HYPERINSULINISM-HYPERAMMONEMIA SYNDROME
IN AN INFANT WITH SEIZURES
Strajnar A1, Tansek MZ2, Podkrajsek KT3,4, Battelino T2,5, Groselj U
*Corresponding Author: Assistant Professor Urh Groselj, M.D., Ph.D., Department of Pediatric Endocrinology, Diabetes
and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000 Ljubljana,
Slovenia. Tel: +386-1-5229270. Fax: +386-1-2320190. E-mail: urh.groselj@ kclj.si
page: 77
|
|
DISCUSSION
Recurrent hypoglycemia in early infancy is most frequently
caused by congenital hyperinsulinism (CHI) [4].
Transient forms of CHI are mainly a consequence of other
disorders such as gestational diabetes, perinatal asphyxia
or intrauterine growth retardation [5]; persistent forms are
known as persistent hyperinsulinemic hypoglycemia of
infancy (PHHI) (Table 1) [6]. The incidence of PHHI is
estimated to be around 1/35,000-40,000 [7]. Persistent hyperinsulinemic
hypoglycemia of infancy is characterized
by unsuppressed insulin secretion, in spite of a low level of
blood glucose, most frequently presenting in newborns with
mild or severe hypoglycemia [8]. Clinical symptoms of hypoglycemia
could be non specific (e.g., lethargy, irritability,
poor feeding) or in some cases severe (apnea, seizures or
coma) [9]. As hypoglycemia could lead to brain injury and
impairment of neurological development, timely diagnosis
and management are essential to prevent the sequelae [8].
Hyperinsulinism-hyperammonemia syndrome is
the second most frequent cause of PHHI, after the pancreatic
β-cell KATP channel defects [10]. The main clinical
characteristics of HI/HA syndrome are repeated episodes
of symptomatic hypoglycemia [10,11]. Hypoglycemia is
usually less severe as compared to that observed in the
defects of the KATP channel and frequently not diagnosed
in the first months of life [10]. Our patient first displayed
convulsions at 8 months. This could also be a result of
the higher protein intake with the solid food introduction
at this age; the normal results of brain ultrasound, EEG,
brain MRI and ECG ruled out most other possible causes.
Hyperinsulinism-hyperammonemia syndrome is a
con-sequence of a mutated GLUD1 gene for the mitochondrial
enzyme glutamate dehydrogenase (GDH). Glutamate
dehydrogenase is substantially expressed in liver,
pancreatic β-cells, kidney and in brain. It catalyzes the
oxidative deamination of glutamate to α-ketoglutarate and
ammonia [10,12]. The GDH is allosterically activated by
leucine and adenosine diphosphate (ADP) and is inhibited
by guanosine triphosphate (GTP) [13]. In the pancreatic
β-cells, α-ketoglutarate is metabolized in the tricarboxylic
acid (Krebs) cycle, increasing the cellular ATP concentration
that closes the ATP-sensitive potassium channels. The
resulting cell membrane depolarization causes Ca2+ influx via voltage gated calcium channels and insulin exocytosis
[14] (Figure 1).
The GLUD1 gene mutations lead to an increased
enzyme activity, causing increased insulin secretion by
pancreatic β-cells, increased ammonia production and its
decreased removal by the hepatocytes. Leucine stimulates
insulin secretion by allosterically activating GDH activity
[15]. Typically, hypoglycemia follows meals with a high
protein content [12,15,17,18] (Figure 1).
In our patient, the autosomal dominant syndrome, a
mutation on the GLUD1 gene (p.Arg274Cys), was confirmed
with genetic analysis. The same mutation (p.Arg
274Cys) has previously been reported as p.Arg221Cys in
patients with HI/HA, who also had epileptic seizures and
mild mental retardation [3,4]. Our patient had no epileptic
seizures and his neurocognitive development was within
normal ranges at the age of 2 years.
We also performed genetic analyses on our patient’s
father who had hypoglycemia episodes in his childhood.
Initially, we suspected the father to have the same mutation,
as the boy displayed autosomal dominant syndrome
and the father had hypoglycemia episodes in his childhood.
However, the father’s (as well as his mother’s) genetic
analyses results were normal. De novo mutations of the gene GLUD1 account for 80.0% of cases [16], as happened
in our patient.
Normally, protein intake stimulates insulin release
without causing hypoglycemia because glucagon is also
secreted to neutralize the effect of insulin on glucose production
in the liver [15,20]. Protein-induced hypoglycemia
in HI/HA might be a consequence of impaired regulation
of pancreatic α-cells, as well as β-cells [15]. Patients with
HI/HA are susceptible to hypoglycemia in response to
both fasting and protein feeding, but in most instances
hypoglycemia occurs within a few hours after a meal [15].
The same was seen in our patient who had the hypoglycemia
episode during his afternoon rest (probably caused
by protein load in his meal half an hour before afternoon
rest) and only after 11 hours of fasting. Thus, HI/HA must
be considered in the differential diagnosis of postprandial
or reactive hypoglycemia [15].
In HI/HA, plasma ammonia levels are increased
3-5 times normal as a consequence of the hyperactivity
of GDH, which causes increased ammonia release from
glutamate and its diminished elimination [10] (Figure 1).
Hype-rammonemia in patients with HI/HA syndrome tends
to be asymptomatic and ammonium lowering therapy is
not considered to provide any benefits in HI/HA syndrome.
Ammonia levels in HI/HA syndrome are also not shown
to depend on fasting, protein intake or on blood glucose
levels [10]. All the above mentioned clinical and biochemical
features were present in our patient.
Therapy with diazoxide is shown to be effective in
PHHI, binding to the intact SUR1 component of the ATPsensitive
potassium (KATP) channels in the pancreatic β-cell,
preventing the cell membrane depolarization and insulin
secretion [6]. The HI/HA patients with a GLUD1 mutation
usually respond to diazoxide therapy, only very rarely is a
pancreatectomy needed [21]. Our patient has now been on
therapy for more than 1 year, without documented hypoglycemia
or seizures and with normal growth and development.
Conclusions. It is important to always consider hypoglycemia
and hyperammonemia when a baby “is not well,”
as symptoms may not be specific. If transient hypoglycemia
in an infant is ruled out, metabolic disorders must be
taken into account. In HI/HA syndrome, diazoxide is the
first line of treatment; hypoglycemia is well controlled and
hyperammonemia appears to be asymptomatic.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This study was supported by the Slovenian
Research Agency [grant number P3-0343].
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
