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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2984_Библиотеки_им_академика_М_И_Перельмана
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
2
ABSTRACT
The prevalence of autosomal recessive diseases in the United Arab
Emirates (UAE) is known to be relatively high, mainly due to the
increase rates of consanguineous marriages among its population.
Lysosomal storage disorders are a group of more than 60 different
inherited metabolic diseases that are collectively considered to be
common in the UAE population. Among the Lysosomal disorders,
mucolipidoses (ML) are classified into four subtypes (I – IV),
characterized by the accumulation of carbohydrates and lipids in different
types of cells to result abnormal function and eventually death.
Symptoms in ML diseases may vary from mild musculoskeletal
symptoms or learning disabilities to severe intellectual impairment and
skeletal deformities. Among the four subtypes of ML, types II and III are
common in the Emirati population and only one case of type IV has been
reported. In contrast, ML type I has not been reported up to date. In this
chapter, cases of different types of ML from the UAE are presented
highlighting the main phenotype/genotype correlations.
1. INTRODUCTION
The term of “ mucolipidosis” was coined in 1970, when Spranger and
Wiedemann defined a group of storage diseases which had signs of both
mucopolysaccharidosis and sphingolipidosis [1]. Mucolipidoses (ML) are a
group of four types of disorders, classified as lysosomal storage diseases
(LSDs), because they accumulate substances in the lysosomes, which are
specialized sac-like components within the cells [2]. The four types of ML
numbered from I – IV are classified according to the type of the mutated
enzyme(s) [3]. ML II and III are caused by mutations in the same gene
(GNPTAB), whereas ML types I and IV are caused by defects in NEU1 and
MCOLN1 genes, respectively [4]. ML type I, also called sialidosis, results
from the deficiency of the lysosomal enzyme sialidase, leading to the
accumulation of its metabolites in various tissues like the brain and bone
marrow [5]. The disease onset is mainly at birth or at early childhood, as
affected children are recognized with coarse facial features and presented
with symptoms like skeletal malformations, cherry-red macules, tremors,
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and seizures. Most infants with ML I have poor prognosis and die before
the age of one year. ML II and III result from deficiencies in
N-acetylglucosamine-1-phosphotransferase enzyme that aids the
transportation process of mannose 6 phosphate dependent lysosomal
enzymes [6]. ML II is a severe form of ML resembling Hurler syndrome,
while ML III is a milder type of the disorder. Like ML I, ML II has an
early onset, while patients affected with ML III often don’t show
symptoms until 3-5 years of age. Genetic defects in the MCOLN1 results in
ML IV, as most of the affected patients present with severe psychomotor
delay, visual impairment, speech problems, intellectual disability,
hypotonia, and spasticity [4]. It also has an early disease onset like type I
and II. Therapeutic options are still unavailable for all ML types. The
storage of undergraded metabolites in ML due to the quantitative and/or
qualitative loss of their corresponding enzymes causes cellular and tissue
dysfunction. Such metabolites may accumulate in various organs like nerve
cells, liver, and muscle tissue as well as in bone marrow leading to a range
of clinical presentations and phenotype based on the type of the
accumulated metabolite and the affected organs [7]. Symptoms may range
from mild skeletal dysfunction to severe intellectual disability and skeletal
deformities [8]. The clinical diagnosis of different ML subtypes can be
challenging due to the similarities in their presentations with another group
of LSDs called mucopolysaccharidoses (MPS). They can be differentiated
via urine analysis where patients with MPS show accumulated
glycosaminoglycans molecules in their urine samples unlike ML patients.
2. UNITED ARAB EMIRATES AND ITS POPULATION
United Arab Emirates (UAE) is one of the six gulf countries located
along the eastern coast of the Arabian Peninsula [9] (Figure 1). It is a
federation of seven emirates that have been united in the 1971 with Abu
Dhabi as the capital of the country which compromises about 87% of the
UAE's total area (Figure 1). The country officially speaks Arabic.
However, most of the population speak other languages of their non-
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
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Arabic origin speaking countries while English is mainly spoken in many
institutions.
Figure 1. The Map of United Arab Emirates showing the surrounding countries (grey
map) and the seven Emirates (coloured map).
The local citizen of UAE has a tribal society of which compromises
more than 70 tribes of different origins. These tribes have taken place in
the UAE as part of the successive waves of population movements from
Yemen, Oman, and the Central and Northern Arabia. In a 2014
phylogenetic study, Garcia-Bertrand, R et al. have found that the Emirati
population is genetically heterogenous [10].
The UAE has the seventh highest migration rate worldwide. The
largest group of non-UAE nationals are South Asian (58%), followed by
other Asians (17%) and Western expatriates (8.5%).
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3. GENETIC DISEASES IN UAE:
FOCUS ON LYSOSOMAL STORAGE DISEASES
Despite the heterogenous mix in the UAE population with the
increasing numbers of immigrants from Oman, Yemen, Middle Eastern
countries, North Africa, Iran, India, Pakistan, Bangladesh, Baluchistan and
Europe, most of the local Bedouins are still form tribal communities which
are quite isolated. Intermarriages with different nationalities are still
limited [9]. The rate of consanguinity in the UAE is high and still
increasing which is estimated to reach up to 50.5% among local citizens
[9]. The custom of consanguinity marriages is mainly due to cultural and
historical reasons not to religious aspects. Such marriages are more stable
and economically beneficial through the conservation of the tribe fortune
that is kept within the family structure [11]. This practice is deeply rooted
in the Arabian culture and very hard to change due to the mentioned
reasons. Therefore, consanguinity resulted in high prevalence of different
genetic disorders, more predominantly autosomal recessive types. Diseases
like, α- and β- Thalassaemia, Sickle Cell Disease, and multiple types of
lysosomal storage diseases (LSDs).
Lysosomes are enclosed cytoplasmic organelles that contain a various
classis of acidic hydrolases that aid the degradation of different biological
components in the cell [12]. The qualitative or quantitative loss of any of
these enzymes will lead to the accumulation of its corresponding substrate,
hence, the occurrence of lysosomal storage disease [13]. To date, more
than 60 different related LSDs have been reported [14]. In the United Arab
Emirates, about 22 different LSD diseases have been reported in the
population with a collective prevalence of 26.9 per 100,000 live births [15,
16] (Table 1). Based on the previously LSDs’ reported cases, most of the
affected individuals were mainly diagnosed with the severe infantile forms,
while the milder adult forms were less common. That can be explained due
to the easier recognition of such forms by their striking clinical
manifestations compared to the milder forms which are easily
misdiagnosed. From the Sphingolipidoses disorders group, GM1-
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
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gangliosidosis reported the highest prevalence among all other lysosomal
storage with 4.7 per 100,000 individuals [15]. Among mucopoly-
saccharidoses (MPS), MPS IIIB, IVA, and VI were found the most
common types with a sum birth prevalence of 5.5 per 100,000. In contrast,
MPS I and II are the most prevalent worldwide [15]. On the other hand,
lipid storage disorders and mucolipidoses diseases prevalence were almost
like the other populations. For Mucolipidoses (ML), the most reported
cases were from type II and III with a prevalence of 1.35 per 100,000 live
births [15] (Table 1). Only one case of ML IV has been reported in the
Emirati population while no cases of ML type I (Sialidosis) have been
recognized to date.
3.1. Mucolipidosis Type II/III: Classification, Molecular
Background and Diagnosis
Mucolipidosis type II and III (known as I‐cell disease and
pseudo‐Hurler dystrophy; respectively) are autosomal recessive inherited
LSDs [8]. Both disorders resulted by the malfunction of
N‐acetylglucosamine (GlcNAc)‐1‐phosphotransferase enzyme which is the
main player in formation of the mannose 6‐phosphate (M6P) residues that
facilitates the transportation of most of the soluble lysosomal enzymes
from the Golgi apparatus to lysosomes through the secretory pathway [17].
The GlcNAc‐1‐phosphotransferase enzyme is composed of three main
subunits that are combined in a hexamer complex. The three subunits are
α‐ and β‐subunits that are expressed via the GNPTAB gene while the γ
subunit is expressed via the GNPTG gene [18]. Both the α‐ and β‐subunits
are first synthesized and assembled in the endoplasmic reticulum (ER) in
their inactive forms that’s gets proteolytically activated in the Golgi
compartment where the γ‐subunit subsequently binds to the activated
complex generating a fully functional enzyme for M6P formation [19].
Lysosomal enzymes are synthesized in the ER as part of the secretory
pathway [20]. The nascent polypeptide chain goes through multiple folding
steps through the aid of a group of ER-residing molecular chaperones and
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acquires a various number of glycosylation moieties on multiple
asparagine residues [21]. Upon their proper folding, these enzymes will be
transported to the cis Golgi network where their high mannose
oligosaccharide chains will be phosphorylated generating a M6P moiety
[17]. In the trans-Golgi, lysosomal enzymes carrying M6P residues will
bind to the M6P receptors expressed on trans-Golgi membrane [22]. Once
bound to M6P receptors, bound enzymes will be taken up via endosomes
budded from the trans-Golgi to be transported to lysosomes by fusion and
fission events of the two compartments [22]. In addition, a small portion of
the synthesized lysosomal enzymes may get exocytosed to the extracellular
milieu where they will be taken back to the cell via M6P receptors
expressed on the plasma membrane via endocytosis to the lysosomes [23].
Mucolipidosis II (MIM #252500) is mainly caused by GNPTAB
genetic modifications but it is characterized by a severe clinical
manifestation. Symptoms have an early onset with fetal and early
childhood occurrence and affected patients usually have short life
expectancy as the disease prognosis is poor [24]. In ML II, genetic variants
in GNPTAB are mostly deleterious resulting in almost complete loss of
GlcNAc‐1‐phosphotransferase enzymatic activity that is comparable to the
patients underlying severe clinical presentation [6]. In contrast, ML III is a
milder form to ML II that is further subclassified to ML III α/β (MIM
#252600) and MLIII γ (MIM #252605) caused by mutations in GNPTAB
and GNPTG, respectively [6]. These forms of the disease have a late onset
of symptoms and relatively better life expectancy. Usually MLIII γ patients
have milder phenotype to patients affected with ML III α/β as most
probably due to higher residual GlcNAc‐1‐phosphotransferase activity.
Mucolipidosis II can be clinically recognized due to its very early
onset that can be as early as in-utero stage. Disease prognosis is poor and
causes death in early childhood. Affected patients mainly present with
severe musculoskeletal deformities (spinal deformity, hip dislocation and
joint contractures) and progressive psychomotor retardation [25]. Most of
the affected patients complain from cardiac problems, of which cardiac
hypertrophy or thickening and insufficiency of the mitral and aortic valve.
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
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Table 1. Prevalence of lysosomal storage disorders in UAE
Disorders
Total No. of
patients
No. of
patients
Prevalence (per
100,000)
Mucopolysaccharidoses (MPS)
MPS I
4
1
0.25
MPS II
2
0
–
MPS IIIB
6
5
1.05
MPS IIIC
1
1
0.25
MPS IVA
4
2
1.41
MPS VI
13
2
2.51
Oligosaccharidoses
α-Mannosidosis
6
5
1.51
β-Mannosidosis
0
0
–
Fucosidosis
3
2
2.02
α-N-acetyl-galactosaminidase defic.
0
0
–
Aspartylglucosaminuria
0
0
–
Sialidosis
0
0
–
Galactosialidosis
0
0
–
Sphingolipidoses
GM1 gangliosidosis
20
14
4.66
Tay-Sachs
7
3
0.74
Sandhoff
10
4
1.21
Galactosialidosis
0
0
–
Metachromatic leukodystrophy
3
2
1.50
Niemann-Pick A
0
0
–
Niemann-Pick B
1
1
0.25
Gaucher (all types)
5
1
a
0.25
Fabry
1
1
0.25
Krabbe
2
0
0
Farber
2
2
0.96
MSD
1
0
0
Lipid storage disorders
Niemann-Pick C
3
1
0.25
Wolman
1
0
–
Mucolipidoses
Mucolipidosis I
0
0
–
Mucolipidosis II/III
11
7
1.35
Mucolipidosis IV
0
0
–
Other LSD disorders
Cystinosis
1
1
0.25
ISSD
0
0
–
Pompe disease
10
8
2.66
b
Batten disease
2
2
3.54
Total
119
65
26.87
MPS: mucopolysaccharidoses, MSD: multiple sulfatase deficiency, ISSD: infantile sialic acid storage
disease. a = Gaucher type 2, b = All cases are the infantile type.
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The most common cause of death in ML II affected patients is respiratory
insufficiency due to progressive narrowing of airways as result of mucosal
thickening and stiffening of thoracic cage [24]. On the other hand, the two
forms of ML III (ML III α/β, MLIII γ) appear with much milder range of
symptoms, later onset, and slower progression. Symptoms like joint
stiffness, skeletal pain, and spinal deformities [6]. The clinical presentation
of ML resemble other storage disease and it should be further confirmed
via biochemical analysis. Due to the reduced activity of GlcNAc‐
1‐phosphotransferase enzyme, different lysosomal enzymes residual
activities are extremely elevated (5 – 10 folds) in patients’ plasma and
dried blood samples compared to low activities in leucocyte or fibroblast
cells. [6]. At the molecular level, targeted sequencing of GNPTAB and
GNPTG genes are required to confirm the clinical diagnosis [6].
3.2. Mucolipidosis IV
Mucolipidosis IV (OMIM #252650) is a rare neurodegenerative
lysosomal storage disorder inherited in an autosomal recessive manner
caused by mutations in MCOLN1 gene that encodes for the Zn
2+
lysosomal
channel mucolipin-1 [26]. Genetic defects in the gene will result in the
overload of lysosomal Zn
2+
that is thought to be the main reason for the
ML IV pathology resulting in the accumulation of different lipids and
proteins in cytoplasmic vacuoles derived from lysosomes [26, 27]. About
70 – 80% of reported ML IV related mutations were detected in the
Ashkenazi Jews [28]. Most of ML IV patients are clinically recognized
with severe cognitive impairment, eye abnormalities, increased blood
gastrin levels, and iron deficiency anaemia. Unlike most LSDs, ML IV
patients’ usually have normal lysosomal enzymes activities and eventually
normal levels of mucopolysaccharides and oligosaccharides in their
urine/blood samples [29]. Neurological manifestations are common in ML
IV patients who are mainly presented with spasticity, hypotonia, and
inadequate mobility.
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Fedah E. Mohamed, Jozef Hertecant, Fatma Al-Yahyai et al.
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In addition to the clinical examination, ML IV is further confirmed via
multiple molecular and biochemical analyses. Elevated blood gastrin levels
is commonly used to confirm ML IV which is combined with MRI
imaging showing a thin corpus callosum which a major feature in ML IV
patients [30]. Using fibroblast cells, ML IV cells show cytoplasmic
inclusions under electron microscopy. A clear cut of the diagnosis can be
confirmed via targeting sequencing of the MCOLN1 gene.
4. CLINICAL CASES FROM THE UAE
In this section of the chapter, multiple ML cases from the Emirati
population as well as cases from UAE residents of various nationalities are
discussed.
4.1. Family 1
A 2-year-old female presented with coarse facial features, failure to
thrive, developmental delay, recurrent chest infection, obstructive sleep
apnea, skeletal deformities, and inguinal hernia. Genetic analysis has
revealed a homozygous dinucleotide deletion GNPTAB gene. Together, the
genetic testing, enzymatic analysis, and the patient severe progressive
clinical presentation confirmed that the patient is affected with ML type II.
Due to the disease progression, the child passed away at 2 years of age as a
result of respiratory failure.
4.1.1. Clinical Presentation and Phenotype
The clinical presentation of the proband was consistent with the
diagnosis of Mucolipidosis type II. She presented with coarse facial
feature, corneal clouding, shallow orbit, gingival hypertrophy, failure to
thrive, skeletal manifestations “lordosis, finger contracture”,
developmental delay, at two years of age, she was able to walk in her
walker, sit alone for few seconds, and speak using 6 words only.
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Mucolipidosis Disease in the United Arab Emirates
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Polysomnography study consistent with the diagnosis of severe degree
of obstructive sleep apnea complicated by frequent oxygen desaturation to
less than 50% with severe sleep fragmentation and disturbed sleep
architecture. Status post adenoidectomy, there were no improvement in her
symptoms and still suffering from the same noisy breathing and snoring
with frequent sleep apnea. CPAP or tracheostomy was recommended.
Parents declined tracheostomy and patient did not have access to paediatric
size CPAP machine. Echo showed pulmonary hypertension and thickened
mitral valve leaflets with Mild Mitral Regurgitation, thickened aortic valve
leaflets, and mild TR with RVSP = 40-45 mmHg (estimated 45% of
systemic). Therefore, she had severe progressive obstructive sleep apnea
and secondary pulmonary hypertension which was managed with
lisinopril. She had several hospitalizations because of recurrent respiratory
tract infection and eventually died at 2 years of age post cardiorespiratory
arrest, diabetes insipidus and severe hypoxic encephalopathy.
Figure 2. In silico analysis of c.3503_3504delTC ML II disease causing variant.
4.1.2. Biochemical and Molecular Analysis
GNPTAB gene full sequencing revealed a dinucleotide deletion in exon
19 of the gene. The detected deletion interferes with the normal reading
frame resulting in a frame shift mutation that lead to the generation of a
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