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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
22
with irregular articular surface, in addition to extensive subarticular fatty
changes with no signs of acute ischemia. There are also extensive
osteoarthritic changes.
Figure 8. Family 6 MLIII characterization. A) Wild type GNPTG gene and its
corresponding N- acetylglucosamine-1-phosphate transferase gamma subunit protein
sequences. In red, the wild type codon at which the insertion was detected. B) Family 6
MLIII characterization. Sequences of the mutated gene and protein due to the insertion
of C nucleotide at the DNA level leading to a frame shift and the generation of a
premature stop codon at the protein level.
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Mucolipidosis Disease in the United Arab Emirates
23
4.6.2. Biochemical and Molecular Analysis
Based on the clinical symptoms, the proband’s GNPTG gene was fully
sequenced via Sanger Sequencing which revealed a novel homozygous
c.499_500insC. The detected variant was segregated from the patient’s
parents who were heterozygous carriers while his two female siblings were
positive for variant in a homozygous state. At the protein level, the
detected insertion interrupts the gene reading frame resulting in a frame
shift starting from the Leucine amino acid at 167 (p.L167fs*30) that will
generate a premature stop codon after 31 amino acids leading to the loss of
a big chunk of the protein (108 amino acids) (Figure 8A,B). Furthermore,
affected individuals had lysosomal enzymes analysis which was 10-30
folds increased in serum samples and about low/normal borderline in
leukocyte cells (Table 4).
Table 4. Lysosomal enzymatic analysis in affected individuals’
serum samples
Patient
Control
Family A
Family B
Patient 1
Patient 2
Patient 3
Patient 4
Hexosaminidase (A+B)
96
2623
2841
3148
2350
β-Glucoronidase
10
105
105
105
-
4.7. Family 7
The proband is a 6-years-old female with a confirmed diagnosis of
Mucolipidosis type IV. She has been clinically evaluated with global
developmental delay, hypotonia, anemia, thrombocytopenia, and abnormal
ophthalmological findings. Her parents are first cousins of Persian descent
(Figure 9A). She has two older sisters, one of which was reported with
thrombocytopenia in infancy that has resolved. She has two maternal
cousins evaluated with isolated speech delay.
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
24
Figure 9. Characterization of an ML IV family with MCOLN1 mutation. A) Family
pedigree B) Sequences of wild type and mutated MCOLN1 gene and mucolipin-1
protein showing the underlying detected missense mutation in exon 3 of the gene and
its corresponding amino acid substitution at position 102.
4.7.1. Clinical Phenotype
The proband was born after an uneventful pregnancy and delivery at
term by spontaneous vaginal delivery with a birth weight of 2.9 kilograms.
There were no immediate postnatal complications and she was discharged
home after her first day of life. After three days, she was readmitted to the
neonatal care unit due to neonatal jaundice with indirect hyperbili-
rubinemia. She was also noted to have low platelets of 38 x10
^9
/L. She
underwent phototherapy and her bilirubin levels were monitored for 5 days
after which she was discharged with an acceptable platelets level of
77x10
^9
/L. Subsequently, she was followed in the haematology clinic for
thrombocytopenia which was thought to be immune mediated. She first
came to medical attention when she was presented at the age of 16 months
with concerns of delayed walking. There is no clear history of motor
regression. She was able to sit unsupported at the age of one year. She
crawled at two years and started to stand with support and cruise at age
four years. She can feed herself finger foods and drink from a cup.
However, she has no pincer grasp. Currently she is unable to stand or walk
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Mucolipidosis Disease in the United Arab Emirates
25
independently and fully wheelchair dependent. Her parents describe slow
improvement with physical therapy. In terms of speech development, there
is possible regression since she was previously able to say "dada" and the
names of her siblings, but she has currently lost this skill and is unable to
say any words. Her mom relates this to episode of high fever at age of 1
year after which she lost speech. She has recently started to vocalize, but
still communicates mainly via pointing and gestures. She is not toilet
trained. There are no behavioural concerns except for occasional
irritability. She has not had any major hospitalizations or chest infections.
She had a hearing assessment (auditory brainstem response) which was
normal. Subsequently due to hypotonia, she had a swallowing assessment
which showed delayed swallow and she is currently fed a regular diet
orally with no concerns. Her haematological parameters continue to show a
microcytic hypochromic anaemia with a haemoglobin ranging from 72 to
101 g/L. Her serum iron levels were low; therefore, she was commenced of
iron supplementation which helped to raise her iron level slightly. Platelet
levels ranged from 36 - 76 x10
^9
/L. Brain MRI performed at two years of
age showed a thin hypo-plastic corpus callosum with normal ventricles
associated with diffuse altered signal intensities in the white matter with
hyper intensities on FLAIR sequences. Eye exam revealed strabismus with
clear lens bilaterally. Systemic exam of the chest and abdomen was
normal. There was no detected organomegaly.
4.7.2. Biomedical and Molecular Analysis
The child underwent whole exome sequencing which identified a
previously reported ML IV causing point mutation (c.304C > T) in exon 3
of the MCOLN1 gene in a homozygous pattern. At the protein level, the
detected genetic variant results in the generation of premature stop codons
where protein translation is terminated at position 102 (p.R102X) leading
to the loss of more than two third of the total size of the protein (478/580
amino acids) (Figure 9B). The underlying variant was segregated from
both parents who were heterozygous carriers for the detected change. The
ML cases in UAE is summarized in Table 5.
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Table 5. Summary of ML cases in UAE
Family
Proband’s
age of
onset
ML
type
Mutated
gene
Detected variant
Age of
Death
No. of
affected cases
in family
Main phenotype
Ethnicity
DNA
Protein
1
NA
(female)
II
GNPTAB
c.3503_3504delTC
p.Q1167fs*4
2 years
-
- Congenital mitral insufficiency
- Developmental delay
- Failure to thrive
- Obstructive sleep apnea
Emirati
2
Prenatal
(male)
II
GNPTAB
c.3503_3504delTC
p.Q1167fs*4
2 years
-
-Dysmorphic features
-Developmental delay
Pakistani
3
15
months
female
II
GNPTAB
c.1567T > C
p.C523R
4 years
1
- Coarse facial features
- Severe skeletal deformities with joint
restrictions
-Developmental delay
Egyptian
4
2-year
female
III
GNPTAB
c.1567T > C
p.C523R
-
4
- Late onset of skeletal symptoms
began complaining of joint stiffness
and loss of flexibility
Emirati
5
(NA)
female
III
GNPTG
IVS7-10G > A
(g.11120G > A in
intron 7)
p.V176Gfs*18
-
1
- Multiple joints contractures since
early life
Emirati
6
5-year
male
III
GNPTG
c.499_500insC
p.L167fs*30
-
3
- Progressive stiffness in joints
- No facial dysmorphism
- Normal development
Pakistani
7
16
months
female
IV
MCOLN1
c.304C > T
p.R102X
-
-
- Global developmental delay
- Hypotonia
- Anemia and thrombocytopenia
- Abnormal ophthalmological findings
Persian
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Mucolipidosis Disease in the United Arab Emirates
27
CONCLUSION
Like most of LSDs, ML of all types are very rare disorders that are
often evades diagnosis. Although the cases are increasing in this region,
little clinical knowledge is known about these diseases. Further analysis is
urgently needed to better understand and differentiate the subtypes of these
disorders clinically as well as find a better phenotype-genotype correlation.
Although multiple cases were reported with the same genotype, their
clinical presentation and disease progression are totally different. As
reported from families 3 and 4 mentioned in this chapter, both were
reported with the point mutation (c.1567T > C) in their GNTPAB gene, but
family 3 was diagnosed with the ML II resulting in early childhood death,
while the same genetic variant resulted in the milder ML III in family 4
with several affected individuals reaching their late 20s who are university
graduates.
To date, there is no approved treatment for ML diseases and patients
are mainly under supportive management to ameliorate the underlying
symptoms, which is mainly because of the limited knowledge available
about these diseases due to its rarity. Thus, genetic counselling in families
with known history of these diseases is crucial to prevent its occurrence
and help the families to take correct decisions toward future marriages and
pregnancies.
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In: Neurochemistry of Metabolic Diseases ISBN: 978-1-53618-339-9
Editor: Sankar Surendran © 2020 Nova Science Publishers, Inc.
Chapter 2
SIALIDOSIS AND GALACTOSIALIDOSIS:
MOLECULAR MECHANISM
AND THERAPEUTIC EFFECT
Consolato M. Sergi
Department of Laboratory Medicine and Pathology,
University of Alberta, Edmonton, AB, Canada and
Stollery Children’s Hospital, Edmonton, AB, Canada
ABSTRACT
More than 40 years ago, two patients with clinical features
reminiscent of mucopolysaccharidosis Type IH (MPS-IH), Hurler’s
disease, characterized by an accumulation of glycosaminoglycans or
mucopolysaccharides in lysosomes, presented in pediatrics. Both patients
had, however, a normal urinary excretion of acid mucopolysaccharides.
The histological and ultrastructural examination of neurons, as well as
Corresponding Author’s Email: sergi@ualberta.ca.
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