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International Journal of Developmental Disabilities logoLink to International Journal of Developmental Disabilities
. 2019 Jan 15;66(3):190–195. doi: 10.1080/20473869.2018.1533084

Biochemical screening of intellectually disabled and healthy children in Punjab, Pakistan: differences in liver function test and lipid profiles

Muhammad Wasim 1,2,*, Haq Nawaz Khan 1,2,*, Hina Ayesha 3, Fazli Rabbi Awan 1,2,✉
PMCID: PMC8142844  PMID: 34141381

Abstract

Objectives: Inborn errors of metabolism (IEMs) are rare genetic disorders. Generally, IEMs are untreatable; however, some IEMs causing intellectual disability are potentially treatable if diagnosed earlier. In this study, levels of some clinically important biochemical parameters in intellectually disabled children suspected for IEMs were tested to see their association with intellectual disability, which could be helpful in preliminary screening.

Methods: This comparative cross-sectional observational study was carried out from 2014 to 2017. Blood samples from 800 boys and girls (aged 4–24 years) were collected, of which 391 were healthy (IQ >90) and 409 were intellectually disabled (IQ <70) children with unknown cause. Clinically important (Liver and kidney enzymes etc.) biochemical parameters were analyzed in sera samples using commercial kits on semi-automated clinical chemistry analyzer.

Results: Serum analysis showed the levels of ALP (p < 0.00001), ASAT (p = 0.001), ALAT (p = 0.016), albumin (p < 0.001), uric acid (p < 0.001), cholesterol (p < 0.001), triglycerides (p < 0.001), and hemoglobin (p = 0.005) were significantly different between healthy and intellectually disabled children.

Conclusion: Changes in the liver function test and lipid profile parameters were significantly different in children with intellectual disability; however, it requires further detailed analysis for complete characterization of these diseases.

Keywords: Intellectual disability (ID), inborn errors of metabolisms (IEMs), liver function test, newborn screening (NBS), hyperlipidemia

Introduction

Inborn errors of metabolism (IEMs) are rare inherited metabolic disorders when taken individually but collectively these disorders are reasonably frequent in different populations with an overall frequency of 2–3% worldwide. More than 700 IEMs have been reported so far and several of the IEMs may cause intellectual disability (ID) in children, which are generally not treatable (van Karnebeek and Stockler 2012, Colonetti et al. 2018, van Karnebeek et al. 2018). However, fortunately, 100 such disorders are potentially treatable, if diagnosed at an earlier stage of life (Graham et al. 2018). IEMs can affect liver, kidney, heart, brain, and other vital organs of the body. If such patients are left untreated, pathological consequences will develop with the conditions of neurodevelopmental and neurocognitive problems, delayed developmental milestones, poor feeding, vomiting, seizures, loss of consciousness, and intellectual disability or even death in the early years of life (Graham et al. 2018, Wasim et al. 2018). However, timely screening and diagnosis can help the affected children to live healthy life. To initiate evidence based treatment for such disorders, early diagnosis is of paramount importance.

The IEMs are neglected disorders in Pakistan due to burden of other common infectious, metabolic and genetic diseases, so there is limited data available about the screening of IEMs in this country (Cheema et al. 2016a). Clinical awareness and accurate biochemical analysis play a key role for the diagnosis of metabolic disorders (Karam et al. 2013, Bonham 2014). Most of the developed countries have established their newborn screening (NBS) programs, where they routinely screen the most prevalent IEMs with respect to their population-specific prevalent diseases (Wilcken et al. 2003, Tiwana et al. 2012, Ozben 2013, Villoria et al. 2016, Ibarra-Gonzalez et al. 2017, Yunus et al. 2016, Arelin and Beblo 2016, Chong et al. 2017). Different analytical techniques have been used in NBS programs for the screening of metabolic disorders like HPLC, LC-MS, GC-MS, etc. (Wang et al. 2014, Bennett 2014, Hampe et al. 2017, La Marca and Rizzo 2011, Sun et al. 2017). Conversely, in Pakistan there is no local or national level NBS program available for the early diagnosis of such diseases. Hence, there is a dire need for NBS program in Pakistan. Therefore, in this study, we made efforts for the differential diagnosis of intellectually disabled children who were strongly suspected for having any of the IEM. In this pilot study, some of the clinically important parameters have been estimated from the serum samples of intellectually disabled children and compared them with healthy children. Samples with abnormal values will be further pursued for analysis by advance analytical techniques (e.g. HPLC, GC, GC-MS, LC-MS/MS, PCR, DNA sequencing and whole exome and/or next generation sequencing etc.) for characterization of the respective diseases in our subsequent studies. This data and further advance techniques will help us to initiate a NBS program in Pakistan.

Here we report our preliminary findings for abnormal changes in the routine but clinically important biochemical parameters in intellectually disabled IEM patients relative to the healthy subjects.

Subjects and methods

This study was carried out at the National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan from 2014 to 2017. Children of both genders in the age range 4–24 years included in this study were intellectually disabled without diagnosis having intelligence quotient (IQ) < 70 and healthy children having IQ more than 90. For the collection of blood samples, collaborations were developed with the local public sector hospitals and pediatricians. To collect large number of samples, permission was taken from the respective Education District Officers (EDO) of Special Education Centers from Lahore and Faisalabad regions of Punjab, Pakistan. Each Head of Special Education Center was properly informed at least one day before sample collection. Consent forms were duly filled by the parents and head of the center, and then bio-demographic information for each child was recorded on a specified questionnaire form.

This study was also approved by the institutional (NIBGE, Faisalabad, Pakistan) ethics review committee. After obtaining informed consent, 5 ml venous blood sample was taken from each child, of which 2 ml was transferred to a gel containing vacutainer without anticoagulant from each subject and rest was saved for DNA analysis at later stages. The blood sample of every subject was allowed to clot at room temperature for about 30 minutes, centrifuged it to separate serum and kept in the Eppendorf tubes until further analysis. As IEMs can affect liver, kidneys, brain and other vital organs of the body, so serum was used for the biochemical analyses of glucose, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (ALP), albumin, total protein, urea, uric acid, hemoglobin (from whole blood sample), creatinine, cholesterol, and triglyceride. These biochemical parameters were determined by colorimetric methods using commercial kits (Merck, Germany), on a semi-automated clinical chemistry analyzer (Microlab-300, Merck, Germany). Statistical analysis was carried out in MS® Excel 2013 and ANOVA:single factor was used for p-value determination. All results are presented as mean ± standard deviation (SD) with minimum and maximum range and p-value. Comparison between patients and healthy samples with respect to their Body Mass Index (BMI) and biochemical parameters were also carried out.

Results

A total of 800 sera samples were collected from different areas of Lahore and Faisalabad regions of Punjab, Pakistan. 409 samples were from intellectually disabled patients and 391 were from healthy children from the same areas. Consanguinity rate was 75% and most of the patients came from middle class families, who were not even able to afford the routine medications. Microcephalic or Down syndrome children were excluded during sampling because our focus was only on treatable IEMs; however, head circumferences of both patients and healthy control children were in the normal range. A summary of bio-demographic information for both groups of children is provided in Table 1.

Table 1.

Bio-demographic measurements of healthy and patient samples

Healthy children
 Intellectually disabled children
Number (Male:Female)
 391 (220:171)
   409 (288:121)
Parameters
 Age (years)
 BMI (Kg/m2)
 Head circumference (cm)
 Parameters
 Age (years)
 BMI (Kg/m2)
 Head circumference (cm)
Min-Max range
 5–14
 10–21
 45–54
  
 4–24
 12–24
 44–54
Age intervals Number Mean ± SD Mean ± SD Mean ± SD Number (Mean ± SD) (Mean ± SD) (Mean ± SD)
1–5 years 9 5.0 ± 0.0 13.12 ± 1.54 47.12 ± 0.83 7 4.75 ± 0.5 13.62 ± 0.99 48.0 ± 4.35
5.1–10 years 296 7.9 ± 1.38 14.65 ± 2.64 49.69 ± 1.59 113 8.66 ± 1.19 15.8 ± 2.72 49.21 ± 2.78
10.1–15 years 86 11.7 ± 0.76 16.82 ± 3.41 51.27 ± 1.21 204 12.90 ± 1.33 16.11 ± 3.81 50.0 ± 2.57
15.1–20 years   – – – 68 17.56 ± 1.39 18.45 ± 4.56 50.7 ± 3.1
20.1–25 years   – – – 17 22.0 ± 1.6 18.21 ± 5.25 50.18 ± 3.22
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SD, Standard Deviation; BMI, Body Mass Index.

Clinically important biochemical parameters

Biochemical parameters were analyzed in all the collected healthy and patient samples. Most of the clinically important parameters were significantly different in the intellectually disabled patient samples (Table 2).

Table 2.

Clinically important parameters in healthy and patient samples

Biochemical parameters Healthy (n = 391) Patient (n = 409) p-value
  Mean ± SD Mean ± SD  
Haemoglobin (g/dL) 12.5 ± 2.2 13.0 ± 3.1 0.005
Glucose (mg/dL) 92.6 ± 12.2 81.9 ± 22.0 0.2
Uric Acid (mg/dL) 7.0 ± 1.3 5.5 ± 1.9 <0.001
ALAT (IU/L) 25.0 ± 5.6 26.4 ± 9.1 0.016
ASAT (IU/L) 31.3 ± 11.1 40.4 ± 16.6 0.001
ALP (IU/L) 204 ± 74 474 ± 288 <0.00001
Albumin (g/dL) 3.9 ± 0.2 4.3 ± 0.5 <0.001
Total Protein (mg/dL) 6.6 ± 1.1 7.4 ± 1.6 1.00
Creatinine (mg/dL) 0.6 ± 0.1 0.7 ± 0.2 1.00
Urea (mg/dL) 25.1 ± 4.8 25.7 ± 8.0 0.202
Cholesterol (mg/dL) 139 ± 24.1 176 ± 47.6 <0.001
Triglyceride (mg/dL) 139 ± 38.7 179 ± 64.6 <0.001
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ALAT, Alanine aminotransferase; ASAT, Aspartate aminotransferase; ALP, Alkaline phosphatase; SD, Standard Deviation.

*shows significant associated with the intellectually disabled samples.

**shows highly significant associated with the intellectually disabled samples.

It has also been reported previously that elevated level of ALP is associated with different metabolic conditions like Wilson disease, obesity and with intellectual disability (Cheema et al. 2016b, Khan et al. 2015). In the present study, besides, ALP other parameters were also associated with the patient samples. Some of the patient samples having high levels of cholesterol and triglycerides may be the cases of suspected hyperlipidemia.

For further understanding, different quartiles ranges have been used for ALP, cholesterol and triglyceride levels. In all the healthy samples ALP levels were in the normal range but patient samples had variable (mostly higher) ALP levels (Figure 1).

Figure 1.

Figure 1

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Range of ALP levels in the healthy and patient samples.

Values of all the healthy samples are in the range of (10–300 IU/L) but intellectually disabled patient samples have different ranges (10–2100 IU/L) of serum ALP.

In case of cholesterol and triglycerides, some of the patient samples had high levels (suspected hyperlipidemia cases) as shown in Figures 2 and 3, respectively.

Figure 2.

Figure 2

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Range of cholesterol levels in the healthy and patient samples.

Values of cholesterol in all the healthy samples are in the range of (50–300 mg/dL) but some of the intellectually disabled patient samples have higher values as well and fall in the range (50–500 mg/dL).

Figure 3.

Figure 3

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Range of triglyceride levels in the healthy and patient samples.

Values of serum triglycerides in the healthy samples are in the range of (50–300 mg/dL) but some of the intellectually disabled patient samples have higher range as well (50–500 mg/dL).

Discussion

One of the hallmarks of several IEM is intellectual disability in children and many of such disorders are not treatable. However, fortunately, some of the IEMs causing intellectual disability are potentially treatable, if diagnosed at an earlier stage of life. Working with the clinically important biochemical parameters is a complex task but their values can be considered for further investigations (Edvardsson et al. 2018). There are always some uncertainties regarding biochemical analysis but these are complementary when evaluating important biological data (Oosterhuis et al. 2018). Screening of IEMs require special planning and determination to improve quality of patient life (Tezel et al. 2014). As, in Pakistan, there is limited data available for the screening and diagnosis of IEMs. Our laboratory at the National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan has started research on the treatable IEMs which cause intellectual disability in children. In the current study, most of the sampled intellectually disabled patients had moderate IQ level, since government run special schools/centers only take intellectually disabled patients with mild or moderate IQ levels as per policy. Here, we report our initial findings regarding biochemical analysis of intellectually disabled children suspected for IEM. We are now working with advanced analytical techniques like HPLC, LC-MS/MS, and PCR which will be published soon like development of HPLC and PCR based assays for the early screening of treatable IEMs.

In the present study, blood and serum samples were analyzed to find any association among clinically important biochemical parameters with intellectual disability in children. These parameters were tested in the collected blood serum samples. Interesting results have been found, that in the intellectually disabled children the levels of ALP, ASAT, ALAT, albumin, cholesterol, triglyceride, hemoglobin, and uric acid were found significantly different as compared to healthy children as shown in Table 2. Elevated ALP level has also been reported in different metabolic conditions like obesity, Wilson disease and intellectual disabilities (Khan et al. 2015, Cheema et al. 2016b). Genetic analysis showed that mental retardation syndrome is also associated with the high level of serum ALP due to mutations in the post-GPI (glycosylphosphatidylinositol) attachment to protein factor 2 and 3 (Krawitz et al. 2013, Abdel-Hamid et al. 2018). It has been reported that GPI deficiency also causes intellectual disability and epilepsy due to hyperphosphatasia (Nakamura et al. 2014). Level of ALP was also significantly high in the investigated intellectually disabled patients, which could be associated with intellectual disability in the affected children; however, evidence from molecular studies is required to confirm this association. Most of the IEMs affect kidneys so the level of uric acid is important to check the function of the kidneys (Friedman et al. 2001), and it has also been reported that iron metabolism especially haemoglobin involved in some of the rare genetic disorders (Chen et al. 2017, Worwood 1999). So, in the current study, hemoglobin was significantly high and uric acid was significantly low in intellectually disabled patients as shown in Table 2, however, further investigations are needed at the molecular and genetic levels for the early diagnosis of different metabolic disorders that causes intellectual disability in children.

Furthermore, some suspected hyperlipidemia patients having high levels of cholesterol and triglycerides were also found, but were not associated with the obesity. As all the studied samples were collected from the same area, so diet was also same for both groups. Most of the intellectually disabled patients did not use any type of medications; therefore, the biochemical results were not grossly interfered. In future, these suspected hyperlipidemia samples will be further investigated by advance analytical (HPLC, GC, GC-MS, LC-MS/MS) and genetic based (PCR, whole exome sequencing, next generation sequencing) techniques. Moreover, advance research is needed in developing countries like Pakistan for the early diagnosis and treatments of intellectually disabled patients because affected children can live a healthy life, if diagnosed earlier (before 5–6 years of age) and treatment is started in a timely manner. This can be possible after implementing a national level NBS program. Therefore, the present study will help to initiate advance research on these neglected disorders for the development of such screening program in Pakistan.

Conclusion

Inborn errors of metabolism are rare genetic disorders, and several of them cause intellectual disability in children. Therefore, in this study, we have investigated clinically important biochemical parameters in healthy and suspected IEM children with intellectual disability in Pakistan to find out any association among such parameters with the intellectual disability. In our collected samples, we have found that several biochemical parameters were significantly different in patient samples as compared to healthy samples. Elevated level of ALP has already been reported in different metabolic conditions like obesity and Wilson disease patients. In this study, levels of ALP, ASAT, ALAT, albumin, hemoglobin, and uric acid were found significantly different as compared to healthy children. Some of the intellectually disabled patients in this study also had high levels of cholesterol and triglyceride and are suspected for hyperlipidemia. Consequently, intellectually disabled patients might have been associated with the high levels of above mentioned parameters, but further research is needed to confirm this finding. Moreover, advance analytical tools like HPLC, GC, GC-MS, LC-MS/MS, PCR, and DNA sequencing etc. are needed for the earlier diagnosis and treatment of IEMs in Pakistani patients. Finally, this study will help to initiate a NBS program in Pakistan for the screening of different inherited metabolic disorders, which can help the affected patients to live a healthy life.

Acknowledgements

This work was supported by the International Centre for Genetic Engineering and Biotechnology (ICGEB), Italy. The research project was “Diagnosis of treatable inborn metabolic disorders of intellectual disability” (Project No. CRP/PAK14-02; Contract No. CRP/14/012). Moreover, Muhammad Wasim was funded by the High Education Commission (HEC), Islamabad, Pakistan by the Indigenous Ph.D. fellowship program.

Disclosure statement

All the authors have no conflict of interest related to this article.

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