Metabolic disorders are rare genetically determined disorders, affecting up to 1 in 1000 infants worldwide. More than 7000 Rare diseases have been reported globally and same is expected to be found in India. Genetic metabolic disorders contribute to about 10-15 per cent of them all. Although culturally we are a heterogeneous population and a melting pot of genetic diversity, our population is also known to indulge in consanguineous marriages and endogamy or marrying within communities, contributing somewhat to increasing the risk for acquiring Rare Diseases. One such rare group, commonly seen is a category of diseases called Inborn Errors of Metabolism (IEM).
The term IEM dates back to 1908 when it was coined by a British scientist, Sir Archibald Garrod referring to a group of disorders which have some biochemical aberration in body. In general, the metabolic diseases span across a wide range of conditions rising from defective genes resulting in enzyme deficiency. They account for 1-10 per cent of ICU admissions with 30-35 per cent mortality.
IEMs are broadly classified into three types: Intoxication type such as Aminoaciduria, urea cycle disorders, organic acidemias etc, these are the most commonly seen IEM’s and they lead to the increased accumulation of toxic substances that can lead to harmful effects. The second type are the Energy deficiency type such as Mitochondrial and glycogenosis & gluconeogenesis defects. The third are the storage type disorder such as lysosomal storage disorders, peroxisomal disorders etc, these disorders are gradually progressive.
IEM’s are caused due to genetic mutations in the child’s DNA that can lead to abnormal metabolic functions. These mutations are passed down from the parents and are commonly seen in couples who are carriers of certain mutations in their own DNA. These can be either autosomal recessive, wherein two defective genes from the parents come together in the affected child or X-linked where it is passed down through the X chromosome. There are also cases where mutations can occur spontaneously in the child without a family history, such mutations are called denovo mutations. The onset of symptoms can be sudden or may progress slowly over a period of time. Symptoms can occur at any age and the main symptoms seen are altered sensorium, seizures, stroke like episode, muscle spasms, poor feeding, fast breathing etc.
Diagnosis of IEM is usually carried out through routine biochemical analysis of the child’s blood or urine. These tests can be carried out in most diagnostic laboratories. Since IEM’s have a genetic basis a through genetic investigation using techniques such as Next Generation Sequencing (NGS) can give an accurate diagnosis or confirmation of the diagnosis previously made. NGS based genetic tests also provides clues to the origins of the mutations and strategies to prevent them from affecting future children. Using this information, the couple can undergo more rigorous prenatal screening if they decide to try for another child. In cases where natural pregnancy is an issue or depending upon their choice, the couple can go in for an In-vitro Fertilization (IVF) procedure and screen out affected embryos using a technique called Pre-Implantation Genetic Testing or Diagnosis (PGD). Healthy embryos after screening can be implanted and thus prevent the disorder from being passed on to future generations. Proper genetic counselling should be provided to the couple before they decide on their course of action.
Most IEM’s are treatable if they are identified early, parents and doctors need to be vigilant and spot the early warning signs of IEM’s. If caught early IEM’s can be effectively treated and long-term damage to the child can be prevented. One such example is one child, SP, who was well till 1 year of age. He developed breathlessness and some lethargy during a bout of acute gastroenteritis (loose motions). He received treatment and recovered well. But, similar episodes kept occurring every month, becoming more severe each time. In the third episode, the doctors realized that it could be an IEM and advised them to go to a higher centre, should the episode recur. The next episode occurred after a month, and the parents started for Delhi immediately. However, it was a long journey of 8-10 hours and by the time he reached our hospital, he was very sick, breathless, with poor pulse rate – in shock and severe metabolic acidosis. He was quickly revived and taken in to Pediatric ICU and investigated. After the metabolic testing an empirical treatment for an energy deficiency type of IEM was started, using high dose glucose infusions among other treatment. His liver had started to get worse and he was ventilated. Within hours of treatment for the IEM, he started improving.
Genetic testing results from MedGenome confirmed the diagnosis of Fructose-1,6-bisphosphatase deficiency (FBP1). This is a disorder of gluconeogenesis, meaning generation of energy or glucose from other sources such as fructose, galactose and amino-acids. A specific block in the pathway leads to stalling of glucose generation, severe metabolic and lactic acidosis, which may be life-threatening if left untreated. Upon timely detection, the simplest measures such as feeding glucose (either orally if stable, or intravenous) saves life and improves condition dramatically. Such is the power of genetic diagnosis, giving ‘sweet rewards’. The child is since doing well, under supervision, and has normal developmental milestones.
Today with technological advancements, we have come to a stage where in the improvements in neonatal healthcare has resulted in a decline in infant mortality. IEM’s although rare are commonly missed out. New Born Screening is a public health measure that can go a long way in catching these disorders much earlier and further reducing infant mortality. Innovation in diagnostics technology has benefitted patients with metabolic disorders and has helped in the early detection and prevention. The only thing that is needed is awareness so that we don’t miss out on these treatable disorders.
(The author is a Senior Consultant at Sir Ganga Ram Hospital, New Delhi)
