498 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (6): 498-502
INTRODUCTION
Metabolic diseases or inborn errors of metabolism (IEM)
are significant cause of mortality and morbidity among
children in both the developed and developing countries.
The variety and complexity of IEM along with diverse
clinical pictures present a formidable challenge to the
treating paediatrician. At the same time, prevention of
death or severe neurological sequelae is dependent on
prompt and early diagnosis. These inherited disorders
are caused by genetic mutations leading to defective
protein function. Most are inherited in autosomal
recessive pattern and few are X-linked recessive
disorders. In Pakistan, it is reported that more than half
of all marriages (56%) are between first and second
cousins.
1
Consanguinity increases the risk of these rare
genetic recessive disorders.
2
The prevalence of IEM in various countries varies
between 1 in 800 to 1 in 5000.
3
In one study from UK,
the overall incidence of recorded IEM was 10-fold
greater among Pakistanis compared to white children
(1:318 vs. 1:3760). Tyrosinemia type-1, cystinosis,
mucopolysaccharidosis type-1, non-ketotic hyper-
glycinemia and hyperchylomicronaemia, all occurred
more frequently among the Pakistanis.
4
There is no
reported study regarding incidence of metabolic
disorders from Pakistan. That may be, in large part, due
to non-availability of comprehensive testing for
diagnosis of these disorders.
The objective of this study was to determine frequency,
presentation and outcome of various inherited metabolic
diseases in children presenting in a tertiary care hospital
in Lahore, Pakistan.
METHODOLOGY
It was an observational study conducted at the
Department of Paediatric Gastroenterology and
Hepatology at The Children's Hospital, The Institute of
Child Health, Lahore, and included all children with high
suspicion of a metabolic disorder (inborn errors of
metabolism) from November 2011 to October 2014.
Complete history, physical examination and routine
specific laboratory investigations were recorded.
Routine laboratory investigations included: CBC, blood
sugar, serum electrolytes, anion gap, serum calcium, PT,
ORIGINAL ARTICLE
Spectrum of Inherited Metabolic Disorders in Pakistani Children
Presenting at a Tertiary Care Centre
Huma Arshad Cheema, Hassan Suleman Malik, Arit Parkash and Zafar Fayyaz
ABSTRACT
Objective: To determine the frequency, presentation and outcome of various inherited metabolic diseases in children
presenting in a tertiary care hospital, Lahore, Pakistan.
Study Design: An observational study.
Place and Duration of Study: Gastroenterology, Hepatology and Nutrition Department of The Children Hospital and
Institute of Child Health, Lahore, from January 2011 to October 2014.
Methodology: All children aged < 14 years with high suspicion of a metabolic disorder were inducted. Routine and
radiological investigation were carried out at the study place. Comprehensive diagnostic testing of particular metabolic
disorder was sent abroad. Those with a specific metabolic disorder were included in the study while those with normal
metabolic work-up were excluded. All data was collected on preformed proforma.
Results: A total of 239 patients were enrolled. Nineteen different types of inherited metabolic disorders were diagnosed
in 180 patients; age ranged from 8 days to 14 years. Consanguinity was positive in 175 (97%) among the parents of the
affected children, with previously affected siblings in 64 (35.5%). The most frequent disorders were inherited disorders of
carbohydrate metabolism (92, 51%), lipid storage disease (59, 32.7%), organic acidemia and energy defects (18, 10%),
amino acid disorder (6, 3.3%), and miscellaneous (4, 2.2%). Fifty-eight (32.2%) presented with acute metabolic crisis, 28
(15.5%) patients presented with early onset liver failure, and 24 (13.3%) with mental retardation. Out of these, 16 (8.8%)
expired.
Conclusion: Glycogen storage disorders being the commonest followed by Gaucher disease and Galactosemia.
The associated complications resulted in high morbidity and mortality.
Key Words: Metabolic disorders. Gaucher's disease. Galactosemia. Pakistan.
Department of Gastroenterology, Hepatology and Nutrition,
The Children Hospital and Institute of Child Health, Lahore.
Correspondence: Prof. Dr. Huma Arshad Cheema, Head of
the Department of Gastroenterology, Hepatology and Nutrition,
The Children Hospital and Institute of Child Health, Lahore.
E-mail: pedliverunit@gmail.com
Received: March 09, 2015; Accepted: January 23, 2016.
APTT, liver and renal function tests, arterial blood gas,
serum ammonia, urinary ketones, C-reactive protein,
blood, and urine culture. Specific comprehensive testing
was done according to clinical suspicion. Skeletal survey
was done in suspected patients of mucopolysaccharides
(MPS) and Gaucher's disease. Bone marrow biopsy and
eye examination was done in suspected lipid storage
disorders. Liver biopsies were done in suspected cases
of glycogen storage disease (GSD). All these routine,
radiological and histological investigations were carried
out at the study centre. As facility of comprehensive
diagnostic testing of particular metabolic disorder is not
available there, so these were sent abroad. Three ml
each of heparinized blood, EDTA, and clotted sample for
serum, dried blood spot on filter paper, and 20 ml of
urine were saved before starting of management and
sent abroad urgently after explaining and taking written
consent from parents in clinically suspected cases.
DBS for suspected Gaucher and various verities of MPS
was done. Enzyme assay for galactosemia, biotinidase
deficiency and other disorders was done wherever
indicated. Blood tandem mass spectrometry (TMS) for
amino acid and acyl carnitine levels, blood and urine
amino acid levels by HPLC or chromatography, urine
organic acids analysis by GCMS and urine mucopoly-
saccharides and oligosaccharides was carried out from
abroad in clinically suspected cases.
All the relevant data including demographics, clinical
presentation and outcome was filled in pre-designed
proforma. SPSS Statistics version 19.0 was used to
analyze the data. Descriptive statistics has been used
for computing frequency and percentage. On diagnosis,
the specific nutritional intervention was discussed with
an expert dietician before being implemented. Constant
monitoring during the diet was done with frequent
counselling of parents. Written information was given to
parents in Urdu (local language).
RESULTS
A total of 239 subjects were enrolled in the study, out of
which 180 (75.3%) tested positive for a specific
metabolic disorder while 59 (24.7%, male=38 and
female=21) had normal metabolic work-up. Out of 180
subjects, who were tested positive for metabolic
disease, male predominance was noted 62.2% (n=112)
and females were 37.8% (n=68). Nineteen different
types of inherited metabolic disorders were diagnosed.
Age ranged from 1 day to 14 years. Consanguinity was
positive among parents of 175 (97%) affected children.
Family history of previously affected children was noted
in 64 (35.5%).
Inherited disorder of carbohydrate metabolism topped
the list in order of frequency with n=92 (51%), followed
by lipid storage disorder 59 (32.7%), organic acidemia
and energy deficient defects 18 (10%), amino acid
disorder 6 (3.3%), and miscellaneous 4 (2.2%). Fifty-
eight (32.2%) patients presented with metabolic crisis,
28 (15.5%) with neonatal cholestasis and 24 (13.3%)
had mental retardation. Out of these, 16 (8.8%) expired
(tyrosinemia n=5, GSD n=4, Gaucher’s disease n=4 and
methyl-melonic-academia (MMA) n=3).
Table I describes the etiologies of hereditary metabolic
disorders with frequencies and percentages (n=180).
Figure 1 describes the frequency distribution of the types
of Gaucher's disease and Figure 2 describes the same
of MPS.
Spectrum of inherited metabolic disorders in Pakistani children presenting at a tertiary care centre
Table I: The etiologies of hereditary metabolic disorders with frequencies
and percentages (n=180).
Inherited metabolic disorder Number (%)
A-Carbohydrate disorders 92 (51%)
1.Glycogen storage disease 62 (67.4%)
2.Galactosemia 22 (24%)
3.Fructose 1,6- bisphosphatase deficiency (FDPase) 8 (8.6%)
B-Lysosomal storage disease 59 (32.7%)
1.Gaucher’s disease 32 (54.2%)
2.Mucopolysaccharides (MPS) Sub-types MPS-1 n=8,
MPS -II n=2, MPS-IV n=6 and MPS-VI n=1 17 (28.8%)
3.Mucolipidosis-II 3 (5%)
4.Niemenn pick disease 3 (5%)
5.Sialidosis (Mucolipidosis-1) 2 (3.5%)
6.Pompe disease 2 (3.5%)
C- Organic acid and energy metabolism defects 18 (10%)
1.Mitrochondriopathy 8 (44.5%)
2.Fatty acid oxidation defect (FAOD) 4 (22.25%)
3.Methylmalonic acidemia (MMA) 3 (16.5%)
4.Biotidinase deficiency 1 (5.5%)
5.2-Methyl-2-hydroxybutyric aciduria (MHBD) 1 (5.5%)
6. 3-Hydroxymethylglutaryl-coa (3-hmg coa) lyase deficiency 1 (5.5%)
D-Amino acid disorders 6 (3.3%)
1.Hereditary Tyrosinemia 6 (100%)
E- Miscellaneous 4 (2.2%)
1.Neonatal hemochromatosis 2 (50%)
2.Bile acid synthesis defect (BASP) 1 (25%)
3. Lysinuric protein intolerance 1 (25%)
Figure 1: Types of Gaucher's disease (n=32).
Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (6): 498-502
499
DISCUSSION
Metabolic disorders are group of inherited disorders that
cause significant morbidity and mortality. Archibald
Garrod in 1909 introduced the concept of inborn errors
of metabolism (IEM).
5
These are congenital metabolic
disorders, caused by genetic mutations leading to
defective protein function, resulting in the absence or
abnormality of an enzyme or cofactor, causing either
accumulation or deficiency of a specific metabolite.
Outcome depends upon recognition of the signs and
symptoms, timely evaluation, and transfer to facility
which is familiar with the evaluation and comprehensive
testing along with experience of management of these
disorders. Any delay in diagnosis can lead either early
death or significant morbidity in the form of neurological
deficit.
Majority of severe forms of metabolic disorders present
in childhood. Most paediatricians have to face these
disorders; hence they should have experience in
diagnosing and treating these diseases. Moreover,
improved and available treatments which include
enzyme replacement therapy (ERT), toxic substrate
inhibitors and diet restrictions have changed the
prognosis of some of these diseases. Possible improved
outcome increase the importance of recognizing these
disorders.
In this study, the authors found variety of patients of
metabolic disorders including rare disorders. Individual
IEM are rare disorders, most having reported incidence
of less than 1 per 100,000 births. However, the
incidence may approach 1 in 800 - 2500 births when
considered collectively.
6,7
Incidence of metabolic
diseases in Pakistan is not known. In studies from
Pakistan, IEMs were confirmed in 5/10 (50%)
8
cases at
the Shifa International Hospital, Islamabad, and in 16/62
(26%) cases at National Institute of Child Health,
Karachi.
9
In a study from India, 869 cases were
screened among whom 2.65% were diagnosed to be
having specific IEM.
10
In this study consanguinity rate was present in 97%.
This is comparable to a study from Libya where
consanguinity was observed in 86.9%.
9
Family history of
previously affected children was noted in 35.5% in this
study as compared to the Libyan study where family
history of the disorder was noted in 63.5% of cases.
11
In this study, GSD was the commonest disorder in the
studied population followed by Gaucher’s disease,
galactosemia and MPS with frequency of 34.4%, 17.7%,
12.2% and 9.4%, respectively. In contrast, frequencies
of 23%, 6%, 4% and 20%, respectively have been
reported of these disorders by Roy
et al. from India.
12
Patients from group of organic acids and energy
deficient defects disorders mainly presented with
metabolic crisis. We had 4 cases of falty acid oxidation
defect (FAOD). Huang et al. described 8 cases of FAOD
in his study in which 11,060 patients were screened.
13
Biotinidase deficiency has already been reported from
Pakistan, one case reported from Islamabad and 4
cases reported from Karachi.
6,13
In this study, a very rare
disorder 2-m Methyl-3-hydroxybutryl CoA dehydro-
genasee (MHBD) was also found, which was reported
previously only in less than 10 cases in literature.
15,16
One case of 3-hydroxymethylglutaryl-CoA (3-hmg CoA)
lyase deficiency was diagnosed, this type of organic
acidemia occurs without ketogenesis. This is a very rare
disorder and there are few published case reports of this
disorder in literature.
17,18
There was a case of lysinuric
protein intolerance; approximately 140 individuals with
this disorder have been reported in literature.
19
In this study, 24 (13.3%) patients had mental retardation.
In a recent study, 81 IEMs were described to have
intellectual delay as a clinical feature.
20
In a study from
Libya, 87.5% of children were developmentally delayed
which is higher as compared to our study.
11
Children
presenting with MMA and tyrosinemia had the worst
prognosis even with early treatment, all 3 patients of
MMA and 5 patients of tyrosinemia expired. Four
patients of GSD expired who came with severe crisis
and reached hospital late. Four patients of Gaucher’s
disease expired; out of these 3 patients were of type-I
and died of severe cachexia, bleeding and infections,
while another patient of type-II died of severe
neurological involvement (seres, squint, and bulbar
palsy).
In Pakistani population, owing to high rate of inter-
marriages and large family size, our assumption that
these metabolic disorders including rare disorders, all
are prevalent in Pakistan, seems to be true. One
hundred and eighty (180) cases of 19 different disorders
were found in this study. The diagnosis of inherited
metabolic disorders has increased in recent years in our
country. Some centres have initiated work-up and
Huma Arshad Cheema, Hassan Suleman Malik, Arit Parkash and Zafar Fayyaz
500 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (6): 498-502
Figure 2: Types of MPS disease (n=17).
management of these disorders. But there is a lack of
therapeutic and diagnostic resources, including
metabolic laboratories, confirmatory DNA testing,
specialist in this field, and specialized metabolic
dietitians. For this study, the authors had to send
samples for diagnostic work-up to a laboratory in
another country. Most of diagnoses were made on the
basis of enzyme assay and substrates analysis,
whereas, genetic mutations are not being done. The
authors were unable to gather data for the type of
mutations prevalent in this population. Gene analysis
has significantly improved prenatal diagnosis and
identification of healthy heterozygotes, thus significantly
improving importance and application of genetic
counselling.
21
Without knowledge of these mutations,
antenatal diagnosis is not possible.
In the last decade, introduction of tandem mass
spectrometry has expanded newborn screening (NBS).
Now, this programme is mandatory in most of the
developed and developing countries as a public health
strategy.
22
In Pakistan, however, neonatal screening
programme is not available.
There is a need of creating local facilities for diagnosing
these disorders and awareness of primary as well as
tertiary care level for proper referral, as most cases of
crisis are treated as sepsis, mental retardation and
cerebral palsy, and there is no further evaluation and
proper management. This study provides valuable
information for future metabolic newborn screening
programme, which is treatable; and most frequent
metabolic disorders should be considered for screening.
To treat acute and life-threatening cases in the treatment
of metabolic disorders, the priority was given to manage
intoxication. However, the treatment for lysosomal
diseases like Gaucher's disease and MPS, where
enzyme replacement therapy is available and in vogue,
paediatricians should make themselves familiar with
these sophisticated regimens.
23
Dietary management is
essential for metabolic disorders. Dietitians in
association with metabolic specialists should make
plans for protein restricted or modified diet for these
patients and must provide adequate nutrition to them.
Diets normally consist mainly of special medical milk
formulas for specific disorders and selective natural
foods. Cost, unavailability of drugs, poor medical and
nutritional compliance reduce the efficacy of treatment in
population of developing countries.
Inherited metabolic disorders were not only common in
first cousin marriages but also in non-cousin marriages
of the same caste. Arian was the most commonly
affected caste showing IEM.
CONCLUSION
Different types of rare disorders were diagnosed with
glycogen storage disorders being the commonest,
followed by Gaucher's disease and galactosemia. This
study highlights the presence of various metabolic
disorders in Pakistan and the need for starting a
newborn screening program to include most frequent
and treatable disorders such as Gaucher’s disease,
galactosemia, MPS, fructose1, 6-bisphosphatase
deficiency, FAOD, Pompe’s disease and biotinidase
deficiency.
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