Inborn Errors of Metabolism (IEM)

• Inborn Errors of Metabolism (IEM) are genetic diseases involving metabolic disorders.
• IEMs are often referred to as congenital metabolic diseases or inherited metabolic diseases.
• The majority of IEMs are caused by defects in a single gene coding for an enzyme.
• These defects cause deficiencies in enzymes or accumulation of abnormal metabolites.

Garrod's Hypothesis

• Illustrates how inherited metabolic disorders can lead to enzyme deficiencies.
• These deficiencies can result in substrate excess or the production of toxic metabolites.

Mode of Inheritance of IEM

• IEMs are usually autosomal recessive.
• Consanguinity, ethnicity, and inbreeding can increase the risk of autosomal recessive IEM.
• Some IEMs are sex-linked recessive, like Fabry's Disease, Hunter Syndrome, Menke Syndrome, and Lesch-Nykan Syndrome.
• Some IEMs are autosomal dominant, including Maturity Onset Diabetes of the Young (MODY), hyperlipidemia, and Hereditary angioedema.

Early Clinical Signs of IEM (Neonatal Period)

• Acute life-threatening illness with encephalopathy (lethargy, irritability, coma), vomiting, and respiratory distress.
• Unusual odor of body fluids and dysmorphia may be present.
• Emesis, hiccups, seizures, and hypotonia can occur.
• Fetal history may show unexplained death or illness.
• Extensive dermatitis can be a sign.

Early Childhood Manifestations of IEM

• Include mental retardation, myopathy/cardiomyopathy, and hepatic dysfunction.
• Dysmorphia, facial distortion, convulsion, and renal dysfunction are also indicators.

Diagnosis of IEM

• Includes family history with DNA analysis and analysis of metabolites associated with early symptoms.
  • Tandem mass spectrometry is used.

Medical Intervention for IEM

• Involves dietary therapy and educational counseling to ensure adherence to specific diets, such as protein restriction.
• Restriction of environmental triggers and pre-conception counseling are also essential.

Major Categories of IEM

• Disorders of carbohydrate metabolism, such as Galactosemia, glycogen storage disorders, and diabetes
• Disorders of protein/amino acid metabolism, like organic acidopathies, amino acidopathies, and urea cycle defects.
• Disorders of fatty acid oxidation, such as medium-chain acyl CoA dehydrogenase (MCAD) deficiency.
• Mitochondrial disorders
• Lysosomal disorders, such as Hurler syndrome, Hunter syndrome, and Tay-Sachs.
• Peroxisomal disorders , like Zellweger spectrum and X-linked adrenoleukodystrophy (X-ALD).

Organic Acidemias

• Important inherited metabolic disorders resulting from defects in carbohydrate, amino acid, and fatty acid oxidation pathways.
• Leads to accumulation of organic acids in tissues, excreted in urine.
• Characterized by metabolic acidosis with ketosis and elevated lactate.
• Mild to moderate hyperammonemia can occur. Symptoms include vomiting, signs of encephalopathy, neutropenia, and thrombocytopenia.

Fatty Acid Oxidation Defects

• Distinct type of organic acid disorder characterized by hypoketotic hypoglycemia, hyperammonemia, and cardiomyopathy.
• Can present clinically with Reye's syndrome.
• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) is common, accounting for about 5% of SIDS cases.

Primary Lactic Acidaemia

• Involves mitochondrial enzyme defects, such as deficiencies in pyruvate dehydrogenase, pyruvate carboxylase, and cytochrome oxidase.
• Results in severe lactic acidaemia.

Aminoacidopathies

• Conditions often associated with a distinct odor.
• Three types: Phenylketonuria, Homocystinuria, and Maple Syrup disease.
• Can have similar presentations to organic acidemias but are a heterogeneous group of disorders.

Phenylketonuria (PKU)

• Caused by a mutation in a gene on chromosome 12 that codes for phenylalanine hydroxylase (PAH), an enzyme in the liver.
• Autosomal recessive metabolic genetic disorder characterized by a deficiency in hepatic enzyme PAH.
• This enzyme is needed to metabolize phenylalanine.
• A deficiency causes phenylalanine to accumulate, converting into phenylpyruvate, which is detected in the urine.
• Problems with brain development can occur, leading to progressive mental retardation, brain damage, and seizures.
• Optimal treatment involves lowering blood phenylalanine to a safe range and monitoring diet and cognitive development.
• PKU is normally detected using the HPLC test after birth.
• Disease presents clinically with seizure, albinism, and a "musty odour" in the baby's sweat and urine.
• Diagnosis is through Guthrie Test or Tandem Mass Spectrophotometry, indicated by > 20mg/dl of Phenylalanine and elevated Phenyl pyruvic acid.
• Management involves controlling phenylalanine levels through diet and medication.
• Patients must adhere to a special diet low in phenylalanine for at least 16 years, restricting meat, chicken, fish, eggs, nuts, cheese, legumes, and dairy.
• Starchy foods like potatoes, bread, pasta, and corn must be monitored.
• Infants require commercial formula free from phenylalanine.
• Tyrosine, normally from phenylalanine, must be supplemented.
• Aspartame must be avoided, as it contains phenylalanine and aspartic acid.
• L-dopa and tetrahydrobiopterin (BH4) can reduce blood phenylalanine levels.
• Fruits and vegetables low in phenylalanine are added to the diet during childhood.

Homocystinuria

• Disorder of methionine metabolism, causing abnormal accumulation of homocysteine in blood and urine.
• Normally, methionine converts to homocysteine, which undergoes trans-sulfuration to yield cysteine, catalyzed by cystathionine beta synthase (CBS).
• Those with homocystinuria cannot synthesize CBS, leading to an inability to metabolize methionine.
• Under normal conditions homocysteine, is remethylated to methionine, catalyzed by methionine synthase.
• Reactions require 5-methyltetrahydrofoliate and Vitamin B12, as well as S-adenosylcobalamin as co-factors.
• Treatment options include restricted diet, Vitamin B6, folate and Trimethylglycine (lowers homocysteine levels)
• Diagnosis includes elevation of methionine and homocysteine in bodily fluids.
• Freshly voided urine should be tested for homocysteine, as it is unstable and degrades in stored urine.
• Cystineis is low or absent in the plasma.

Maple Syrup Urine Disease (MSUD)

• Branched-chain ketoaciduria, an autosomal recessive metabolic disorder affecting branched-chain amino acids.
• Caused by a deficiency of branched-chain alpha-keto acid dehydrogenase complex (BCKDH).
• Leads to a buildup of branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products.
• Characterized by sweet smelling urine in infants, resembling maple syrup.
• Infants appear healthy at birth, but without treatment, can suffer severe brain damage and death.
• Early infancy symptoms include poor feeding, vomiting, dehydration, lethargy, seizures, hypoglycaemia, ketoacidosis, pancreatitis, coma, and neurological decline.
• Keeping blood chemistry under control requires special and frequent testing
• Maintaining low leucine, isoleucine, and valine prevents neurological damage.
• Specialized protein preparations with substitute and adjusted amino acid levels are used to meet nutritional needs without harm.

Lipidoses

• The body cannot properly digest fats, leading to abnormal lipid accumulation in tissues. Examples include Sandhoff disease, Niemann-Pick Disease, Gaucher disease, Metachromic Leukodystrophy, GM1 ganglosidosis, and GM2 gangliosidosis (Tay-Sach).

Peroxisomal Disorders

• Peroxisomes are essential for anabolic, catabolic, and biosynthesis of plasmanogens and bile salts.
• Disorders occur when there is a reduced number or dysfunction of peroxisomes and its enzymes.
• Types include Hyperpipecolic acidemia and Zellweger Spectrum (Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease).
• Clinical signs include hypotonia, dysmorphia, psychomotor delay, epilepsy, hepatomegaly, retinitis, and presbycusis (hearing loss).
• Diagnosis is via Immunoassay for peroxisomes and Aminocytes culture

Inborn Errors of Carbohydrate Metabolism

• Several forms of diabetes are associated with monogenic defects in β cell (insulin producing) function.
• Frequently characterized by onset of hyperglycemia at an early age.
• Referred to as maturity onset diabetes of the young (MODY).
• Inherited in an autosomal dominant pattern.
• MODY1 involves mutations in the gene that encodes Hepatocyte Nuclear Factor (HNF)-4α, located on chromosome 20q, altering glucose metabolism in the liver and impairing insulin secretion in β cells.
• MODY2 is caused by heterozygous mutation in the GCK on chromosome 7 for glucokinase, expressed in pancreatic β cells and liver, acting as a glucose sensor.
• Defective glucokinase activity decreases rate of glycolysis in pancreatic β cells.
• MODY3 involves HNF-1α mutations, resulting in mild diabetes symptoms.
• Mutations are located on Chromosome 12.
• MODY4 - Insulin promoter factor-1 (IPF-1) is a transcription factor required for the pancreas development, on chromosome 13q,.
• IPF-1 is implicated in the transcriptional regulation of key β cell specific genes GLUT-2 and glucokinase.
• MODY5 - HNF-1β located on chromosome 17q, is mutated which lead to cause end-stage renal failure and proteinuria.
• MODY6 - NeuroD1 is located on chromosome 2, causes defective binding of NeuroD1 to target promoters in pancreatic islets, leads to development of type 2 diabetes.

Urea Cycle Defects

• Include Citrullinemia, ornithine transcarbamylase deficiency, and arginosuccinic aciduria
• Result from inability to detoxify nitrogen.
• Characterized by severe hyperammonemia and respiratory alkalosis, onset after 24 hours of age.