Approach And Basics Of Inborn Errors Of Metabolism

Inborn Errors of Metabolism (IEMs) 

The All India Institute of Medical Sciences (AIMS) protocol states that over 500 metabolic disorders have been described. It is also referred to as a metabolic disorder. A genetic fault of a particular enzyme produces an obstruction in the normal metabolic route that results in an illness known as an inborn error of metabolism (IEM). This genetic problem can be inherited or result from random mutations like de novo. Familial inheritance accounts for the majority of cases.

Three Major Mechanisms

One of two things will happen: either there won't be enough of a certain product produced, or there won't be any of it.  An excess of metabolites resulting from an enzyme deficiency might occasionally cause disorders like phenylketonuria. Aberrant mediators are formed as a result of an enzyme deficit.

Suspension of Inborn Errors of Metabolism

A decline following a time of seeming normalcy In this case, the youngster appears normal at first, but all of a sudden, several organ function systems may begin to fail. The consanguinity of parents
Consensus marriages are strongly correlated with inborn metabolic diseases, specifically mitochondrial illnesses.

Neonatal death history in the family Inborn errors of metabolism should be considered by the patient if early, unexplained newborn deaths occur.
According to the 19th edition's diagnosis and therapy, metabolic mistakes should be suspected in cases of unexplained neonatal fatalities in the family.

Seizures and encephalopathy that worsen quickly and have no known etiology. However, if there is an unexplained encephalopathy that is progressing quickly with seizures, inborn metabolic abnormalities should be explored. Severe, unexplained metabolic acidosis suggests the possibility of IEM. Inborn abnormalities in metabolism may manifest as persistent vomiting. Odor, especially peculiar, especially coming from the urine and occasionally the breath, will be a specific indicator of inborn metabolic abnormalities.

Clinical Pointers Toward a Specific Item   

1. Cherry Red Spot

The cherry red patch is observed in cases of Niemann Pick , Tay-Sachs diseases and GM1 Gangliosidosis.

2. Coarse Facies

Seen in 

• Polymeric acid synthases.
• Gangliosidosis type 1.
• Pompe's disease, which is essentially a disease of glycogen storageSort 2.

Q. Which is the glycogen storage disease shown in coarse facies?

Ans. Pompe’s disease is the glycogen storage disease shown in coarse facies.

1. Cataract

Galactosemia is associated with cataracts. This will demonstrate whether oil drop cataracts are present. It is evident in Wilson's illness as well. This will demonstrate whether sunflower cataracts are present.

2. Skin Rash / Eczema / Alopecia

Multiple carboxylase deficiency is notably associated with certain dermatological abnormalities. It also manifests in the absence of biotinidase.

Hypopigmentation: This could indicate tyrosine metabolic disorders such phenylketonuria. Albinism also exhibits it.

3. Renomegaly 

 In 2019, it is included in the AIIMS protocol. Renomegaly is a characteristic of Zellweger syndrome as well as Von-Girke illness. Under certain conditions, an ultrasonography can reveal abnormal increases in the size of the kidneys.

4. Retinitis Pigmentosa

It is a feature of mitochondrial defects.

Abnormal Urine Odours

• Mousy Odour: This is also known as a Musty odor which is the feature of Phenylketonuria.
• Rancid odor(like expired butter): This is the feature of tyrosinemia.
• Cabbage-like odor: This is seen in methionine defects.
• Tom cat urine odor: This is seen in multiple carboxylase deficiencies.
• Sweaty feet odor: This is seen in isovaleric acidemia.
• Fruity/Sweety odor: This is seen in ketones due to Diabetic ketoacidosis, Starvation, and Vomiting.
• Maple syrup odor: This is seen in Maple syrup urine disease.

Also Read: Development & Behaviour Disorders Image Based Question

Screening for Neonatal Inborn Errors of Metabolism

The screening for neonatal IEM is done by Dried Blood Spot (DBS) method.

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Using aseptic measures, the child's heel pad is removed for pricking at certain locations, as illustrated in the image. Avoid pricks in the upper, middle, and lower portions of the heel by not squeezing the pad.  Spots of freely flowing blood are taken on blotting paper and treated with various reagents. A single drop is extracted and used for analysis for every circle. Tandem mass spectrometry (TMS) is the method used for analysis.

Panel of Investigation Needed

First-line investigation in IEM is complete hemogram: RBC indices, DSR platelet count, or High-Performance Liquid Chromatography (HPLC) are utilized. 

Blood glucose: A baby can have any random blood glucose sample collected; fasting is not necessary because it is not practical for them.  ABG with lactate levels: This indicates whether the patient exhibits any signs of metabolic acidosis. Serum lactate levels operate as a marker for a number of problems, including fatty acid oxidation defects, mitochondrial defects, and Won Gierke disease (Type 1 GSD). Serum electrolytes.

Plasma ammonia: In cases of hyperammonemia and urea cycle abnormalities.

Serum uric acid: Hepatic involvement is typical of many IEMs.  

Urine analysis: To diagnose individuals with Galactosemia and check urine for ketones, urine-reducing agents are essential. 

Four Vial Systems

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The image's purple vial, which already contains EDTA, is used to collect the hemogram sample. The red vial, commonly known as the serum separator, is helpful for checking electrolytes among other things.
Heparin, which is helpful for taking blood ammonia levels, is contained in the green vial. Oxalate, an anticoagulant, is contained in the grey vial.

Ancillary and Confirmatory Tests

Tandem Mass Spectrometry for Plasma (TMS)
• It helps identify problems in the urea cycle.
• Eczema of organic acid.
• Defects related to the oxidation of fatty acids (FAO).
• Disorders involving amino acids

Organic Acidemias can be performed with Urine Gas Chromatography-Mass Spectrometry (GCMS). 

Urinary Orotic Acid (UAA): This is helpful in identifying the many cycles of Urea Cycle Defects. 

High-Performance Liquid Chromatography (HPLC): It helps with Aminoacidopathies and Organic Acidemias.

Role of Imaging in Inborn Errors of Metabolism

1. MRI Brain

Patients with Zellweger Syndrome exhibit anomalies related to Sulcation or Diffuse Cortical migration in the brain. So, one characteristic of Zellweger Syndrome is a relatively smooth brain. 
Three IEMs—Pyruvate decarboxylase deficiency, Non-Ketotic Hyperglycemia, and Menke's disease—are linked to Agenesis of Corpus Callosum. It more frequently manifests as a solitary finding or a portion of a condition.
Maple syrup urine disease frequently manifests as brainstem and cerebellar edema.  Changes in the basal ganglia are frequently observed in organic acidemias, including methylmalonic acidemia (MMA) and propionic acidemia.  Patients with glutaric aciduria may experience repeated subdural hematomas and frontotemporal atrophy.

Magnetic Resonance Spectroscopy (MRS)

• MRS can be understood by evaluating different peaks.
• Lactate peak is seen in mitochondrial disorders.
• Glycine peak is seen in patients with NKH.
• Leucine peak is seen in patients with Maple syrup urine disease.

Q. Which peak is seen in MSUD?

Ans. Leucine peak is seen in MSUD.

2. Electroencephalography in Inborn Errors of Metabolism

Comb like  Rhythm It is sometimes referred to as excessive frequent new activity and is a characteristic of MSUD.

Burst suppression pattern 

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Holocarboxylase Synthetase Deficiency and NKH are associated with it.  Patients with stage 3 HIV are the ones that experience it the most frequently. 

Approach

Two types Of Approach

• On basis of Blood ammonia level
• On basis of Blood glucose level

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On basis of Blood ammonia level

Let's say a patient may have IEM. The blood ammonia levels will then be tested as the initial procedure.  There are two possible outcomes: either blood ammonia levels are normal or they are elevated, a condition known as hyperammonemia. In both cases, an Arterial Blood Gas (ABG) test is carried out. 

There are two possible states of normal after ABG in which acidosis is not observed. In the event that acidosis is observed, the patient will either receive a new diagnosis or have one made.  The blood ammonia level is normal on the right side of the flow chart, which may indicate that there is no acidosis.

There won't be any ketosis if the ammonia levels are elevated and the ABG doesn't indicate acidosis. Consequently, the most likely diagnosis will be urea cycle defects.  A different diagnosis should be suspected if there is a substantial acidosis.  Ketosis may or may not be present in individuals with acidosis.  A patient in ketosis may have organic acidemia or mitochondrial problems, while the likelihood of no ketosis is a fatty acid deposition defect.  If everything checks out OK, PKU, NKH, peroxisomal abnormalities, amino acidopathies, and galactosemia are the most likely diagnoses.

Based on Blood Glucose Level

Approach to Inborn Errors of Metabolism

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The first test that should be performed when a newborn patient has hypoglycemia that is recurrent or resistant is a urine examination for reducing substances, especially non-glucose-reduction medications. 

Galactosemia is most likely the diagnosis if it is present.
Urine ketone levels will be measured in the event that the urine-reducing drug is not present.  Whereas the condition will be fatty acid defects, oxidative defects, ketogenic defects, and hyperinsulinism if ketone levels are absent, the likely diagnosis will be glycogen storage disease, gluconeogenesis defects, and organic acidaemia.

Q. Cardiomyopathy is a feature of which Inborn Errors of Metabolism?

Ans:

• Pompe’s disease (Glycogen storage disorder, type 2)
• Fatty acid oxidation Defect
• Mitochondrial electron transport chain defects.

Also Read: NEET SS Pediatrics Growth and Development Questions

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