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Indian Pediatr 2017;54: 775 -776 |
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Glycogen Storage Disease Type VI With a
Novel Mutation in PYGL Gene
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Barath Jagadisan and *Prajnya Ranganath
From the Department of Pediatrics, JIPMER, Puducherry; and
*Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics,
Department of Medical Genetics, Nizam’s Institute of Medical Sciences,
Hyderabad; India.
Correspondence to: Dr Barath Jagadisan,
Associate Professor, Department of Pediatrics, JIPMER, Puducherry 605
006, India. Email:
[email protected]
Received: December 03, 2016;
Initial review: March 02, 2017;
Accepted: July 05, 2017.
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Background: Glycogen storage disease type VI (GSD-VI) presents with
failure to thrive and also fibrosis in some cases, without cirrhosis.
Case characteristics: 2½-year-old girl presented with short stature,
transaminase elevation and significant fibrosis, suggesting GSD-III.
Observation: A pathogenic mutation in PYGL gene suggested
GSD-VI. Message: GSD-VI should be a differential diagnosis
whenever GSD-III is suspected.
Keywords: Chronic liver disease, Mutation analysis, Storage
disorders.
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G lycogen storage disease type VI (GSD-VI) (OMIM #
232700) is an inherited disorder of glycogen metabolism. It has an
autosomal recessive pattern of inheritance and is caused by homozygous
or compound heterozygous mutations in the PYGL gene on chromosome
14q22.1, that codes for liver glycogen phosphorylase [1]. It has an
estimated world-wide prevalence of 1 in 1,00,000. We report here a
mutation-confirmed case of GSD VI with significant fibrosis.
Case Report
A 2-year-5-month-old, developmentally normal female
child was brought with complaints of progressive abdominal distension
noticed since one year of age. There was no history of fever, vomiting,
loose stools or constipation. Jaundice or bleeding manifestations were
absent. Poor weight- and height-gain were noticed since infancy. There
were no seizures, altered sensorium, early morning lethargy or earlier
hospital admissions. The child was the first-born of second-degree
consanguineous parents. There was no similar illness in the family. She
had a cherubic facies. There was no pallor, icterus or clubbing. The
height (74 cm) and weight (8.45 kg) were less for the age
(weight-for-age z-score was -3.4; height-for-age z-score was -4.7). A
firm hepatomegaly was palpable 12 cm below the costal margin. The spleen
was not palpable.
The haematological workup, serum electrolytes,
bilirubin, creatinine, International Normalized Ratio, uric acid, and
Creatinine phospho kinase (and its MB component) were within normal
range. The child had serum aspartate trans-aminase of 445 IU/L, serum
alanine aminotransferase of 484 IU/L, serum alkaline phosphatase of 813
IU/L, serum albumin of 4.2 g/dL, serum total protein of 7 g/dL. Serum
triglycerides were 854 mg/dL and serum cholesterol was 249 mg/dL.
Fasting blood glucose was 60 mg/dL and serum bicarbonate was 23 meq/L.
Ultrasound showed hepatomegaly without any adenoma or nodularity and
normal-sized kidneys. Liver biopsy showed mildly distorted architecture.
Hepatocytes were swollen with rarefaction of cytoplasm, prominent cell
membrane and centrally placed nucleus. Portal tracts showed mild to
moderate inflammatory infiltrate composed predomi-nantly of lymphocytes
and few neutrophils. There was fibrous expansion of portal tracts with
porto-portal bridging and occasional incomplete nodule.
Periodic-Acid-Schiff staining positivity with diastase-sensitivity was
present. Esophago-gastroduodenoscopy did not show varices. Type-III GSD
was suspected. Uncooked cornstarch fourth hourly with high protein diet
and restriction of refined sugars was advised.
Molecular genetic testing was done through Next
generation sequencing-based multigene panel testing for the GSD-related
genes. Following targeted gene capture using a custom capture kit,
sequencing was done with the Illumina sequencing platform (Illumina
Inc., San Diego, California, United States). A homozygous nonsense
variation c.1297 G>T (p.Glu433Ter) was identified in exon 11 of the
PYGL gene. Sanger sequencing of exon 11 of the PYGL gene
confirmed the presence of this homozygous pathogenic variant in the
proband and heterozygous carrier status in her father; her mother was
not available for testing. The p.Glu433Ter mutation in the PYGL
gene is a variant, not previously reported in mutation databases such as
the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/.
Accessed November 10, 2016) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/.
Accessed November 10, 2016), which is expected to result in a stop codon
and premature truncation of the protein at the 433 rd
amino acid position. This variant was not present in the 1000 Genome (http://phase3browser.1000genomes.org/.
Accessed November 10, 2016) and Exome Aggregation Consortium databases (http://exac.broadinstitute.org/.
Accessed November 15, 2016), thereby confirming that it was not a known
polymorphism. The pathogenicity of this variant was inferred based on
the results of the mutation prediction software Polyphen-2 (http://www.ngrl.org.uk/Manchester/page/polyphen-2-polymorphism-phenotyping-version-2.
Accessed November 15, 2016), Mutation Taster (www. mutationtaster.org.
Accessed November 15, 2016) and SIFT (http://sift.jcvi.org/.
Accessed November 15, 2016).
The child was continued on the above diet and after a
year the weight was 9.9 kg and height 80.5cm. There was no adenoma at
1-year follow-up.
Discussion
GSD VI presents with hepatomegaly, failure to thrive
and short stature as seen in the index case. Hypoglycemia may be mild to
moderate; it is present only in 5% of larger cohorts and was absent in
the child. The heart and skeletal muscles are usually normal [2]. The
intellectual ability and development is found to be normal, as in the
propositus. Around 86-90% of GSD VI patients have serum transaminase
elevation [2]. Hyper-cholesterolemia and hypertriglyceridemia was
present in the girl as in 67%, and 76%, respectively of a cohort of 21
patients reported from Canada. Incomplete nodules were already present
in liver biopsy in the propositus. Even though fibrosis is known to be
present in GSD VI, cirrhosis is uncommon. In the cohort reported by
Roscher, et al. [2], GSD VI and GSD IX were mistaken for GSD III
and also GSD IV which usually presents with significant inflammation and
fibrosis. The child needs further follow-up over years to assess the
progression of the fibrosis.
Uncooked cornstarch and restriction of refined sugars
is essential in managing these children. The prognosis is usually good.
Failure to thrive or short stature have been shown to normalize in 84%
of treated patients even though 93% do not show improvement in
hepatomegaly [2]. GSD.VI is known to develop hepatic adenoma in
follow-up and in some cases hepatocellular carcinoma and focal nodular
hyperplasia [2-4].
Around 40 different mutations in the PYGL gene
have been reported world-wide, including point mutations, splice site
mutations and deletions [2]. Mutations in the intron 13 splice donor
site of the PYGL gene have been detected in upto 3% of
chromosomes in a Mennonite population, based on which targeted mutation
testing is used to detect the disease and carrier state in this
population [5]. The mutation reported in our patient has not been
reported earlier.
GSD VI, an important differential diagnosis of GSD
III, has not been reported from India possibly because GSD VI can be
mistaken for type III on liver biopsy [2]. With the easier availability
of genetic testing in India, this case underscores the need for mutation
analysis in all cases for correct diagnosis, accurate prognostication
and management along with appropriate genetic counseling and prenatal
diagnosis.
Contributors: Both authors contributed to the
manuscript and approved the final manuscript.
Funding: None; Competing interest: None
stated.
References
1. Burwinkel B, Bakker HD, Herschkovitz E, Moses SW,
Shin YS, Kilimann MW. Mutations in the liver glycogen phosphorylase gene
(PYGL) underlying glycogenosis type VI (Hers disease). Am J Hum.
1998;62:785-91.
2. Roscher A, Patel J, Hewson S, Nagy L, Feigenbaum
A, Kronick J, et al. The natural history of glycogen storage
disease types VI and IX: long-term outcome from the largest metabolic
center in Canada. Molec Genet Metab. 2014;113: 171-6.
3. Ogawa A, Ogawa E, Yamamoto S, Fukuda T, Sugie H,
Kohno Y. Case of glycogen storage disease type VI (phosphorylase
deficiency) complicated by focal nodular hyperplasia. Pediatr Int.
2010;52:e150-3.
4. Manzia TM, Angelico R, Toti L, Cillis A, Ciano P,
Orlando G, et al. Glycogen storage disease type Ia and VI
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Proc. 2011;43:1181-3.
5. Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker
LG. Identification of a mutation in liver glycogen phosphorylase in
glycogen storage disease type VI. Hum Molec Genet. 1998;7:865-70.
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