Selective screening for organic acidurias and amino acidopathies in Pakistani children

Objective: To determine the frequency of organic acidurais [OA] and amino acidopathies [AA] in selected high-risk patients screened in two years

Study Design: Retrospective Observational study

Place and Duration of Study: The Aga Khan University Hospital [AKUH], Karachi, from January 2013 to December 2014

Methodology: Patients with OA and AA were included in the study and patients with IMDs other than OA and AA were excluded. Amino acids and organic acids were analyzed on high performance liquid chromatography and gas chromatography-mass spectrometry respectively. Clinical data and chromatograms of patients screened for IMDs were reviewed by chemical pathologist and metabolic physician

Results: Eighty-eight cases [4.7%] were diagnosed including 41 OA [46.5%], 28 AA [31.8%] and 19 others [21.5%] from 1,866 specimens analyzed. Median age of the patients was 1.1 years, with high consanguinity rate [64.8%]. Among OA, methyl CoA mutase deficiency was diagnosed in 9 [10.2%] and was suspected in 2 [2.3%] cases. Five [5.7%] cases of MHBD [2-methyl-3-hydroxybutyryl-CoA], 4 [4.5%] each of PPA [propionic aciduria] and HMG-CoA lyase deficiency, 3 [3.4%] cases each of IVA [isovaleric aciduria], multiple carboxylase deficiency, fructose-1, 6-biphosphatase deficiency, fumarase deficiency, GA-1 [glutaric aciduria type 1] and 2 [2.3%] cases of EMA [ethyl-malonic aciduria]. AA included 8 [9.1%] cases of MSUD [maple syrup urine disease], 6 [6.8%] cases of CBS [cystathionine beta-synthetase] and UCDs [urea cycle disorders] each, 5 [5.7%] cases of hyperphenylalaninemia and 3 [3.4%] cases of hyperprolinemia were reported. Other inherited metabolic disorders included: 9 [10.2%] cases of intracellular cobalamin defects, 2 [2.3%] cases each of alkaptonuria, Canavan's disease, SUCL [succinate CoA ligase] deficiency, and 1 [1.1%] case each of DPD [dihydropyrimidine] deficiency, GA-2, NKH [non-ketotic hyperglycinemia], AADC [aromatic amino acid decarboxylase] deficiency

Conclusion: This study presents frequency of OA and AA in the high-risk Pakistani pediatric population analyzed locally

Ethical issues in managing Lysosomal storage disorders in children in low and middle income countries

The lysosomal storage diseases are a group of rare, inherited metabolic diseases affecting about 1 in 7000 to 8000 people. In recent years, the introduction of enzyme replacement therapy, substrate reduction therapy and small molecule therapy, has changed the natural course of this otherwise progressive group of disorders leading to severe morbidity and early mortality. These treatment options, however, are extremely expensive and are needed for life thus presenting an economical as well as ethical challenge to the affected families and the health care system of a country. This paper presents a case for the prevention of the lysosomal storage disorders as a model for other inherited metabolic disorders in the form of antenatal testing and cascade screening for couples and families at risk of having affected off-springs and compares it to the cost incurred on the enzyme replacement therapy in the backdrop of the health care priorities of Pakistan, a low middle income country. Similar economic and ethical challenges are faced by most low and middle income countries. The literature search was done using Pubmed and Clinical trials databases using keywords: [Lysosomal storage disorders], [natural course], [ethics], [cascade screening], [Thalassemia] and [cascade screening]. A total of 225 articles in English language were scanned from 1980-2016, 80 articles describing the natural course of LSD with and without ERT, ethical issues related to the treatment of LSD and strategies employed for the prevention of genetic disorders were prioritized

Griscelli syndrome type 2 - A case report and clinical approach to silver blonde hair

Griscelli syndrome type 2 is a rare autosomal recessive disease caused by mutations in the RAB27A gene. It is characterized by pigmentary dilution of the skin and hair causing silvery gray hair, hemophagocytic lymphohistiocytosis and characteristic light microscopy findings in scalp hair shaft seen as large irregular clumps of pigment as opposed to the evenly distributed pigment along the hair shaft without any clumps. We describe a boy with classic features of Griscelli syndrome type 2 from Pakistan in whom a homozygous mutation in the RAB27A gene was identified that showed a single base substitution [c.598C>T] predicted to cause premature protein termination [p.Arg200[asterisk]]. We also present a clinical approach to silver blonde hair differentiating between the Griscelli syndrome types 1, 2 and 3, Chediak Hegashi Syndrome and Elejalde Syndrome

Diagnosis, treatment and follow-up in four children with biotinidase deficiency from Pakistan

Biotinidase deficiency is an inherited disorder in which the vitamin biotin is not recycled. If untreated, affected individuals develop neurological and cutaneous symptoms. Untreated individuals with biotinidase deficiency either succumb to disease or are left with significant morbidity. We describe clinical course and follow-up of 4 children from Pakistan. All 4 presented with classical symptoms of biotinidase deficiency and responded dramatically to oral biotin within days to weeks. Biotinidase deficiency is reported in Pakistani children from different part of world, however; there is no such report from Pakistan. This highlights lack of awareness of biotinidase deficiency among physicians in Pakistan.

Newborn screening in Pakistan - lessons from a hospital-based congenital hypothyroidism screening programme

We are living in a time of unprecedented increase in knowledge and rapidly changing technology. Such biotechnology especially when it involves human subjects raises complex ethical, legal, social and religious issues. The establishment of newborn screening programmes in developing countries poses major challenges as it competes with other health priorities like control of infectious diseases, malnutrition and immunization programmes. Despite this, it is imperative that the importance of newborn screening programmes is recognised by developing countries as it has been proven through decades of experience that it saves thousands of babies from mental retardation, death and other serious complications. Pakistan has an estimated population of 167 million inhabitants, 38.3% of whom are under 15 years of age. Pakistan lacks a national programme for newborn screening. However, as individual practice at the local level, Aga Khan University Hospital (AKUH) and a few other hospitals are doing newborn screening for congenital hypothyroidism. The main hurdle in the implementation of newborn screening in Pakistan is the lack of good infrastructure for health. Eighty percent of deliveries take place at home. Moreover, little resources are available for children identified with a genetic condition due to the non-existence of genetic and metabolic services in Pakistan. In a 20-year audit of congenital hypothyroid screening at AKUH we found 10 babies with congenital hypothyroidism. However due to missing data links spanning several years, we were unable to calculate its true incidence during this period. In order to estimate the incidence of congenital hypothyroidism (CH) we reviewed in detail data over 10 months in 2008, a period where there was better compliance for repeat thyroid stimulating hormone (TSH) testing, and found 2 babies with CH. This gave an estimated incidence of 1 in 1600 live births.