Inborn Errors of Metabolism PDF

Dr. Nahed Elghareeb Genetic and Metabolic Counselor [email protected]  Objectives: * Clinical Approach to Inborn Errors of Metabolism in Pediatrics * Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations * Diagnostic Procedures...

Dr. Nahed Elghareeb Genetic and Metabolic Counselor [email protected]  Objectives: * Clinical Approach to Inborn Errors of Metabolism in Pediatrics * Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations * Diagnostic Procedures * Emergency Treatments  Inborn errors of metabolism Inborn errors of metabolism (IEM) are a group of genetic disorders. They are individually rare, but collectively numerous. The application of tandem mass spectrometry (tandem MS) to newborn screening and prenatal diagnosis has enabled presymptomatic diagnosis for some IEM.  Inborn errors of metabolism Up to 85% of IMDs impact on neurodevelopment or are responsible for neurodegeneration. Acute, chronic or progressive neurological syndromes, psychiatric presentations, developmental delay, intellectual disability, neurodevelopment disturbances and neurodegeneration at any age deserve special attention.  Recent international classification of Inborn Errors of Metabolism While the most recent international classification of inborn errors of metabolism (IEM) encompasses >1400 disorders, from a clinical point of view, all IEM can be maintained in a simplified classification that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large groups Small molecule disorders have biomarkers and are divided in two subcategories: accumulation and deficiency. Accumulation of small molecules leads to acute or progressive postnatal “intoxication”, present after a symptom-free interval, aggravated by catabolism and food intake. These treatable disorders must not be missed! Deficiency of small molecules is due to impaired synthesis of compounds distal to a block or altered trans- port of essential molecules. This subgroup shares many clinical characteristics with complex molecule disorders. Complex molecules (like glycogen, sphingolipids, phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogen and lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take place in organelles. They may interfere with fœtal development. Most present as neurodevelopmental or neurodegenerative disorders unrelated to food intake. Complex molecules Peroxisomal disorders, Congenital Disorders of Glycosylation CDG defects of intracellular trafficking and processing, recycling of synaptic vesicles, and tRNA synthetases also belong to this category. Only few have biomarkers and are treatable. energy metabolism Disorders involving primarily energy metabolism encompass defects of membrane carriers of energetic molecules as well as cytoplasmic and mitochondrial metabolic defects. This oversimplified classification is connected to the most recent available nosology of IMD. Inheritance  In the nucleus of cells in a human body are 46 chromosomes: one set of 23 chromosomes inherited from one’s biological mother and a second from one’s biological father. Each chromosome is made up of tightly coiled strands of deoxyribonucleic acid (DNA). These strands of DNA contain genes that provide instructions, or codes, for making cellular proteins necessary for life. DNA is composed of four nucleotides: Adenine Thymine Guanine Cytosine Three adjacent nucleotides code for one amino acid in the protein. The triplet of adjacent nucleotides is called a codon. Single- Gene Inheritance Patterns The clinical diagnosis of IEM relies upon a limited number of principles:  In the appropriate clinical context consider IEM in parallel with other more common conditions.  Be aware of symptoms that persist and remain unexplained after the initial treatment and usual investigations have been performed for more common disorders, may be due to an IEM. The clinical diagnosis of IEM relies upon a limited number of principles:  Suspect that any neonatal death may possibly be due to an IEM, particularly those that have been attributed to sepsis. Additionally, true sepsis can trigger acute decompensation when there is an underlying IEM. Carefully review all autopsy findings.  Remember that IEM can present at any age, from fetal life to old age. The clinical diagnosis of IEM relies upon a limited number of principles:  Be aware that because most IEM have a recessive inheritance (although some have dominant, X-linked, or maternal inheritance), the majority of individual cases may appear sporadic.  In the acute emergency situation first consider those IEM that are most amenable to treatment. The clinical diagnosis of IEM relies upon a limited number of principles:  Get help from specialized centers.  Do not miss a treatable disorder Criteria for Newborn Screening To provide early detection of children at increased risk for disorders in which promptly initiating treatment prevents a metabolic crisis and/or irreversible sequelae, thus improving outcome. Principles of screening based on Wilson and Jungner’s criteria 1. The condition is an important health problem. 2. There is an acceptable treatment. 3. Facilities for diagnosis and treatment are  Principles of screening based on Wilson and Jungner’s criteria 4. There is a recognizable early asymptomatic stage. 5. There is a suitable screening test. 6. The test is acceptable to the population. 7. The natural history of the condition is adequately understood. 8. There is an understanding of whom to treat as patients. 9. It is cost-effective. 10. Identification of affected patients is a continuing Disorders identified by newborn screening using tandem mass spectrometry (MS/MS) Disorders identified by newborn screening using tandem mass spectrometry (MS/MS) Disorders identified by newborn screening using tandem mass spectrometry (MS/MS) Expanded Newborn Screening for Inherited Metabolic Diseases Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease  Change in Marker Suspected Disease Acylcarnitines 3 Acylcarnitines 3 Acylcarnitines 2  Change in Marker Suspected Disease Acylcarnitines 5 Acylcarnitines 5 Acylcarnitines 3 Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Change in Marker Suspected Disease Clinical Approach the clinical diagnostic circumstances observed in IEM are divided into five categories: 1. Antenatal and congenital presentations 2. Neonatal presentations 3. Later-onset emergencies (from early childhood to adulthood) with acute (and recurrent) manifestations such as coma, ataxia, acidosis, exercise intolerance, or visceral failure… clinical diagnostic circumstances categories 4.Chronic and progressive neurological presentation (from early childhood to adulthood) (developmental delay, intellectual disability, epilepsy, neurological deterioration, psychiatric signs). 5. Specific and permanent organ/system presentations that may concern all medical specialities (cardiology, dermatology, endocrinology, gastroenterology, hematology … etc.). Signs and Symptoms Symptoms of metabolic disease generally occur postnatally, appearing after an interval period of apparent good health and following a normal pregnancy. The interval may be as short as a few hours or be several days or even longer. The infant may do well until subjected to a catabolic insult (infection, fasting, dehydration) or an excessive protein or carbohydrate load. Signs and Symptoms Following exposure to a stressor, the child may become strikingly ill very suddenly and can present as sudden infant death of unexplained etiology. On the other hand, the absence of a normal period does not exclude an inborn error from diagnostic consideration. Neonatal distress from asphyxia or complications of prematurity may constitute the environmental stress that unmasks an underlying metabolic disease. Signs and Symptoms Irritability and feeding difficulties may be associated with uncoordinated sucking and swallowing or abnormal muscle tone. Persistent and severe vomiting and convulsions may occur. In mildly affected neonates, symptoms can disappear, only to recur in days or weeks. More severely affected infants have inexorable progression from lethargy to coma to episodic apnea and death. More limited symptoms, often in the form of generalized or partial seizures, may occur in some instances. Signs and Symptoms Seizures can include staring spells, eye rolling or myoclonus. Various combinations of tone abnormalities, tremulousness, lethargy, and a weak cry. Electroencephalography may suggest nonspecific diffuse encephalopathy. Unless an inborn error is suspected, the child may be misdiagnosed as having hypoxic-ischemic encephalopathy, intraventricular hemorrhage, sepsis, heart failure, or a gastrointestinal illness, such as pyloric stenosis or intestinal obstruction. A concomitant acquired disorder may confound the diagnosis of an inherited metabolic disease. For example, neutropenia may occur in an organic acidemia that has a neonatal presentation, but sepsis with leukocytosis (or neutropenia) also may be present because of an increased susceptibility to bacterial infection. Escherichia coli sepsis is frequent in infants who have galactosemia, and the inanition and jaundice of that disorder might be ascribed incorrectly solely to sepsis. Other examples of acquired conditions that may complicate the presentation of a metabolic disorder include pulmonary hemorrhage or primary respiratory alkalosis in urea cycle defects. Ocular Findings in Infants Who Have Inborn Errors of Metabolism Ocular Findings in Infants Who Have Inborn Errors of Metabolism Ocular Findings in Infants Who Have Inborn Errors of Metabolism Urine Odors Associated With Inborn Errors of Metabolism Unusual Urine Colors Associated with Inborn Errors of Metabolism  Inborn Errors of Metabolism Associated With Encephalopath y Without Metabolic Acidosis Inborn Errors of Metabolism Associated With Encephalopathy With Metabolic Acidosis Inborn Errors of Metabolism Associated With Encephalopathy With Metabolic Acidosis Inborn Errors of Metabolism Associated With Dysmorphic Features Inborn Errors of Metabolism Associated With Dysmorphic Features  Open book Questions 1. You are examining a newborn delivered at term gestation. His mother is concerned about the risk of a metabolic disorder because of the history of early neonatal deaths involving her two brothers. Of the following, this pattern of inheritance is most consistent with: A. Glycogen storage disease. B. Hereditary fructose intolerance. C. Mitochondrial respiratory chain disorder. D. Ornithine transcarboxylase deficiency. E. Propionic acidemia 2. A newborn in whom an inborn error of metabolism is suspected should receive a careful eye examination. Conversely, a newborn in whom ophthalmic findings are unusual should receive a detailed metabolic evaluation. Of the following, a cherry red spot observed on retinal examination of a neonate is most likely to indicate: A. Aspartoacyclase deficiency. B. Galactosemia. C. GM1 gangliosidosis. D. Peroxisomal disorder. E. Sulfite oxidase deficiency. 3. Several inborn errors of metabolism are characterized by unusual odors. The odor may be appreciated best in a urine specimen. Of the following, the odor of sweaty feet is most associated with: A. Isovaleric acidemia. B. Methylmalonic acidemia. C. Phenylketonuria. D. Trimethylaminuria. E. Tyrosinemia. 4. A 10-day-old female infant is lethargic and feeding poorly. She has a weak cry, rolling of the eyes, and poor muscle tone. Electroencephalographic findings are consistent with nonspecific diffuse encephalopathy. During the metabolic evaluation of this infant, an arterial blood gas reveals a pH of 7.38 and bicarbonate concentration of 24 mEq/L. Of the following, these blood gas results are most compatible with: A. Carnitine-acylcarnitine translocase deficiency. B. Maple syrup urine disease. C. Mitochondrial respiratory chain disorder. D. Propionic acidemia. E. Pyruvate dehydrogenase deficiency.