Mendelian Disorders: Inborn Errors of Metabolism (IEM)

Mendelian Disorders: Inborn Errors of Metabolism (IEM)

Introduction to Metabolic Disorders

Metabolic disorders are a group of genetic conditions resulting from defects in the biochemical pathways that process nutrients for energy and cellular function. These disorders often arise due to mutations in genes encoding enzymes, leading to either the accumulation of toxic intermediates or the deficiency of essential products.

• Metabolism is the breakdown of ingested materials (carbohydrates, proteins, lipids) to produce energy.

• Genetic abnormalities affecting enzyme function can cause metabolic disorders.

• Disorders typically result from:

  • Inability to break down a substance, causing toxic intermediate accumulation.

  • Inability to synthesize an essential product.

• Most inborn errors of metabolism (IEM) are inherited in a Mendelian fashion (often autosomal recessive).

Energy Sources and Metabolic Pathways

Overview of Major Nutrient Classes

• Carbohydrates: Broken down into glucose; main storage form is glycogen (in liver and muscle).

• Lipids: Broken down into fatty acids; stored as triglycerides in adipose tissue.

• Proteins: Broken down into amino acids; used for protein synthesis and energy.

Carbohydrate Metabolic Disorders

Glycogen Storage Diseases (GSD)

Glycogen storage diseases are a group of inherited disorders caused by defects in enzymes involved in glycogen synthesis or breakdown. This leads to abnormal storage and utilization of glycogen, primarily affecting the liver, muscle, and other tissues.

• Glycogen: Main storage form of carbohydrates, composed of glucose units.

• Enzymes convert glucose to glycogen (glycogenesis) and glycogen to glucose (glycogenolysis).

• Type I (von Gierke disease): Deficiency of glucose-6-phosphatase in liver/kidney; leads to hypoglycemia, hepatomegaly, nephromegaly, and metabolic complications.

• Symptoms include chronic hunger, fatigue, irritability, and seizures (especially in infants).

Name & Enzyme	Affected Organs	Symptoms
Type 0 (Glycogen synthase)	Liver, muscle	Enlarged liver with fat accumulation; hypoglycemia when fasting
Type IA (von Gierke's disease, Glucose-6-phosphatase)	Liver, kidney	Enlarged liver/kidney, low blood sugar, growth delay, high uric acid
Type IB (Microsomal glucose-6-phosphate translocase)	Liver, white blood cells	Similar to Type IA, plus low white blood cell count, infections
Type II (Pompe's disease, Lysosomal glucosidase)	All organs	Enlarged liver/heart, muscle weakness
Type III (Forbes' disease, Debranching enzyme)	Liver, muscle, heart, white blood cells	Enlarged liver/cirrhosis, hypoglycemia, muscle/heart damage
Type IV (Andersen's disease, Branching enzyme)	Liver, muscle, most tissues	Cirrhosis, muscle/heart failure
Type V (McArdle's disease, Muscle phosphorylase)	Muscle	Muscle cramps/weakness during activity
Type VI (Hers' disease, Liver phosphorylase)	Liver	Enlarged liver, hypoglycemia when fasting
Type VII (Tarui's disease, Muscle PFK-1)	Skeletal muscle, red blood cells	Muscle cramps, hemolysis during activity

Galactosemia

Galactosemia is an inherited disorder caused by the inability to convert galactose to glucose due to deficiency of the enzyme galactose-1-phosphate uridyltransferase. This leads to toxic accumulation of galactose and its metabolites.

• Symptoms: Liver damage, central nervous system dysfunction, jaundice, vomiting, lethargy, convulsions.

• Treatment: Elimination of galactose/lactose from the diet to prevent brain and organ damage.

Fructose Intolerance

Hereditary fructose intolerance is caused by a deficiency of the enzyme aldolase B, leading to the inability to metabolize fructose. This results in hypoglycemia and accumulation of toxic substances in the liver.

• Symptoms: Hypoglycemia, vomiting, liver dysfunction, aversion to sweet foods.

• Inheritance: Autosomal recessive; prevalence up to 1 in 20,000 in some populations.

• Treatment: Avoidance of fructose, sucrose, and sorbitol in the diet.

Protein Metabolic Disorders

Phenylketonuria (PKU)

PKU is a common inborn error of amino acid metabolism caused by a deficiency of phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine. Accumulation of phenylalanine leads to neurotoxicity and intellectual disability if untreated.

• Symptoms: Intellectual disability, developmental delay, seizures, lighter skin/hair, musty odor.

• Inheritance: Autosomal recessive.

• Treatment: Lifelong dietary restriction of phenylalanine.

Inheritance Pattern:

• Both parents must be carriers for a child to be affected (25% risk per pregnancy).

Maple Syrup Urine Disease (MSUD)

MSUD is a rare disorder affecting the metabolism of branched-chain amino acids (leucine, isoleucine, valine) due to defects in the branched-chain alpha-keto acid dehydrogenase complex.

• Symptoms: Poor feeding, vomiting, lethargy, developmental delay, seizures, coma, and death if untreated.

• Characteristic: Sweet-smelling urine (like maple syrup).

• Inheritance: Autosomal recessive; incidence ~1 in 185,000 infants worldwide.

• Treatment: Dietary restriction of BCAAs.

Lipid Metabolic Disorders

Lipid Storage Diseases (Lipidoses)

Lipid storage diseases are inherited disorders in which harmful amounts of fatty materials accumulate in cells and tissues, leading to progressive organ dysfunction.

• Commonly affected organs: Brain, peripheral nervous system, liver, spleen, bone marrow.

Gaucher Disease

• Most common lipid storage disease; caused by deficiency of glucocerebrosidase.

• Accumulation of glucocerebroside in spleen, liver, kidneys, lungs, brain, bone marrow.

• Symptoms: Enlarged spleen/liver, bone pain, anemia, low platelets, neurological complications.

Niemann-Pick Disease

• Caused by deficiency of acid sphingomyelinase (ASM), leading to accumulation of sphingomyelin in lysosomes.

• Symptoms: Hepatosplenomegaly, neurodegeneration, failure to thrive, early death (in severe forms).

Diagnosis of Metabolic Disorders

Diagnostic Approaches

• Diagnosis is challenging due to symptom overlap with common diseases.

• Requires multidisciplinary coordination and thorough clinical assessment.

• Key diagnostic tools:

  • Blood and urine analysis

  • Genetic testing (DNA sequencing, protein/enzyme assays, chromosomal analysis)

  • Prenatal screening (amniocentesis, chorionic villus sampling, ultrasound, maternal serum sampling)

  • Newborn screening

Test	Gestation	Abnormalities Detected	Risk of Procedure
Amniocentesis	16-18 weeks	Fetal karyotyping, biochemical assays	Miscarriage rate 0.5-1% above normal at 16 weeks
Chorionic villus sampling	10-12 weeks	Fetal karyotyping, biochemical assays, DNA analysis	Miscarriage rate 1.5% above normal at 10 weeks
Ultrasound	Any time	Congenital malformations	Very low risk
Maternal serum sampling	16-18 weeks	Maternal infection, serum levels of hCG, AFP, estradiol	Very low risk

Genetic Testing

• Can detect mutations in DNA, protein abnormalities, or chromosomal defects.

• Essential for confirming diagnosis and carrier status in families.

References

• Biochemistry – Lippincott’s Illustrated Reviews

• Any standard biochemistry or genetics textbook