Inborn Errors of Metabolism Dr Lucy Mungai University of Nairobi

Inborn Errors of Metabolism(IEM) Disorders in which a gene defect causes a clinically significant block in a metabolic pathway(enzyme deficiency or transport protein defect). Resulting either in accumulation of substrate before the block or deficiency of the product. Genetically transmitted congenital disorders of metabolism. The term inborn errors of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.[3]

What is a metabolic disease? Garrod’s hypothesis product deficiency Substrate excess toxic metabolite C A B D

Pathophysiologic classification Disorders that result in toxic accumulation Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) Disorders of carbohydrate intolerance Lysosomal storage disorders Disorders of energy production, utilization Fatty acid oxidation defects Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Mitochondrial disorders Peroxisomal disorders

An integrated view of the metabolic pathways GLYCOGEN FAT PROTEIN FRUCTOSE GALACTOSE AMINO ACIDS GLUCOSE FREE FATTY ACIDS ORGANIC ACIDS AMMONIA PYRUVATE LACTATE ACETYL CoA UREA CYCLE KETONES UREA KREBS CYCLE NADH ATP An integrated view of the metabolic pathways

Classification of IEMs Aminoacidopathies e.g., phenylketonuria, hereditary tyrosinemia, nonketotic hyperglycinemia, maple syrup urine disease and homocystinuria. Hereditary tyrosinemia can present in the neonate with a bleeding diathesis due to liver disease, or later in infancy with a renal Fanconi syndrome. nonketotic hyperglycinemia presents as unremitting seizures with hypotonia and hiccoughs. MSUD classically presents at the end of the first week of life with feeding difficulties, lethargy, coma, seizures and the characteristic odor. Urea cycle defects (e.g., citrullinemia, ornithine transcarbamylase deficiency, and arginosuccinic aciduria) result from the inability to detoxify nitrogen and are characterized by severe hyperammonemia and respiratory alkalosis, with a typical onset after 24 hours of age Aminoacidopathies may have similar presentation to the organic acidemias, but are a very heterogeneous group of disorders

Classification of IEMs Disorders of carbohydrate metabolism (e.g., galactosemia, hereditary fructose intolerance, fructose 1,6-diphosphatase deficiency and the glycogen storage diseases) inability to metabolize specific sugars, aberrant glycogen synthesis, or disorders of gluconeogenesis. manifest with hypoglycemia, hepatosplenomegaly, lactic acidosis or ketosis. Lysosomal storage disorders (e.g., mucopolysaccharidosis, Tay-Sachs, Niemann-Pick disease, Gaucher’s disease) caused by accumulation of glycoproteins, glycolipids, or glycosaminoglycans within lysosomes in various tissues. present later infancy, not with a specific laboratory abnormality, but with organomegaly, facial coarseness ,neurodegeneration and show a progressively degenerative course.

Classification of IEMs Organic acidemias (e.g. propionic acidemia, multiple carboxylase deficiency) abnormal metabolism of proteins, fats or carbohydrates with marked metabolic acidosis with ketosis, elevated lactate &hyperammonemia. Common signs include vomiting, signs of encephalopathy, neutropenia and thrombocytopenia. Fatty acid oxidation defects/Beta-oxidation defects e.g., short, medium, and long- chain acyl-CoA dehydrogenase deficiencies characterized by hypoketotic hypoglycemia, hyperammonemia & cardiomyopathy. (MCAD) is among the most common of all IEMs and may account for 5% of SIDS cases. Primary Lactic Acidoses present with severe lactic acidosis (e.g., pyruvate dehydrogenase, pyruvate carboxylase and cytochrome oxidase deficiencies). Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)

Clinical Presentation Fetal development may have been normal, provided that the metabolites are able to cross the placenta and metabolized by mom. neonates may be asymptomatic, and may only become symptomatic after the initiation of feeds Newborn crash Multiple stillbirths or early childhood deaths suggestive, consanguinity unusual odor of urine or sweat  Usually term infant with well interval (The placenta filters the fetuses blood prior to birth) „ non-specific poor feeding, vomiting lethargy, progressing to seizures and coma „ occasionally abnormal odor of urine. Differentials of newborn crash:Adrenal insufficiency, sepsis, congenital heart disease, asphyxia

Clinical Presentation Toddlers and preschool-aged children present with stagnation or loss of cognitive milestones- language,attention developmental regression growth retardation seizures. History of growth disturbances, lethargy, recurrent emesis, poor feeding, rashes, seizures, hiccoughs, apnea, tachypnea.

History and Physical Subtle signs or symptoms Overt signs or symptoms Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changes Overt signs or symptoms Persistent hypoglycemia, acidosis, dehydration, shock, apnea, seizures, abnormal mental status, temperature instability, arrhythmia, cardiomyopathy, sudden death Dysmorphic features, strange odor, rashes, jaundice, organomegaly Some of the history deals with the usual questions we would ask about any sick kid. However some questions that specifically target IEM’s include sudden death of an infant, odd odor to infant, hx of birth trauma, parental consanguinity (remember most of these defects are autosomal recessive and consanguinity can select for recessive genes). Dysmorphic features should be looked for, but they are rare in most of these diseases. If they are present, they may be very helpful. Many of the signs and symptoms listed above can be seen in 100’s of diseases, but there can be clues that they are from a metabolic disease. The hypoglycemia is severe and persistent and can be difficult to treat. The acidosis is severe and not controlled by conventional cardiovascular support. In addition, you can dump significant amounts of bicarb in these infants and the acidosis doesn’t budge. One last thing about odors; in textbooks, you will read about sweaty foot odor or burnt sugar, fishy odor, etc. Many of these are not found in infants early on. Don’t rely on their presence to make a disgnosis. If present they are helpful, but if absent it doesn’t mean much, they still can have MSUD without the smell of burnt sugar in their urine.

Abnormal odors Burnt sugar,maple syrup — MSUD Sweaty socks /cheese-like — Isovaleric acidemia Fruity/ammoniacal — Methylmalonic acidemia or propionic acidemia Mouse urine/musty — Phenylketonuria Cabbage-like/rotten eggs — Tyrosinemia Malt/hops — Methionine malabsorption Cat urine — 3-Methylcrotonic acidemia, 3-hydroxy-3- methylglutaric aciduria Fish-like — Trimethylaminuria and carnitine excess

Laboratory findings Metabolic acidosis with increased anion gap, Primary respiratory alkalosis, hyperammonemia Hypoglycemia, ketosis or ketonuria, low BUN, Hyperbilirubinemia, elevated liver function tests including PT and PTT, lactic acidosis, high lactate/pyruvate ratio Non-glucose-reducing substances in urine, neutropenia and thrombocytopenia.

Reduce precursor substrate load Approach to treatment Reduce precursor substrate load Removal of toxic compounds – hemodialysis, chelators, trapping agents Enhancement of the activity of the deficient enzyme Decreasing the flux through the deficient pathway by restricting precursors in the diet. If an inborn error of metabolism is suspected in a neonate they should be kept NPO but given IV fluids containing dextrose so as to keep the infant anabolic. Provide caloric support Provide fluid support Divert metabolites Supplement with cofactor(s) Treatment is obviously dependent on the disorder suspected. General principles however are:

Hunter syndrome,mucopolysaccharidosis type 2 Mucopolysacchridoses –disorder in breakdown of glycosaminoglycans(GAG) due to deficiency of lysosomal enzymes GAG- oligosaccharide components to protein skeleton in extracellular matrix Deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S)  The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. Exhibit X-linked recessive inheritance A lysosome is a membrane-bound organelle found in nearly all animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, cell signaling, and energy metabolism These chemicals are types of glycosaminoglycans (GAGs), also known as mucopolysaccharides. Hunter syndrome is the only MPS syndrome to

Epidemiology There are estimated to be approximately 2,000 people afflicted with Hunter syndrome worldwide, 500 of whom live in the United States. A study in the United Kingdom indicated an incidence among males of approximately 1 in 130,000 male live births. In severe cases, death usually occurs by age 15. In attenuated cases, patients may survive into their 50s

The symptoms not apparent at birth. Clinical Presentation: Categorized as either "mild" or "severe" depending on the presence of central nervous system symptoms The symptoms not apparent at birth. As the buildup of GAGs continues throughout the cells of the body, signs of Hunter syndrome become more visible. distinctive coarseness in their facial features, prominent forehead, a nose with a flattened bridge, and an enlarged tongue. Communicating hydrocephalus can develop The gastrointestinal system is also affected via autonomic dysregulation , mucosal dysfunction. For severe cases of MPS II, a diagnosis is often made between the ages of 18 and 36 months. In milder cases, patients present similarly to children with Hurler–Scheie syndrome, and a diagnosis is usually made between the ages of 4 and 8 years Often, the first symptoms may include abdominal hernias, ear infections, runny noses, and colds

Clinical Presentation: Valvular heart leaflets with GAG accumulation. A thickened myocardium eventually leads to coronary artery compromise, The walls of the airway may become thickened, as well, leading to obstructive airway disease. All major joints may be affected by Hunter syndrome, leading to joint stiffness and limited motion. carpal tunnel syndrome,short stature Pebbly, ivory-colored skin lesions may be found on the upper arms, legs, and upper back :pathognomic for the disease. After 18 months, children with severe MPS II may suffer from developmental decline

Cardiac echocardiography and ECG Investigations: Urine spot tests are readily available to screen for mucopolysaccharidoses (MPSs). ELISA technique has recently been shown to accurately quantify GAGs in urine (eg, dermatan and heparan sulfate excretion) and in blood. Lysosomal enzymes are present in all cells except mature erythrocytes. Iduronate sulfatase deficiency is determined by the direct enzymatic assay of leucocytes and fibroblasts as skin biopsy. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or in chorionic villus tissue A full skeletal survey Ophthalmologic examination with slit lamp: visual acuity and corneal and retinal . Cardiac echocardiography and ECG Airway evaluation: Assess for upper airway obstruction and sleep apnea and determine pulmonary function. [30 These tests are associated with false-positive and false-negative results; testing more than one urine sample is recommended

GAUCHERS

BIOTIN

IEM- Index of Suspicion: Rapid deterioration in an otherwise well infant. Septic appearing infant or abnormal sepsis such as E.coli. Failure to thrive, Regression in milestones. Recurrent emesis or feeding difficulty, alterations in respirations, abnormal urine/body smell, changing MS/lethargy, jaundice, seizures, intractable hiccups. Can masquerade like pyloric stenosis. Dietary aversion- proteins, carbs.