Study Calls for Improved Screening, Diagnosis of Inherited Metabolic Disorders in Pakistan

Pakistan has a high rate of inherited metabolic disorders (IMDs) and needs better facilities and resources for improving the screening, diagnosis, and genetic counseling of families across the country, a nationwide screening study says.

In two years, 88 cases were confirmed of organic acidurias (OA), aminoacidopathies (AA) and other IMDs, including one of aromatic L-amino acid decarboxylase (AADC) deficiency.

The study, “Selective Screening for Organic Acidurias and Amino Acidopathies in Pakistani Children,” was published in the Journal of the College of Physicians and Surgeons Pakistan.

IMDs are a group of disorders caused by mutations in specific genes that interfere with the metabolism, or how the body processes certain substances. 

They are rare diseases, each occurring in less than one per 100,000 births. As a whole they may affect approximately one in 800 to 2,500 births.

However, some countries like Pakistan have a particularly high rate of IMDs. Their prevalence is attributed to the frequent consanguinity in a country where about 60% of all married couples are relatives.

One study reports an overall frequency of one per 318 Pakistanis living in the West Midlands in the U.K. (western part of central England). Certain IMDs were even 100 times more frequent in this population, as compared to Northwestern Europeans.

But the burden of IMDs in the country is not known. In Pakistan, diagnosing these diseases is challenging given the limited resources and clinical expertise. Moreover, there is no national plan for newborn screening.

To fill this knowledge gap, a group of researchers at The Aga Khan University Hospital in Karachi (AKUH-K), Pakistan, undertook this study.

The main aim was to determine the frequency of two kinds of IMDs, organic acidurias (OA) and aminoacidopathies (AA), in Pakistani children with a clinical suspicion of one such disorder. They also checked for other IMDs, including aromatic L-amino acid decarboxylase (AADC) deficiency.

The selective screening was conducted at the Biochemical Genetics Laboratory (BGL) at AKUH-K from 2013 to 2014. Patient samples came from all over the country, through its 200 phlebotomy centers.

AAs, caused by errors in amino acid metabolism, were diagnosed based on the quantification of amino acids in samples of blood and cerebrospinal fluid (CSF, the body fluid that runs in the brain and spinal cord) by chromatography (HPLC).

OAs, which often result in a build-up of acids, were identified by quantifying organic acids in urine samples by mass spectrometry.

Of the 1,866 children analyzed, 88 (4.7%) were diagnosed with an IMD, including 41 with an OA, 28 with an AA ,and 19 with another IMD (21.5%),  including one with AADC deficiency. The median age of patients was 1.1 years.

There was a high consanguinity rate, with about two-thirds (64.8%) born to consanguineous parents.

Most frequent clinical manifestations were lack of energy, or lethargy (44%), developmental delays (39%), poor feeding (39%), and vomiting (32%), with most patients having a combination of symptoms.

Cases of OA, ordered by frequency, included methyl CoA mutase deficiency, MHBD deficiency, propionic aciduria, HMG-CoA lyase deficiency, isovaleric aciduria, multiple carboxylase deficiency, fructose-1, 6-biphosphatase deficiency, fumarase deficiency, glutaric aciduria type 1, and ethyl-malonic aciduria.

Identified AAs included maple syrup urine disease, cystathionine beta-synthase deficiency, urea cycle disorders, hyperphenylalaninemia, and hyperprolinemia.

Over the two-year study period, a single case of AADC deficiency was detected. Other IMDs were reported in one child, including intracellular cobalamin defects, alkaptonuria, Canavan’s disease, SUCL deficiency, DPD deficiency, glutaric aciduria type 1, non-ketotic hyperglycinemia.

From 2008 to 2012, all diagnostic tests for IMDs in Pakistan were outsourced from Malaysia.

After these tests became available locally at the BGL in AKUH-KA in 2013, the number of diagnosed patients almost doubled in two years compared with those identified in the five years before.

“This highlights the fact that the easy accessibility of a local diagnostic facility to physicians and patients leads to more patients being diagnosed and eventually results in timely management of patients with IMDs,” researchers wrote.

Compared to other Asian countries, Pakistan has a higher prevalence of IMDs (4.7%) as compared to Singapore (3.5%), Japan (2.4%), and Malaysia (2%). This may be explained in detection rates by differences in sample size and a higher consanguinity rate in Pakistan.

The investigators underline that “efforts to establish more diagnostic facilities and allocation of national funds and resources to address the common IMDs can be a way forward in strengthening the IMD services and hope for patients and families fighting with IMDs in Pakistan.”

The country needs better facilities and healthcare expertise to ensure prenatal diagnostic and screening for carriers in families at risk, researchers suggested. Genetic counseling before marriage also may help individuals make informed decisions when choosing their partners. All of these diagnostic approaches “will help in reducing the overall burden of IMDs in Pakistan,” researchers contend.

In addition, screening people highly suspected of disease, as this study did, can reveal the most prevalent IMDs in the country, identifying those to be included in a national newborn screening plan.