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<title>A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report</title>
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Al-Owain et al. Orphanet Journal of Rare Diseases 2010, 5:7
http://www.ojrd.com/content/5/1/7
Open Access
CASE REPORT
A novel mutation and first report of dilated
cardiomyopathy in ALG6-CDG (CDG-Ic): a case
report
Case Report
Mohammed Al-Owain*†1,2, Sarar Mohamed†3, Namik Kaya4, Ahmad Zagal3, Gert Matthijs5 and Jaak Jaeken6
Abstract
Congenital disorders of glycosylation (CDG) are an expanding group of inherited metabolic diseases with multisystem
involvement. ALG6-CDG (CDGIc) is an endoplasmatic reticulum defect in N-glycan assembly. It is usually milder than
PMM2-CDG (CDG-Ia) and so is its natural course. It is characterized by psychomotor retardation, seizures, ataxia, and
hypotonia. In contrast to PMM2-CDG (CDGIa), there is no cerebellar hypoplasia. Cardiomyopathy has been reported in
a few CDG types and in a number of patients with unexplained CDG. We report an 11 year old Saudi boy with severe
psychomotor retardation, seizures, strabismus, inverted nipples, dilated cardiomyopathy, and a type 1 pattern of serum
transferrin isoelectrofocusing. Phosphomannomutase and phosphomannose isomerase activities were normal in
fibroblasts. Full gene sequencing of the ALG6 gene revealed a novel mutation namely c.482A>G (p.Y161C) and
heterozygosity in the parents. This report highlights the importance to consider CDG in the differential diagnosis of
unexplained cardiomyopathy.
Introduction
Inborn errors of metabolism (IEM) account for only 5%
of all pediatric cardiomyopathy and 15% of patients with
known causes. More than 40 different IEM involving cardiomyopathy exist, including energetic diseases with fatty
acid oxidation defects and mitochondrial respiratory
chain defects, organic acidurias, glycogen storage diseases, lysosomal storage disorders and congenital disorders of glycosylation [1]. Cardiomyopathy has been
reported in PMM2-CDG (The novel CDG nomenclature
is used ie the non-italicized gene symbol followed by: CDG [2,3]), ALG12-CDG (CDG-Ig), DK1-CDG (CDGIm) and COG7-CDG (CDG-IIe), as well as in patients
with an unexplained CDG. Both hypertrophic and dilated
cardiomyopathies have been described in CDG, with no
common pattern observed in a particular CDG [4].
Congenital disorders of glycosylation (CDG) are a rapidly growing group of inherited metabolic disorders due
to defects in the synthesis of glycans and their attachment
to proteins and lipids [5]. They show a broad range of
clinical manifestations and may be highly variable within
the same subtype and even among affected siblings [6,7].
The method of choice for screening of these disorders is
still isoelectrofocusing of serum transferrins (IEF) [8].
The N-glycosylation defects can be divided in two
groups: CDG-I caused by dysfunction of glycan assembly,
and CDG-II, caused by abnormal glycan processing
[9,10]. CDG-I patients usually show a type 1 serum transferrin IEF pattern, and CDG-II patients a type 2 pattern.
ALG6-CDG (MIM #603147) is caused by defects in the
ALG6 gene coding for Dol-P-Glc:Man9-GlcNAc2-P-PDol glucosyltransferase (glucosyltransferase 1). It is as a
rule milder than PMM2-CDG (CDGIa) and is characterized by psychomotor retardation, axial hypotonia, seizures, ataxia, strabismus, feeding difficulties and a very
low serum cholesterol and clotting factor XI [11-14].
Other reported features include retinal degeneration [10],
deep vein thrombosis, and pseudotumor cerebri [15].
Here we report a Saudi child with ALG6-CDG and
dilated cardiomyopathy caused by a novel mutation.
* Correspondence: [email protected]
Patient Report
A 9 year old Saudi boy (Fig. 1) was referred for evaluation
of psychomotor retardation, hypotonia and dilated cardi-
1
Department of Medical Genetics, King Faisal Specialist Hospital and Research
Centre, Riyadh, Saudi Arabia
† Contributed equally
Full list of author information is available at the end of the article
© 2010 Al-Owain et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
BioMed Central Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Al-Owain et al. Orphanet Journal of Rare Diseases 2010, 5:7
http://www.ojrd.com/content/5/1/7
Figure 1 The patient at the age of 9 years. Note the low hairline,
broad nasal bridge, hypetelorism, bilateral strabismus, large ears, wide
mouth, thin upper lip, and widely spaced inverted nipples.
omyopathy. He was born at 40 weeks gestation after a
normal pregnancy and delivery with a birth weight of 4.6
kg. Hypotonia without feeding problems was noted in the
neonatal period, bilateral alternating squint at two
months of age, and hypokinesia at four months of age. At
one year of age, he developed febrile seizures followed by
afebrile partial epilepsy that responded well to carbamazepine. At three years of age, he presented with recurrent episodes of difficulty breathing and fatigability.
Chest X-ray revealed cardiac enlargement with increased
pulmonary vascularity. Echocardiography showed moderate dilatation and dysfunction of the left ventricle (LV).
The end-systolic LV dimension was 3 (1.7-2.5 cm) corresponding to a Z-score of 4.3, while the end-diastolic LV
dimension was 4.2 (2.9-3.9 cm) and the Z-score was 3.4.
The ejection fraction and ejection fraction shortening
were slightly subnormal at 56% and 27%, respectively.
The interventricular septum thickness was normal. There
was no mitral regurgitation and no pericardial effusion.
These findings confirmed moderate cardiomyopathy of
the dilated type. He was subsequently placed on captopril
at a dose of 6.25 mg three times daily that was continued
for five years. Captopril was just recently weaned off with
stabilization of the cardiac function. At the age of 6 years,
he was not able to sit unsupported, was nonverbal and is
completely dependent on the family for care. On physical
examination at the age of 7 years, the child was wheelchair bound with severe mental retardation and no
speech. His head circumference and weight were on the
50 centile. His height was on the 25 centile. He had
brachycephaly, bilateral esotropia, coarse hair with double hair whorl, low anterior hair line, broad nasal bridge,
widely spaced eyes, prominent large ears, short philtrum,
wide mouth with a thin upper lip, small teeth, widely
Page 2 of 4
spaced inverted nipples, bilateral cryptorchidism,
reduced muscle bulk and tone with axial hypotonia. Deep
tendon reflex were difficult to elicit. Finger joints were
hyperextensible but knees and hips showed limited joint
extension. Routine laboratory investigations showed normal urinalysis, normal complete blood count, blood glucose, thyroid and kidney function tests, serum amino
acids, lactate, acylcarnitine profile, and urine organic
acids. Serum GOT was 37 (17-59 U/L), GPT 24 (21-72 U/
L). Cholesterol and clotting factor XI were not available.
CSF examination was normal for cells, protein, glucose
and lactate. Brain MRI revealed widening of CSF spaces
and ventricular system with normal brain stem and cerebellum. EMG, nerve conduction velocity, funduscopy,
hearing assessment and abdominal ultrasound were normal. Serum transferrin IEF showed a type 1 pattern.
Phosphomannomutase
2,
and
phosphomannose
isomerase activities were normal in fibroblasts. Molecular genetic testing diagnosed ALG6-CDG with a novel
mutation namely c.482A>G (p.Y161C).
The family history revealed that the patient was the
fourth child born to healthy consanguineous parents, and
he had two healthy siblings. His elder sister died at 7 years
of age with a similar but more severe syndrome comprising microcephaly, deafness, blindness, severe psychomotor retardation and intractable seizures. She had no
cardiac symptoms. She was investigated thoroughly for
metabolic disorders including mitochondrial disorders
and chromosomal abnormalities; however, no diagnosis
was made at that time.
Discussion
ALG6-CDG is the second most frequently described Nglycosylation defect besides PMM2-CDG. At least 30
patients have been diagnosed [16]. Twenty one different
mutations are listed in the Human Genome Mutation
database http://www.hgmd.cf.ac.uk: sixteen point mutations, four deletions (including a large deletion enclosing
the complete ALG6 gene), and one insertion. The
c.998C>T (p.Ala333Val) mutation accounts for the
majority of the alleles. The present patient is homozygous
for a previously not reported mutation. The mutation
found in this study is highly likely to be pathogenic for the
following reasons a) PANTHER[17], POLYPHEN[18],
and SIFT[19] bioinformatics tools all predicted that the
change be deleterious and probably damaging, b) tyrosine
in position p. 161 is phylogenetically conserved. His clinical presentation comprises the known features of ALG6CDG: axial hypotonia, moderate to severe psychomotor
retardation, strabismus, epilepsy, without hepatomegaly,
proteinuria, retinopathy and cerebellar hypoplasia. However, in addition, he shows dilated cardiomyopathy, a feature previously not reported in ALG6-CDG. The severity
of the dilated cardiomyopathy in the present patient was
Al-Owain et al. Orphanet Journal of Rare Diseases 2010, 5:7
http://www.ojrd.com/content/5/1/7
moderate and required long-term cardiac treatment with
captopril.
Cardiomyopathy (hypertrophic and dilated) has been
reported in PMM2-CDG [20-25], in ALG12-CDG [26], in
DK1-CDG [27], and in COG7-CDG [28], as well as in a
number of patients with an unexplained CDG (CDG-Ix
and CDG-IIx) [4,21,29-33]. The age of diagnosis of cardiomyopathy in reported cases ranged from the first week
of life to 7 years of age, and in a few cases it was detected
prenatally [2,25,31]. In addition, this is the first report of
CDG from Saudi Arabia and it is likely that this condition
is underdiagnosed in this region often due to poor access
to appropriate metabolic and genetic testing.
In conclusion, we present the first case of ALG6-CDG
associated with mild dilated cardiomyopathy due to a
novel mutation in the ALG-6 gene. We feel from this
report and along with previous reports that patients with
unexplained (particularly syndromatic) cardiomyopathy
should be investigated for CDG.
Consent
Written informed consent was obtained from the
patient's parents for publication of this case report and
accompanying images. A copy of the written consent is
available for review by the Editor-in-Chief of this journal.
Page 3 of 4
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Abbreviations
CDG: congenital disorder(s) of glycosylation; IEF: isoelectrofocusing; IEM:
Inborn errors of metabolism.
15.
Competing interests
The authors declare that they have no competing interests.
16.
Authors' contributions
MA, SM, AZ and JJ were involved in the clinical evaluation and follow-up of the
patient, the data analysis and interpretation, and drafted the manuscript. GM
carried out the molecular genetic studies and the interpretation of the results.
NK assisted in performing the bioinformatics analysis and was involved in the
write-up of the manuscript. All authors read and approved the final manuscript.
Author Details
1Department of Medical Genetics, King Faisal Specialist Hospital and Research
Centre, Riyadh, Saudi Arabia, 2College of Medicine, Alfaisal University, Riyadh,
Saudi Arabia, 3Department of Pediatrics, Saad Hospital, Al-Khobar, Saudi Arabia
, 4Department of Genetics, King Faisal Specialist Hospital and Research Centre,
Riyadh, Saudi Arabia, 5Center for Human Genetics, University Hospital
Gasthuisberg, Leuven, Belgium and 6Center for Metabolic Disease, University
Hospital Gasthuisberg, Leuven, Belgium
17.
18.
19.
20.
21.
22.
Received: 30 December 2009 Accepted: 16 April 2010
Published: 16 April 2010
© 2010 Al-Owain et Rare Diseases 2010, Central Ltd. terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access licensee BioMed 5:7
Orphanet Journal of al; from: http://www.ojrd.com/content/5/1/7
article is available article distributed under the
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doi: 10.1186/1750-1172-5-7
Cite this article as: Al-Owain et al., A novel mutation and first report of
dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report Orphanet Journal of Rare Diseases 2010, 5:7
Page 4 of 4
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