Metabolic Disorders Laboratory

Inborn Errors of Metabolism

FAQ’s about IEM

1. What are IEM?
2. Why screen for IEM?
3. When to screen for an IEM?
4. When to suspect an IEM?
5. Why do clinicians miss the diagnosis of an IEM?
6. What are the common clinical findings in IEM?
7. What is the role of a laboratory?
8. How does one treat / manage an IEM?
9. What is the significance of Genetic Counseling with respect to IEM?

1. What are IEM?

Inborn errors of metabolism (IEM) are rare a group of disorders that are individually rare but collectively common with clinical presentation ranging from a neonate to adults.

They have been long forgotten for reasons unknown. Rate of occurrence has been estimated at 1 in 5000 livebirths.

Basically, two categories exist based on the cytogenetics of inheritance - autosomal dominant (mostly manifesting in adults) and autosomal recessive (mostly manifesting in infancy and childhood). An X-linked inheritance is also noted.

One of the most common reason for their occurrence among populations is the practice of marriage within the same family. Children born to such couples are at a higher risk and are said to be "genetically pre-disposed".

It is basic to understand that these disorders are the result of defects or malfunction of genes or chromosomes.

2. Why screen for IEM?

The need to screen for an IEM arises out of the fact that most cases take to irreversible effects as time progresses. Emphasis has been laid on early detection and prompt management which have been responsible for alleviating symptoms and preventing complications. As a matter of fact, neonatal screening is mandatory in the United States, UK and other developed countries. Such a screen helps to prevent complications arising out of disorders such as Phenylketonuria, Tyrosinemia, Galactosemia, Hereditary Fructose Intolerance and other IEM. Symptoms of all such disorders could be prevented with dietary restriction of the offending food constituent- for example, Fructose in the case of Hereditary Fructose Intolerance, Tyrosine and Phenylalanine in the case of Tyrosinemia etc.

IEM screening could help in the detection of vitamin dependent states such as Biotinidase deficiency which require only optimal administration of the deficient vitamin. Such states when left unnoticed progress to fatal convulsive disorders.

3. When to screen for an IEM?

Screening for an IEM is done ideally between 5^th day and the 15^th day after birth. This provides an insight to the metabolic systems of the neonate and provides vital clues regarding any possible IEM. However, when neonatal screening has not been performed, the same could be performed at the request of a clinician at a stage when the parents have reported to him/her with a symptom, which raises an index of suspicion of a possible IEM.

4. When to suspect an IEM?

• Poor feeding, vomiting, diarrhoea, dehydration (common causes being ruled out).

• Temperature instability, reduced heart beat, breath holding, involuntary movements, irritability, seizures, abnormal muscular tone, altered levels of consciousness & skin rashes.

• Loss of or no growth of hair, developmental delay and altered facial features.

• In children of school going age, loss of hearing, learning disorders, aggresiveness, anxiety and seizures may necessitate an evaluation for an IEM.

While most IEM diagnosed at this age are not life-threatening, progression may lead to irreversible complications.

It is difficult to ascertain the presence of an IEM with these symptoms alone but they should definitely prompt an immediate evaluation request directed through their physicians.

5. Why do clinicians miss the diagnosis of an IEM?

The physical examination may be normal for patients with an IEM. When present, the physical signs provide important clues about the offending metabolite and consequently the diagnosis.

Clinical symptoms of IEM usually relate to major organ dysfunction and may also be seen in conditions such as sepsis, respiratory illness, cardiac disease and problems of the central nervous system.

A small index of suspicion by the clinician may provide a new direction and better management clues to the worried parents.

6. What are the common clinical findings in IEM?

In infants, recurrent episodes of vomiting, ataxia, convulsions, dysmorphic facial features, organomegaly, cardiomyopathy, respiratory tract infections, develpomental delay with missed milestones and audiovisual disabilities.

In children, learning disorders, behavioural disturbances, delirium, seizures, abnormal muscle tone and aggressive behavior.

7. What is the role of a laboratory?

The Metabolic Disorders Laboratory assumes responsibility when the sample from the suspected patient is sent for a screen or quantitation of a suspected offending metabolite or a specific enzyme assay. The initial evaluation consists of a Complete Blood Count (CBC), measurement of serum levels of lactic acid, electrolytes, glucose and plasma ammonia.

Renal function may be assessed by measurement of BUN, and creatinine. Hepatic function may be assessed by determinations of bilirubin, transaminases and prothrombin time.

Urinary screen to detect the presence of carbohydrates, amino acids, lipids, purines, pyrimidines and their metabolites may provide the necessary clues for further evaluation along with the above mentioned blood studies.

When a confirmation is necessitated, a specific enzyme assay with leucocytes, erythrocytes, fibroblasts or biopsy specimens may be performed. This could decide the further treatment / management of the case.

8. How does one treat / manage an IEM?

IEM in most cases are not treatable. This probably is the most important reason for the resistance offered to screening and detection of IEM. Management of an IEM is basically achieved by removing the offending food constituent from the diet of the neonate / child. In cases of Galactosemia, breast feeding must be stopped and Lactose free supplements need to be instituted as a diet. In cases of hyperammonemia, protein restriction in the diet is the mainstay of management. In aminoacidemias restriction of the aminoacids whose metabolites on accumulation may ameliorate the symptoms of the disorders is probably the best method of management. Management of acidosis, hypoglycemia and electrolyte disturbances need to be undertaken simultaneously, whenever required.

9. What is the significance of Genetic Counseling with respect to IEM?

Since IEM are hereditary disorders, family members need to be counseled about the probability of the next offspring being affected. This is of utmost significance in families who have a known history of such occurrences. Decision on whether or not the pregnancy should be continued should be left to the couple. Wherever applicable, the members of the family need to be evaluated and informed. Genetic counseling should ideally consist of a convincing explanation of the risk factors, possibilities of a prenatal diagnosis and management protocols in the event of occurrence.

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