Inborn Errors Of Metabolism (IEM)

Introduction Metabolism: chemical or physical changes undergone by substances in a biological system. Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm

How do you recognize a metabolic disorder ? Laboratory tests Glucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen), Creatinine. Lactate, Ammonia, Bilirubin. Amino acids, Organic acids, Reducing subst. DNA analysis.

Definition of Inborn errors of metabolism IEM are a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function. Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally. Food not broken down properly may produce chemicals that build up in various parts of the body causing medical problems and learning disorders.

IEM are usually Autosomal recessive. Some are x-linked recessive condition including: Agammaglobulinemia. Granulomatous disease. Hunter’s Syndrome. A few inherited as Autosomal dominant trait including: hyperlipedemia

Categories of IEMs Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, and urea cycle defects) Disorders of carbohydrate metabolism (eg, carbohydrate intolerance disorders, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Lysosomal storage disorders Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders The lysosome is commonly referred to as the cell’s recycling center because it processes unwanted material into substances that the cell can utilize. Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or so-called mucopolysaccharides. Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generates energy for the cell. Mitochondria are found in every cell of the human body except red blood cells and convert the energy of food molecules into the ATP that powers most cell functions.

Pathophysiology Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats. Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, and/or defects in energy production and utilization caused by a deficiency of products beyond the block. Every metabolic disease has several forms that dependent on: age of onset, clinical severity and, mode of inheritance.

The Type of Inborn Errors of Metabolism Type 1: Silent Disorders Type 2: Acute Metabolic Crises Type 3: Neurological

Type 1: Silent Disorders Untreated could lead to brain damage and developmental disabilities. Example: PKU (Phenylketonuria). First newborn screening test was developed in 1959 Error of amino acids metabolism. Incidence of 1: 15,000 No acute clinical symptoms Untreated leads to mental retardation Associated complications: behavior disorders, skin disorders, and movement disorders Treatment: phenylalaine restricted diet (specialized formulas available).

Clinical Features Diagnosis Hyperactivity, vomiting. Blond eczema skin. Seizures. Severe mental retardation. Bad odor of phenyl acetic acid. Diagnosis Screening : Guthrie Test. High Phenylalanine > 20 mg/dl. High Phenyl pyruvic acid. a screening for phenylketonuria (PKU) used to detect the abnormal presence of phenylalanine metabolites in the blood. A small amount of blood is obtained and placed in a medium with a strain of Bacillus subtilis, a bacterium that cannot grow without phenylalanine. If phenylalanine metabolites are present, the bacteria reproduce, and the test result is positive, indicating that the patient has phenylketonuria. 

Nutritional Treatment Restrict the food sources of phenylalanine Supplement the tyrosine Provide adequate calories, protein, fats and carbohydrates, vitamins and minerals for meeting energy needs, growth and development.

Type 2: Acute Metabolic Crisis Life threatening in infancy Children are protected in utero by maternal circulation which provide missing product or remove toxic substance Example: Urea Cycle Disorders: is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic substance, and is not removed from the body.

Urea Cycle Disorders Appear to be unaffected at birth In a few days develop vomiting, respiratory distress, and coma. Symptoms mimic other illnesses Untreated results in death

Type 3: Progressive Neurological Examples: Tay Sachs disease, Gaucher disease DNA analysis show: mutations Nonfunctioning enzyme results: Early Childhood: progressive loss of motor and cognitive skills. Pre-School: non responsive state. Adolescence: death

Disorders of protein metabolism

Tyrosinemia Hereditary tyrosinemia is a genetic inborn error of metabolism associated with severe liver disease in infancy. The disease is inherited in an autosomal recessive. In families where both parents are carriers of the gene for the disease, there is a one in four risk that a child will have tyrosinemia. About one person in 100 000 is affected with tyrosinemia globally.

How Is Tyrosinemia Caused Tyrosine is an amino acid which is found in most animal and plant proteins. The metabolism of tyrosine in humans takes place primarily in the liver. Tyrosinemia is caused by an absence of the enzyme fumarylacetoacetate hydrolase (FAH) which is essential in the metabolism of tyrosine. The absence of FAH leads to an accumulation of toxic metabolic products in various body tissues, which in turn results in progressive damage to the liver and kidneys.

symptoms Of Tyrosinemia The clinical features of the disease ten to fall into two categories, acute and chronic. In the so-called acute form of the disease, abnormalities appear in the first month of life. Babies may show poor weight gain, an enlarged liver and spleen, a distended abdomen, swelling of the legs, and an increased tendency to bleeding, particularly nose bleeds. Jaundice may or may not be prominent. Death from hepatic failure frequently occurs between three and nine months of age unless a liver transplantation is performed.

Some children have a more chronic form of tyrosinemia with a gradual onset and less severe clinical features. In these children, enlargement of the liver and spleen are prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting and diarrhoea occur frequently. Affected patients usually develop cirrhosis and its complications. These children also require liver transplantation.

Disorders of carbohydrate metabolism

Galactosemia is an inherited disorder that affects the way the body breaks down certain sugars. Specifically, it affects the way the sugar called galactose is broken down. Galactose can be found in food by itself. Two types Galactokinase deficiency Galactose-1-phosphate uridyl transferase deficiency (GALT) –Classic galactosemia Because of the lack of the enzyme (galactose-1-phosphate uridyl transferase) which helps the body break down the galactose, it then builds up and becomes toxic. In reaction to this build up of galactose the body makes some abnormal chemicals.

The build up of galactose and the other chemicals can cause serious health problems like a swollen and inflamed liver, kidney failure, stunted physical and mental growth. If the condition is not treated there is a 70% chance that the child could die. Deficiency of galactose-1 phosphate uridy l transferase 1/50,000 Start early after feeding Affect brain, liver, kidny and overies

Clinical management No enzyme: accumulation of galactose1 phosphate Liver: cirrhosis Kidney: fancony syndrome Brain: mental retardation Ovary: amenorrhea management Lactose free formula Control seizure Consult ophthalmology Consult endocrinology

First line investigations (metabolic screen) The following tests should be obtained in ALL babies with suspected IEM. Complete blood count Arterial blood gases and electrolytes Blood glucose Plasma ammonia (Normal values in newborn: 90-150 mg/dl or 64-107 mmol/L). Arterial blood lactate (Normal values: 0.5-1.6 mmol/L) Liver function tests Urine ketones

Second line investigations (confirmatory tests) Gas chromatography mass spectrometry (GCMS) of urine. High performance liquid chromatography (HPLC): for quantitative analysis of amino acids in blood and urine; required for diagnosis of organic acidemias and aminoacidopathies. Lactate/pyruvate ratio: in cases with elevated lactate. Enzyme assay: This is required for definitive diagnosis, but not available for most IEM’s. Available enzyme assays include: biotinidase assay- in cases with suspected biotinidase deficiency. Mutation analysis when available.

Precautions to be observed while collecting samples Should be collected before specific treatment is started or feeds are stopped, as may be falsely normal if the child is off feeds. Samples for blood ammonia and lactate should be transported in ice and immediately tested. Lactate sample should be arterial and should be collected after 2 hrs fasting in heparinized syringe. Ammonia sample is to be collected approximately after 2 hours of fasting in EDTA vacutainer. Detailed history including drug details should be provided to the lab.

Aims of treatment To reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism) To provide adequate calories. To enhance the excretion of toxic metabolites. To institute co-factor therapy for specific disease and also empirically if diagnosis not established. Supportive care