse hyperinsulinism is a heterogeneous disorder involving the genes encoding
the SUR or the inward-rectifying potassium
channel7,16–19 in recessively inherited hyperinsulinism, or more rarely, the glucokinase gene20 or other
loci21 in dominantly inherited hyperinsulinism, and
the glutamate dehydrogenase gene when hyperammonaemia is associated with hyperinsulinism.22,23
In this case, transmission can be sporadic or dominant. More recently, short-chain l-3-hydroxyacylCoA dehydrogenase (SCHAD) has been implicated.24
The clinical presentation of hyperinsulinism
related to potassium channels (with focal or diffuse
lesion) depends on the age of onset of hypoglycaemia. In contrast, hyperinsulinism associated with
hyperammonaemia is less severe, even when the
onset is neonatal. Patients with neonatal CI who
are responsive to diazoxide may have a transient
form of hyperinsulinism or the hyperinsulinism–
hyperammonaemia syndrome. Adenoma differs
radically from focal CI by the late onset of hypoglycaemia and the histological lesion. To date, its
aetiology is unknown apart from adenoma related
to the MEN1 syndrome with dominant mutation
on the MEN1 gene following menine protein
deficiency, a loss of the 11p13 region and
Bourneville's tuberous sclerosis.
Finally, many genes could be implicated, namely
all the genes playing a role in insulin secretion. The
differential diagnosis is Munchausen by proxy.25
Fatty acid oxidation and ketogenesis
disorders
Since the first description of fasting hypoglycaemia
revealing medium-chain acylCoA dehydrogenase
and hepatic carnitine palmitoyl transferase
deficiency,26 defects of FAO have become one of
the most important causes of genetic hypoglycaemia.27 In a series of 107 patients with FAO defects,
hypoketotic hypoglycaemia was observed in 60% of
cases and was the revealing symptom in about 50%.
In most cases, the inappropriately low levels of
plasma ketones were suggested by negative acetest
in urine at the time of acute attack, and then
further demonstrated by carefully supervised fasting test.28 In neonates, hypoglycaemia was
observed within the first 72 h of life in term
eutrophic neonates presenting with hypotonia,
poor feeding and life-threatening events such as
apnea, collapse, dyspnoea or seizures. In almost all
cases, hypoglycaemia was associated with cardiac
symptoms (arrhythmia, conduction defects, cardiomyopathy),27 moderate hepatomegaly, metabolic
acidosis, hyperlactacidaemia, hyperammonaemia,
53
and moderate elevation of transaminases. The glucose requirement to maintain blood glucose within
normal limits was normal. In neonates, hypoglycaemia never raised a real diagnostic problem. In
infancy, by contrast, hypoglycaemia usually
appeared as an isolated revealing sign in the
context of fasting or catabolism. Diagnosis of
hyperinsulinism, hypopituitarism and fructose
biphosphatase deficiency were frequently considered and ruled out before reaching the correct
diagnosis of FAO disorder. A moderate hepatomegaly was very frequent during an acute attack with
negative, inappropriately low urine test for
ketones, mild acidosis, mild hyperlactacidaemia,
mild hyperammonaemia and moderately increased
serum transaminases. As a whole, hypoglycaemic
attacks revealing an FAO disorder in infancy presented either like a fasting hypoglycaemia with no
ketonuria, or resembled Reye's syndrome. In our
series, there were no clinical, biological or histological criteria which allowed us to separate a priori
FAO disorders from idiopathic Reye's syndrome. All
kinds of long- and medium-chain fatty acid disorders can present with Reye's syndrome, hepatomegaly, steatosis and hypoketotic hypoglycaemia.
In these defects, hypoglycaemia results from underproduction of glucose by the liver associated with
above-normal consumption of glucose by peripheral
tissues due to the incapacity of these tissues to
oxidize fatty acids and to the absence of ketone
bodies as alternative fuels. Both phenomena can be
quickly reversed in long-chain FAO disorders by
giving medium-chain triglycerides which dramatically increase blood glucose and ketone body
concentrations. The diagnostic approach to FAO
disorders is mainly based on blood and urine investigations performed during acute metabolic stress.
Investigation of FAO disorders has recently been
simplified radically by investigating acylcarnitine
profiles by FAB-MSMS or electrospray MSMS from
simple blood spots collected on a Guthrie card.29 In
addition to this very efficient technique, the determination of urinary organic acid profiles by classical
GC–MS can give highly specific patterns or suggestive but non-specific patterns (like saturated and
unsaturated medium- and long-chain dicarboxylic
acids). However, a normal pattern does not allow
the exclusion of an FAO disorder.30 If no material is
collected at the time of acute attack or if the
results are incomplete or ambiguous, a function
test that challenges the metabolic pathway may
provide a tentative diagnosis. When performing
such a function test, it is very important to adhere
to a strictly defined protocol to obtain the maximum diagnostic information and minimize the risk
54
of metabolic complications. Two tests are very
informative but dangerous; the fasting test and the
long-chain triglycerides loading test. Finally, inherited defects of FAO can be diagnosed by in vitro
testing using fresh circulating lymphocytes or intact
cultured fibroblasts to oxidize individual fatty
acids. To date, all the described defects involving
the liver have been expressed in these cells.27
HMGCoA lyase and HMGCoA synthetase deficiencies
have a similar presentation to FAO disorders and
can be approached using the same procedures.31–35
However, they require specific enzymatic
determinations for definitive confirmation.
Disturbances in the synthesis and
degradation of glycogen and
gluconeogenesis defects
The most frequent glycogen anomaly leading to
hypoglycaemia is glycogenosis type I.36 Two very
rare enzyme defects disturb the synthesis of liver
glycogen; glycogen synthase deficiency and branching enzyme deficiency or glycogen storage disease
type IV. The latter presents mainly with cirrhosis
and not with preponderant hypoglycaemia. In glycogen synthase deficiency,37 the synthesis of liver
glycogen is profoundly, although not completely,
impaired. The defect provokes a severe morning
hypoglycaemia with a very characteristic profile
that appears in early infancy with cessation of
nocturnal feeding. After an overnight fast (second
phase of glucose homeostasis), there is a severe
hypoglycaemia with hyperketonaemia, low lactate
and low alanine. Conversely, hyperglycaemia and
hyperlactataemia occur after meals, while ketonaemia decreases to a normal value. Glucagon
causes a rise in glucose 3 h after a meal with a fall
in lactate and alanine, but no effect of glucagon is
seen after a 12-h fast. The enzyme defect can only
be demonstrated in the liver, and not in other
tissues.
Several enzyme defects in the glycogenolytic
pathway impair the degradation of liver glycogen,
and present with a profound hypoglycaemia which
also appears in the second phase of glucose
homeostasis. In glucose-6-phosphatase deficiency
(glycogen storage disease type Ia) and glucose-6phosphate translocase (glycogenosis type Ib), profound hypoglycaemia generally appears 2.5–3.5 h
after a meal because the enzyme defect not only
suppresses the release of glucose from glycogen but
also the formation of glucose by the gluconeogenic
pathway. Diagnosis is easy, based upon the large
hepatomegaly, lactic acidosis, slight ketosis and
hyperuricaemia. In glycogenosis type Ib, fluctuant
P. de Lonlay et al.
neutropenia responsible for recurrent infections is
a near-constant finding. Confirmation of diagnosis
is now based directly upon molecular investigation
of the glucose-6-phosphatase gene36 or of the
glucose-6-phosphate translocase gene. This molecular diagnosis avoids performing a liver biopsy
for enzymatic assay. In amylo-1,6-glucosidase
deficiency (glycogen storage disease type III),
hypoglycaemia is usually mild compared with glycogenoses type I because degradation of glycogen
by phosphorylase remains possible and the gluconeogenic pathway is intact. In this disorder, a protuberant abdomen with an enormous hepatomegaly
is the striking feature. There is no fasting lactic
acidosis and frank ketonuria is associated with fasting hypoglycaemia. A moderate elevation of lactate
concentration can be observed in the postabsorptive state. A mild elevation of creatine
kinase reflects associated muscular glycogenosis.
Cardiomyopathy is present in some molecular
subtypes.
Hypoglycaemia is very rare in phosphorylase
complex deficiency (phosphorylase itself and
phosphorylase-b-kinase = glycogenosis type VI and
IX). Hypoglycaemia does not exist in glycogenosis
type II (alpha-glucosidase deficiency).
In addition to glucose-6-phosphatase deficiency,
several enzyme defects disturb the formation of
glucose by the gluconeogenic pathway,38 namely
the deficiencies of fructose-1,6-biphosphatase,
phosphoenolpyruvate carboxykinase and pyruvate
carboxylase. Hypoglycaemia is a major feature in
fructose-1,6-biphosphatase deficiency. It usually
strikes after an overnight fast or during catabolic
states at the end of phase 2 or the beginning of
phase 3 of glucose homeostasis. Moderate
hepatomegaly is frequent during an acute attack
but does not always occur. Hypoglycaemia is associated with moderate hyperketonaemia and lactic
acidosis which can be preponderant. Diagnosis relies upon a fasting test performed under careful
supervision that displays a characteristic profile
with a progressive decrease of glucose concentrations contrasting with a progressive increase of
lactate concentrations. These patients are fructose
intolerant; acute fructose administration lead to
acute hypoglycaemia, as in fructose-1-phosphate
aldolase deficiency. Diagnosis relies on the
measurement of fructose biphosphatase activity in
lymphocytes or on liver biopsy. To date, there is no
well-documented case of phosphoenolpyruvate
carboxykinase deficiency presenting with recurrent
hypoglycaemia. Hypoglycaemia is also only occasionally mentioned in pyruvate carboxylase
deficiency, probably because this defect does not
Neonatal hypoglycaemia: aetiologies
affect the entrance of a number of substrates, such
as glycerol and serine, into the gluconeogenic
pathway.4
Other rare enzymatic or transporter
disorders
Ketolytic defects
Ketolytic defects (succinylCoA: acetoacetate transferase and acetoacetylCoA thiolase deficiencies)
rarely present with recurrent attacks of
hypoglycaemia.31–35 Mostly, hypoglycaemia strikes
in the third phase of glucose homeostasis, and is
associated with severe ketoacidosis, low lactate
and low alanine. Diagnosis relies upon the demonstration of a permanent ketosis during a nycthemeral cycle, and on unusually high concentrations of
ketone bodies compared with free fatty acids.
Enzymatic assays (not performed routinely) can be
done on cultured fibroblasts. These cases, like
those with glycogen synthetase deficiency, could
be easily mistaken for ketotic hypoglycaemia syndrome if functional tests, including a 24-h cycle and
fasting test, are not performed in a well-trained
metabolic ward.33 We recently observed two
patients affected with complex IV deficiency and
one patient with complex CIII deficiency of the
respiratory chain, who presented with isolated recurrent attacks of fasting hypoglycaemia mimicking
fructose-1,6-diphosphatase deficiency (with moderate hyperketosis and hyperlactacidaemia) (J.M.
Saudubray, unpublished observations).
Phosphomannose isomerase deficiency
Phosphomannose isomerase deficiency is responsible for congenital glycosylation disorder (CDG)
type Ib. Less frequently, phosphomannomutase
deficiency (CDG Ia) can lead to predominant
hypoglycaemia due to hyperinsulinism.
Glucose transporter deficiencies
The pathophysiology of Fanconi Bickel syndrome
(FBS) was identified recently.39,40 FBS is a rare
well-defined clinical entity which is inherited in an
autosomal-recessive mode. It is characterized
by hepatorenal glycogen accumulation, fasting
hypoglycaemia, postprandial hyperglycaemia and
hypergalactosaemia (indicating an impaired utilization of these two monosaccharides), and proximal
renal tubular dysfunction. In contrast to other
types of glycogen storage diseases caused by enzymatic defects of glycogenolysis, FBS has recently
55
been shown to result from a defective monosaccharide transporter, GLUT2, in cell membranes of different tissues.40 It thus represents the first disease
with hypoglycaemia caused by a defect of a member of the facilitative glucose transporter family.
The diagnosis of this disorder, easily suspected on
the very suggestive clinical pattern, relies upon
molecular investigation of the GLUT2 gene.40
The GLUT1 deficiency syndrome caused by
haplo-insufficiency of the blood–brain barrier hexose carrier described recently41 belongs to the
same family of glucose transporter disorders. However, in this disorder, the low glucose concentration is only demonstrable in cerebrospinal fluid
(CSF) while simultaneous blood glucose concentration is normal. The disorder presents with severe
infantile seizures with delayed development and
acquired microcephaly. The diagnosis is suspected
on persistent hypoglycorrachia (low CSF glucose)
with low to normal lactate, and normal circulating
simultaneous blood glucose. Confirmation can be
made by the demonstration of diminished transport
of hexose into isolated red blood cells and mutation
analyses of the GLUT1 gene.
Genetic endocrine disorders
Hypoglycaemia due to GH deficiency in the newborn has been recognized for many years, with
symptomatic hypoglycaemia as a revealing symptom.42,43 In GH deficiency, hypoglycaemia is rather
rare (less than 20%). Symptomatic hypoglycaemia is
more frequent in lean children below 4 years of
age. If the deficiency is due to defects early in
development, such as GH gene deletion or the rare
instances of mutations in the GH-releasing hormone
(GHRH) receptor,44–46 micropenis is also found in
males.43 As these characteristics are also found in
Laron's syndrome, the early deficiency of male
hormone expression in utero seems to be related to
the absence of GH action and/or IGF1 deficit.47
Similar findings can be observed in malformations
of the hypothalamic area, leading to multiple pituitary hormone deficiencies, in which case the
microphallus and hypogonadism are due to a combination of primary gonadotrophin deficiency and
lack of GH, leading to secondary deficiency of
IGF1. In all these patients, hypoglycaemia occurs
during fasting (second and third phase of glucose
homeostasis); ketone body concentrations are
variable—low in neonates and young infants, and
high in children. Hypoglycaemia responsiveness to
glucagon is also variable—mild, absent or
dramatic—the latter response being similar to that
observed in hyperinsulinism.
56
Laron's syndrome is due to primary IGF1
deficiency (molecular defects of the GH receptor,
in the postreceptor area or in the synthesis and
action of IGF1). Patients with this syndrome are
indistinguishable from patients with isolated GH
deficiency, but have excessively high serum GH
levels which are ineffective (GH resistance, insensitivity). Marked hypoglycaemia in addition to
dwarfism and obesity is one of the characteristics
of these patients. Hypoglycaemia is symptomatic in
infancy and becomes asymptomatic with advancing
age. Before 6 years of age, children with Laron's
syndrome present with insulin hypoglycaemia nonresponsiveness denoting a defect in the counterregulatory mechanism. These rare syndromes raise
the interesting question of the interaction between
GH and IGF1 activities on glucose metabolism. The
mechanism by which IGF1 deprivation induces
hypoglycaemia is probably an interplay between
the role that IGF1 has on glucose transport, phosphorylation, glycolysis and glycogen synthesis, and
the lack of GH-induced hepatic gluconeogenesis.
Hypoglycaemia associated with isolated ACTH
deficiency is as rare as hypoglycaemia due to primary adrenal failure, such as in adrenoleukodystrophy. Glucagon deficiency can also be associated
with hypoglycaemia.48
Conclusions
In our experience, most genetic causes of hypoglycaemia are easy to elucidate. Diagnosis relies upon
a limited number of parameters, mostly clinical,
uncomplicated tests. Commemorative and clinical
features are very important (age at onset, severity
and frequency of hypoglycaemic attacks, timing of
hypoglycaemia, glucose requirement to maintain
normal blood glucose concentrations, ketosis, glucagon responsiveness, hepatomegaly, short stature, dysmorphy). Knowledge of the homeostatic
mechanisms which maintain normal blood glucose
in early life is crucial to the diagnosis. Hypoglycaemia in the absorptive phase is very likely to be due
to hyperinsulinism. Children presenting acutely
with hypoglycaemia are often dangerously ill and
possibly moribund. In such an emergency, a detailed history and examination may have to be
differed. Too often, blood is only taken for glucose
and possible electrolytes before glucose is given.
When the child has recovered, it may be very
difficult to establish a diagnosis without recourse to
a fasting test with the associated risks. It is
extremely important to collect appropriate
samples at the time of the acute event. This will
provide a diagnosis or at least indicate which group
P. de Lonlay et al.
of disorders is likely. Blood should always be taken
for glucose, insulin, GH, cortisol, lactate, amino
acids with alanine quantification if possible,
3-hydroxybutyrate, free fatty acids, Guthrie card
for acylcarnitine profile, and liver function test.
The first urine pass must always be tested for
ketones, allowing a first simple separation between
ketotic and non-ketotic hypoglycaemia, and saved
for organic acids analysis.
Practice points
Clinical features to note
•
•
•
•
Timing of hypoglycaemia (fasting or feeding)
Hepatomegaly
Severity of hypoglycaemia
Quantity of glucose infusion to normalize
glycaemia
• Head circumference
• Other associated symptoms
Measurements during hypoglycaemia
•
•
•
•
•
•
•
•
•
•
Glycaemia
Lactate
NH3
Ketone bodies
Liver function
Insulin, GH, insulin-like growth factor 1,
cortisol, c peptide
Amino acids (plasma)
Organic acids (urine)
Acylcarnitine (plasma)
Glucagon test if feeding hypoglycaemia (not
for fasting hypoglycaemia)
If symptoms: transferrin Western blot (congenital disorders of glycosylation).
Research directions
• New syndromes are known to be associated
with hypoglycaemia, namely Sotos syndrome
and congenital disorders of glycosylation.
• New genes will be found to be implicated in
hypoglycaemia, i.e. all the genes playing a
role in glycaemia regulation.
• Animal models should be researched, i.e.
mice with hyperinsulinism.
• All mechanisms are not yet understood.
Neonatal hypoglycaemia: aetiologies
References
1. Volpe JJ. Hypoglycemia and brain injury. In: Volpe JJ,
editor. Neurology of the newborn. Philadelphia: WB
Saunders Co., 1995;467–89.
2. Cornblath M, Schwartz R, Aynsley-Green A et al. Hypoglycemia in infancy: the need for a rational definition.
Pediatrics 1990;85:834–7.
3. Pagliara AS, Karl IE, Haymond M et al. Hypoglycemia in
infancy and childhood. Part I. J Pediatr 1973;82:365–79.
4. Van den Berghe G. Role of the liver in metabolic homeostasis: implications for inborn errors of metabolism. J Inherit
Metab Dis 1991;14:407–35.
5. De Lonlay-Debeney P, Poggi-Travert F, Fournet JC et al.
Clinical features of 52 neonates with hyperinsulinism. N Engl
J Med 1999;340:1169–75.
6. Leibowitz G, Glaser B, Higazi AA et al. Hyperinsulinemic
hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent
B-cell dysfunction at long-term follow-up. J Clin Endocrinol
Metab 1995;80:386–92.
7. Kane C, Shepherd RM, Squires PE et al. Loss of functional
K+ATP channels in persistent hyperinsulinemic hypoglycaemia of infancy. Nat Med 1996;2:1344–7.
8. Lindley KJ, Dunne MJ, Kane C et al. Ionic control of B-cell
function in nesidioblastosis. A possible therapeutic
role for calcium channel blockade. Arch Dis Child 1996;
74:373–8.
9. Sempoux C, Guiot Y, Lefevre A et al. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and
keys for differential diagnosis. J Clin Endocrinol Metab
1998;83:1455–61.
10. Rahier J, Fälts K, Münterfering H et al. The basic structural
lesion of persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of
B cells? Diabetologia 1984;26:282–9.
11. Rahier J, Sempoux C, Fournet JC et al. Partial or near-total
pancreatectomy for persistent neonatal hyperinsulinaemic
hypoglycaemia: the pathologist's role. Histopathology 1998;
32:15–9.
12. Brunelle F, Negre V, Barth MO et al. Pancreatic venous
samplings in infants and children with primary
hyperinsulinism. Pediatr Radiol 1989;19:100–3.
13. Dubois J, Brunelle F, Touati G et al. Hyperinsulinism in
children: diagnostic value of pancreatic venous sampling
correlated with clinical, pathological and surgical outcome
in 25 cases. Pediatr Radiol 1995;25:512–6.
14. De Lonlay P, Fournet JC, Rahier J et al. Somatic deletion of
the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J
Clin Invest 1997;100:802–7.
15. Verkarre V, Fournet JC, de Lonlay P et al. Paternal mutation
of the sulfonylurea receptor (SUR1) gene and maternal loss
of 11p15 imprinted genes lead to persistent hyperinsulinism
in focal adenomatous hyperplasia. J Clin Invest 1998;
102:1286–91.
16. Thomas PM, Cote GJ, Wohllk N et al. Mutations in the
sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;
268:426–9.
17. Nestorowicz A, Wilson BA, Schoor KP et al. Mutations in the
sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 1996;
5:1813–22.
57
18. Nestorowicz A, Inagaki N, Gonoit T et al. A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2,
is associated with familial hyperinsulinism. Diabetes 1997;
46:1743–8.
19. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet
inward rectifier Kir6.2 also leads to familial persistent
hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet
1996;5:1809–12.
20. Glaser B, Kesavan P, Heyman M et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J
Med 1998;338:226–30.
21. Kukuvitis A, Deal C, Arbour L et al. An autosomal dominant
form of familial persistent hyperinsulinemic hypoglycemia
of infancy, not linked to the sulfonylurea receptor locus. J
Clin Endocrinol Metab 1997;82:1192–4.
22. Stanley CA, Lieu YK, Hsu BY et al. Hyperinsulinemia and
hyperammonemia in infants with regulatory mutations of
the glutamate dehydrogenase gene. N Engl J Med 1998;
338:1352–7.
23. Zammarchi E, Filippi L, Novembre E et al. Biochemical
evaluation of a patient with a familial form of leucinesensitive hypoglycemia and concomitant hyperammonemia.
Metabolism 1996;45:957–60.
24. Clayton PT, Eaton S, Aynsley-Green A et al. Hyperinsulinism
in short-chain l-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin
secretion. J Clin Invest 2001;108:457–65.
25. Dershewitz R, Vestal B, Maclaren N et al. Malicious insulin
administration resulting in transient hepatomegaly and
hypoglycemia. Am J Dis Child 1976;130:998–9.
26. Gregersen N, Lauritzen R, Rasmussen K. Suberylglycine
excretion in the urine from a patient with dicarboxylic
aciduria. Clin Chim Acta 1976;70:417–25.
27. Saudubray JM, Martin D, De Lonlay P et al. Recognition and
management of fatty acid oxidation defects: a series of 107
patients. J Inherit Metab Dis 1999;22:488–502.
28. Vianey-Saban C, Divry P, Gregersen N et al. The inborn
errors of mitochondrial fatty acid oxidation. J Inherit Metab
Dis 1987;10(Suppl 1):159–98.
29. Millington DS, Terada N, Chace DH et al. The role of
tandem mass spectrometry in the diagnosis of fatty acid
oxidation disorders. In: Coates PM, Tanaka K, editors. New
developments in fatty acid oxidation. Progress in clinical
and biological research. New York: John Wiley-Liss,
1992;339–54.
30. Nada M, Rhead W, Sprecher H et al. Evidence for intermediate channeling of mitochondrial B-oxidation. J Biol Chem
1995;270:530–5.
31. Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methyglutarylCoA lyase deficiency: a review of 18 reported patients. Eur J
Pediatr 1988;148:180–6.
32. Thompson GN, Hsu BY, Pitt JJ et al. Fasting hypoketotic
coma in a child with deficiency of mitochondrial 3-hydroxy3-methylglutaryl-CoA synthase. N Engl J Med 1997;
337:1203–7.
33. Leonard JV, Middleton B, Seakins JW. Acetoacetyl-CoA thiolase deficiency presenting as ketotic hypoglycemia. Pediatr
Res 1987;21:211–3.
34. Niezen-Koning KE, Wanders RJ, Ruiter JP et al. SuccinylCoA: acetoacetate transferase deficiency: identification of
a new patient with a neonatal onset and review of the
literature. Eur J Pediatr 1997;156:870–3.
35. Saudubray JM, Specola N, Middleton B et al. Hyperketotic
states due to inherited defects of ketolysis. Enzyme 1987;
38:80–90.
58
36. Lei KJ, Shelly LL, Pan CJ et al. Mutations in the glucose-6phosphatase gene that cause glycogen storage disease type
Ia. Science 1993;262:580–3.
37. Gitzelmann R, Spycher MA, Feil G et al. Liver glycogen
synthase deficiency: a rarely diagnosed entity. Eur J Pediatr
1996;155:561–7.
38. Ruderman NB, Aoki TT, Cahill GF. Gluconeogenesis and its
disorders in man. In: Hanson RW, Mehlman MA, editors.
Gluconeogenesis, its regulation in mammalian species. New
York: John Wiley and Sons, 1976;515–32.
39. De Vivo DC, Trifiletti RR, Jacobson RI et al. Defective
glucose transport across the blood–brain barrier as a cause
of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–9.
40. Santer R, Schneppenheim R, Dombrowski A et al. Mutations
in GLUT2, the gene for the liver-type glucose transporter, in
patients with Fanconi–Bickel syndrome. Nat Genet 1997;
17:324–6.
41. Seidner G, Garcia Alvarez M, Yeh JI et al. GLUT-1 deficiency
syndrome caused by haploinsufficiency of the blood–brain
barrier hexose carrier. Nat Genet 1998;18:188–91.
P. de Lonlay et al.
42. Jaquet D, Touati G, Rigal O et al. Exploration of glucose
homeostasis during fasting in growth-hormone-deficient
children. Acta Paediatr 1998;87:505–10.
43. Lovinger RD, Kaplan SL, Grumbach MM. Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus: four cases secondary to hypothalamic hormone
deficiencies. J Pediatr 1975;87:1171–81.
44. Laron Z, Blum W, Chatelain P et al. Classification of growth
hormone insensitivity syndrome. J Pediatr 1993;122:141.
45. Laron Z, Avitzur Y, Klinger B. Carbohydrate metabolism in
primary GH resistance (Laron syndrome) before and during
IGF-1 treatment. Metabolism 1995;44(Suppl 4):486–90.
46. Laron Z. Short stature due to genetic defects affecting
growth hormone activity. N Engl J Med 1996;334:463–5.
47. Froesch ER, Hussain M. The metabolic effects of insulin-like
growth factor I with special reference to diabetes. Acta
Paediatr 1994;399(Suppl):165–70.
48. Vidnes J, Oyasaeter S. Glucagon deficiency causing severe
neonatal hypoglycemia in a patient with a normal insulin
secretion. Pediatr Res 1977;11:943–9.