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Indian Pediatr 2010;47:
354-355 |
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Prenatal Diagnosis of Glycogen Storage
Disorder Type III |
J Sujatha, IV Amithkumar and B Lathaa
From Department of Clinical Genetics, Fetal Care Research
Foundation, Chennai, India.
Correspondence to: Dr J Sujatha, Consultant and Head,
Department of Clinical Genetics, Fetal Care Research Foundation, Chennai,
India.
Email: [email protected]
Received: January 30, 2009;
Initial review: February 10, 2009;
Accepted: March 6, 2009.
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Abstract
Among glycogen storage disorders, deficiency of
glycogen debranching enzyme causes an incomplete glycogenolysis
resulting in glycogen accumulation with abnormal structure in liver and
muscle. This report describes a novel mutation in a family with glycogen
storage disorder Type III in index child used in prenatal diagnosis in
the fetus in second trimester.
Keywords: AGL gene mutation, Glycogen Storage Disorder Type III,
Prenatal Diagnosis.
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D ebranching
enzyme is required in complete breakdown of the glycogen molecule.
Deficiency of debranching enzyme results in glycogen storage disorder (GSD)
Type III. GSD III is panethnic, with an estimated incidence of 1 in 100
000(7). Type III is further subclassified into IIIa (liver and muscle
form), IIIb (liver form), and IIIc (muscle form)(1-3). Clinically, this
may manifest in childhood with hepatomegaly, liver dysfunction, failure to
thrive, and fasting hypoglycemia, occasionally resulting in hypoglycemic
seizures. Some develop weakness, hypotonia, gross-motor delay, and
cardiomyopathy. So ascertainment of the exact subtype is essential in
management.
Case Report
A mother in her second gravida at 12 weeks presented
with her previous seven year old girl child born of a third degree
consanguineous marriage. She was referred for evaluation of suspected
metabolic disorder in her child, the proband, and with view to explore the
possibility of a prenatal diagnosis. The girl had an apparently normal
perinatal and neonatal period with age appropriate milestones until five
months when she developed an episode of respiratory infection.
Hepatomegaly was docu-mented and a few episodes of hypoglycemic seizures
were noted. Investigations revealed elevated liver enzymes SGOT-400 IU/L
(0-45 IU/L), SGPT - 499 IU/L(0-45 IU/L), and serum alkaline phosphatase
1016 IU/L (100-644). Creatine phosphokinase was elevated 1539 (0-197 U/L).
Blood pyruvate and lactate was within normal range and echocardiogram was
normal. A tandem mass spectrometry screen, which included a screen for
carnitine, amino acid and organic acid was within normal limits. Liver
biopsy was reported to have features suggestive of glycogen storage
disorder. She has had a fairly asymptomatic course from then until
recently (at about 7 years of age) when she developed complains of distal
weakness in her upper limbs. This was evidenced by difficulty in fine
motor tasks as in writing and finger grip. On clinical examination, all
anthropometric measurements were noted to be at fifth centile. Liver size
was increased to 7cm below sub costal region. Neuromotor examination
revealed mild weakness of distal muscle with normal deep tendon reflexes
and muscle tone. Prenatal diagnosis was planned for GSD type III.
Investigations comprised of sequencing the AGL gene which identified a
homozygous insertion mutation (c.3110insT) (p.Lys1038GlufsX32) in Exon 25
in the proband. Lys (Lysine) is the first amino acid affected by this
insertion, changing into Glu(Glutamate) and a stop at 32nd position
downstream from this change resulting in frame shift mutation, thereby
introducing a premature stop codon. Following this, both maternal and
paternal samples were sent and both were identified to be heterozygous
carriers of the same mutation. As the mother was in the 16th week of
gestation, prenatal testing by amniocentesis was performed and the DNA
extracted were analyzed. Sequence analysis revealed the fetus was also
homozygous for the same mutation as in the elder sibling and hence was
found to be affected.
Discussion
In a suspected case of GSD type III, ideally there are
two steps in workup, first is the clinical, biochemical (enzyme analysis)
and histopathological studies (liver and muscle) done as a preliminary
step. The second is molecular confirmation of the index case. Chronic
hepatomegaly, hypoglycemia, elevated liver enzymes and serum CPK levels,
prompted us to suspect glycogen storage disorder initially. Further
evidence from a normal echocardiogram, normal blood lactate and pyruvate
and urine ketone were supportive in ruling out other metabolic conditions.
The presence of liver involvement, recent onset of myopathy and a positive
liver biopsy report, GSD Type IIIa was the most probable provisional
diagnosis. Enzyme studies were not done in our case because in this a
prenatal diagnosis warranted an earlier diagnosis. Moreover, it cannot be
correlated with subsequent prenatal testing as in molecular analysis. It
is understood that the AGL gene located on chromosome 1p21 codes for two
enzymes namely, Amylo-1, 6-glucosidase and 1,
4-Alpha-glucotransferase(1,4). Mutations in AGL gene result in enzyme
deficiency causing GSD Type III. Published reports have identified two
mutations, 3964delT and IVS32-12A>G to represent more than 12% of the
molecular defects among GSD IIIa (4). This clearly signifies the
heterogeneous mutation types identified in this disorder. The mutation
identified in this report, c.3110insT in AGL gene is reported for the
first time in a GSD III family; the index child, the parents and in the
fetus for prenatal diagnosis.
The mutation leads to frame shift and a stop codon;
when retrospectively correlated with clinical phenotype and
histopathology; it can be hypothesized that it is likely to be a
pathogenic mutation in GSD Type IIIa. The couple underwent counseling when
several issues including pregnancy decision were discussed. They chose to
terminate the pregnancy subsequently.
Acknowledgment
Prof Kishnani, Duke University Hospital, Durham USA; Dr
D Bali and Dr Catherine Rehder, Pediatrics Genetics laboratory, Division
of Medical Genetics Research, Duke University Hospital, Durham USA; Dr S
Suresh, Fetal Care Research Foundation, Chennai and Dr J Ramalingam,
Tiruchi.
Contributors: SJ managed the patient will
act as guarantor. IV reviewed literature and drafted the manuscript. BL
edited the paper.
Funding: None.
Completing interest: None stated.
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