Metabolism is the set of life sustaining chemical reactions in organisms to preserve cellular activities and continue life (1). This process relies on specific metabolic pathways in its regulation in order to maintain vital activities (2). Each pathway has a group of specific enzymes that help it in its function (3). Accordingly, the inborn errors of the metabolism process (IEM) can be defined as disturbances that occur in any of the metabolic pathways due to the lack of activity of enzymes (4).
In
other words, IEM are a series of uncommon diseases involving the production,
function, and transportation of the enzymes (5). They are also considered
genetic diseases and they are inherited in an autosomal recessive manner (6). They
are all genetic disorders and can be inherited on nuclear DNA (autosomal or sex
chromosomes) or mitochondrial DNA (7).
Proteins,
lipids, carbohydrates, vitamins, minerals and complex compounds can be affected
in the anabolic or the catabolic pathways (8). Therefore, these groups of
diseases are expressed in different presentations and different age groups (9).
Increase diagnostic facilities such as expanding newborn screening (NBS)
programs, dry blood spot (DBS) testing and Tandem Mass spectrometry (MS-MS) has
enabled making the diagnosis of such rare diseases with increasing rapidity
(10).
IEM
categories are based on various parameters. These parameters may be a predominant
system such as neurologic, age of onset, symptoms, or acuity (11). The symptoms
associated with the IEM disorders are categorized by laboratory tests, for the
first category, it includes one organ (12).The second category has many
disorders divided into three groups: intermediate metabolic disorders that affect
small molecules, disorders that primarily involve energy metabolism, and
disorders that involve complex molecules (12, 13, 14).
There
are categories of patients with IEM who have a wide range of clinical symptoms,
some of which are detected at birth and others that begin to appear during life
(15). Jordanian national screening program screens for phenylketonuria only
from all other IEM (16). This study was conducted to describe the categories of
patients that were seen at the metabolic clinic, King Hussein Medical City,
Queen Rania Abdullah Children’s Hospital, Amman, Jordan. The information collected
their primary clinic, parenteral consanguinity, specific diagnosis and
developmental delay.
METHODS
The medical records of the patient who attended
the metabolic clinic in the 1ST eight months of 2018 were reviewed. Ages ranged
from birth to 24 years old. The recorded data included: age, gender, primary
referral clinic or hospital, the family history; parents’ consanguinity,
affected other family members affected, deaths related to the same
presentation; the presence of developmental delay or regression and the
presence of a laboratory confirmed or clinical diagnosis or not. The family data
were all related only to conditions that may have had the same disease as the
index case. The data of the patients who were seen more than one time in the study
period were recorded for only the last visit. Laboratory investigations were
variable for each patient. Basic investigations such as; CBC, serum electrolytes,
kidney and liver function tests, ammonia, lactate, venous blood gases were done
at the laboratory of Queen Rania Abdullah Children Hospital. Aminoacids
chromatography, organic acids chromatography and MS_MS tandem mass spectrometry
were done at Princess Iman Research Center; King Hussein Medical City.
Lysosomal enzymes activities were measured at Prince Haya Biotechnology Center;
King Abdullah University Hospital. The genetic tests like Next-generation
Sequencing (NGS) and Whole Exome Sequencing (WES) were applied outside of
Jordan in cooperation with specialized private laboratories. IEM disorders that
are mostly diagnosed at the metabolic clinic are classified into [1] Protein
metabolic disorders including aminoacidopathies and organic acidemias. [2]
Carbohydrate metabolic disorders with glycogen storage diseases are the most
common. [3] Lipid metabolic disorders considering familial hyperlipidemias as a
part of this category. [4] Mitochondrial and energy metabolic disorders. [5]
Micro-organelles metabolic disorders with lysosomal storage diseases are the
most common. [6] Other metabolic disorders which are less common like; Vitamins
metabolic disorders and neuro-transmitters disorders.
RESULTS
A total of 429 patients were included in
this study, 218 male and 211 female with male to female ratio of 1.03:1. The
mean age of males was 5.57 ± 0.59 years old with a range from birth to 24
years. The mean age of females was 5.63 ± 0.53 years old with ages ranged from
birth to 19.2 years old. The mean age of the total patients (429 patients) was
5.62±0.55 years old.
Table
(1) summarizes the patients’ primary clinics.242 (56.4%) of the patients were
known to the metabolic clinic and came on a scheduled appointment. 127 (29.6%)
males and 115(26.8%) females. The neurologic clinic had the most referrals with
76 (17.7%) patients. Military hospitals
referred 9 (2%) patients, and governmental hospitals sent 21 (4.9%) patients to
the metabolic clinic.
Parental
consanguinity occurred in 333 (77.6%) of the patients' parents. First cousins
were parents of 238 (55.5%) patients. Second cousins were parents of 39 (9.1%)
patients. Far relatives; parents who are related farther from their
grandparents; were parents of 49 (11.4 %) patients. Double cousins; cousins
from both paternal and maternal sides; were parents of 7 (1.6%) patients. 96
(22.4%) patients were children of non-related parents. Figure (1) summarizes parental
consanguinity and figure (2) summarizes the family history; the presence of
affected family members or relatives and the presence of deaths due to the same
condition.
Table
(I): The patients’ primary clinics:
|
Primary
clinic
|
Gender
|
No. Of
Patients
|
Total
(percentage)
|
|
Metabolic clinic
|
Male
|
127
|
242 (56.4%)
|
|
Female
|
115
|
|
Neurodevelopmental Clinic
|
Male
|
37
|
76 (17.7%)
|
|
Female
|
39
|
|
Gastrointestinal Clinic
|
Male
|
3
|
10 (2.3%)
|
|
Female
|
7
|
|
Genetic Clinic
|
Male
|
3
|
9 (2.1%)
|
|
Female
|
6
|
|
Cardiac Clinic
|
Male
|
4
|
6 (1.4%)
|
|
Female
|
2
|
|
Neonatology Clinic
|
Male
|
7
|
10 (2.3%)
|
|
Female
|
3
|
|
Endocrinology Clinic
|
Male
|
4
|
6 (1.4%)
|
|
Female
|
2
|
|
Hematology Clinic
|
Male
|
1
|
3 (0.7%)
|
|
Female
|
2
|
|
General Pediatric Clinic
|
Male
|
2
|
7 (1.6%)
|
|
Female
|
5
|
|
Pediatric Orthopedic Clinic
|
Male
|
2
|
6 (1.4%)
|
|
Female
|
4
|
|
Pediatric Ophthalmic Clinic
|
Male
|
1
|
3 (0.7%)
|
|
Female
|
2
|
|
Other Clinics
|
Male
|
4
|
6 (1.4%)
|
|
Female
|
2
|
|
Military Hospitals
|
Male
|
4
|
9 (2%)
|
|
Female
|
5
|
|
Ministry Of Health Hospitals
|
Male
|
16
|
31 (7.2%)
|
|
Female
|
15
|
|
Other Hospitals
|
Male
|
2
|
4 (0.9%)
|
|
Female
|
2
|
Figure
(1): Percentage consanguinity (related parents)
Figure
(2): Affected family members and deaths by consanguinity (related parents)
Developmental
delay and/or regression was the most common presenting symptom in the metabolic
clinic. 103 (24%) male patients had a history of developmental delay and 80
(18.6%) patients had developmental regression. Female patients showed
developmental delay in 85 (19.8%) patients and developmental regression in 66
(15.4%) patients. Table (2) summarizes the developmental history in the study
patients.
Table
(II): Developmental history in the patients:
|
|
Developmental
Delay
|
Developmental
Regression
|
|
Gender
|
Male
|
Female
|
Male
|
Female
|
|
No. of
Patients
|
103 (24%)
|
85 (19.8%)
|
80 (18.6%)
|
66 (15.4%)
|
|
Total
(Percentage)
|
188 (43.8
%)
|
146 (34%)
|
A confirmed biochemical and/or genetic
diagnosis was made in137 (31.9%) patients, while 89 (20.7%) patients had a
clinical diagnosis. The rest of the patients; 203 (47.3%) have no diagnosis and
are treated symptomatically at the metabolic clinic in cooperation with other relevant
clinics. Table (3) summarizes whether patients have a confirmed or clinical
diagnosis or not.
Table
(III): Confirmed or clinical diagnosis or no
diagnosis:
|
|
Confirmed
diagnosis
|
Clinical
diagnosis
|
No
diagnosis
|
|
Male
|
Female
|
Male
|
Female
|
Male
|
Female
|
|
No. of
patients
|
71 (16.6%)
|
66 (15.4%)
|
43 (10%)
|
55 (12.8%)
|
99 (23.1%)
|
104 (24.2%)
|
|
Total
|
137 (31.9%)
|
98 (22.8%)
|
203 (47.3%)
|
DISCUSSION
Inborn
errors of metabolism (IEM) disorders are expressed at different ages and with a
variety of phenotypes that make the parents search for medical treatment in
multiple subspecialty clinics for their children’s diagnosis (17). The clinical
presentations of IEMs depend on several factors and the different types of
disorders; because of this, there is a difference in the possibility and the
timing of diagnosis, the availability of treatment options, the ability of a medical
institution to provide care and the appropriate treatment intervention (18).
Among the serious complications for patients diagnosed with IEM neurologic
disability, mental retardation, difficulties in communication and learning, as
well as death (19). Healthcare providers should be more aware of these
disorders and manage them optimally until an early diagnosis is reached where
possible. Good case management may prevent the deterioration of the patient's
health and physical condition (20).
All IEM disorders are inherited and consanguinity is a major risk
factor for new cases. Double cousins and first cousins have the greatest risk
for offspring with metabolic disease and often have a positive history of other
affected children and early deaths in their families. Newborn screening for some
conditions may be the cornerstone for early diagnosis and management, which
leads to prevention of deaths and permanent sequelae, especially when there is
a family history of treatable disorders. Widening the newborn screening program
can detect new cases earlier, even without a positive family history, leads to
better management of patients (21).
Conclusion
and Recommendations:
The metabolic clinic at
Queen Rania Abdullah Children Hospital receives patients almost from all
pediatric clinics and hospitals in Jordan. About 50% of the patients do not
have a diagnosis and treated symptomatically. Awareness of IEM disorders
between pediatricians is important and can lead to earlier diagnosis. The national
newborn screening program needs to be expanded to include more early presenting
and treatable disorders. Metabolic and genetic investigations are still
challenging to be performed and/or analyzed by general physicians and
pediatricians, hereafter, focusing on increasing genetic and metabolic teaching
in universities and during the residential years may increase the awareness in
the future physicians.
Acknowledgment
Gratitude and thanks to the Queen Rania
Abdullah Children Hospital laboratory, Princess Iman Research Center; King
Hussein Medical City, Prince Haya Biotechnology Center; King Abdullah
University Hospital, and specialized private laboratories in Jordan and outside
of Jordan to facilitate to obtain the necessary data to conduct this study.
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