By Dr Akshata Raviraj Gondkar
A significant class of genetic illnesses known as inborn errors of metabolism (IEM) are brought on by single gene mutations (abnormal changes in the sequence of genes that code for certain proteins). When expressed, these mutations can alter the primary protein structure or the amount of protein produced. Whether a protein is an enzyme, receptor, transporter, membrane protein, transcriptional co-regulator, or structural component, its function may be hampered or lost. Inborn errors of metabolism or inherited metabolic illnesses are hereditary conditions that impair normal biochemical processes.
Babies are at risk for IEM when
- The parents may be carriers of the disease. Here the carrier state is not checked, which is not a routine thing anywhere.
- A consanguineous marriage is where there are many chances of the defective gene penetrating the present baby.
- There is an unexplained death of a previous sibling.
- There is developmental delay, Mental retardation in a sibling.
- The sibling had stayed in NICU with Hypoglycemia, Seizures, etc.
- There is a history of any IEM in a family. Mother had a history of Intrauterine death and recurrent miscarriages.
How to diagnose IEM?
The Newborn Screening Program is a method for identifying newborns who may have treatable IEMs. After 48 to 72 hours of delivery, a few blood droplets on Whatman Filter Paper 903TM will be blotted by the baby’s heel prick. The dried blood spot must be analyzed after drying for three to four hours at room temperature.
In India, most private institutions and a few public hospitals have taken the initiative to offer the actual tests listed below
Currently it is offered as Basic Newborn Screening which includes the testing for
1.Congenital Hypothyroidism– TSH
Thyroid function is affected leading to growth failure and mental retardation if not diagnosed and treated early.
2.Congenital Adrenal Hyperplasia- 17 OH Progesterone
Disorder which results in deficiency of synthesis of corticosteroids which can be detrimental and also bringing about gender detection dilemmas
(The most basic CH and CAH which may be considered as mandatory).
3.Glucose 6 Phosphate Dehydrogenase deficiency- G6PD enzyme
Enzyme deficiency leads to hemolytic anemia when exposed to oxidative agents.
Body’s ability to convert galactose to glucose is affected leading to mental retardation, cataract, impaired kidney function etc.
5.Biotinidase deficiency- Biotinidase Enzyme
Enzyme deficiency leading to accumulation of Biotin but Biotin is not able to actively participate in metabolism leads to seizures ,difficulty in vision, Mental retardation etc
(Offered as Basic 5).
Enzyme deficiency of Phenylalanine hydroxylase leading to accumulation of Phenylalanine and getting diverted to produce toxic metabolitesleading to defects in pigmentation, Mental retardation.
7.Cystic Fibrosis- Immunoreactive Trypsinogen
Leads to Respiratory distress, affects the digestive system with blockages etc.
8.Maple Syrup Urine Disease – Branched Chain amino acids
Enzymes which break the branched chain amino acid are deficient or defective leading to accumulation of toxic products.
(Offered as Basic 7)
Similarly through screening for the 22 Acyl carnitines and 12/20 Amino acids along with Urine Organic Acids We can screen for IEMS belonging to below metabolisms which is most of the times offered as the Extended panel for Newborn Screening
Organic acid metabolism disorders
●Methylmalonic acidemia (methylmalonyl-CoA mutase deficiency)
●Methylmalonic acidemia (cobalamin disorders)
●3-methylcrotonyl-CoA carboxylase deficiency
●Holocarboxylase synthetase deficiency
●Glutaric acidemia type 1
Fatty acid oxidation disorders.
●Carnitine uptake defect/carnitine transport defect
●Medium-chain acyl-CoA dehydrogenase deficiency
●Very long-chain acyl-CoA dehydrogenase deficiency
●Long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency
●Trifunctional protein deficiency
Amino acid metabolism disorders.
●Argininosuccinic aciduria, Arginenimia, Citrullinemia type 1- Urea Cycle Disorders.
●Maple syrup urine disease
●Tyrosinemia type I , Type 2
●Screening for Hb S, HbE and Hb D
The earlier someone experiences IEM symptoms; their illness will be more serious. The position of the faulty enzyme within the metabolic pathway and the production of any functional enzymes or co-factors affect how severe the symptoms are, in general. The intensity of symptoms for a particular patient, however, may depend on additional environmental and hereditary factors.
Due to the multisystemic nature of IEM, patients may exhibit a wide range of symptoms, many of which depend on the particular metabolic pathway(s) involved. Low blood sugar, high blood ammonia, abnormal liver function tests, raised blood acid levels, and aberrant blood cell morphology are some symptoms that people with IEM may have. Neurologic issues in some patients, such as seizures and developmental delays, are also possible. Growth may be impacted as well.
Based on the following criteria defined by Wilson Jugner as recommended by WHO. Any region can define its panel for Newborn Screening.
Wilson-Jungner criteria for disease selection in NBS:
1. The condition should be an important health problem
2. The natural history of the situation should be well understood
3. It should be detectable at an early age
4. Treatment at an early stage should be beneficial
5. A suitable test should be devised for early detection
6. The test should be acceptable
7. Intervals for repeating the test should be available
8. Adequate health service provision should be made for the extra clinical workload resulting from the screening
9. The risks, both physical and psychological, should be less than the benefits.
10. The cost should be balanced against the benefits.
Need for Newborn Screening in India:
Although the exact incidence in India is unknown, approximately 4:1000 and 5:1000 are estimated to have hearing defects and congenital heart abnormalities, respectively. In contrast, the incidence of IEMs is estimated to be approximately 1:1000.
Though most of the IEMs are not curable, most of them are treatable. Early diagnosis through Newborn screening, compliance with treatment, and dietary restrictions can ensure an improved quality of life and prevent neurological, developmental, and intellectual disabilities. Thereby we can build a better future INDIA.
Dr Akshata Raviraj Gondkar, Consulatnt Biochemist for Division of Newborn Screening & Biochemical Genetics, Department of Mass Spectrometry, Neuberg Anand Reference Laboratory.
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