BMS 532 Inborn Errors of Metabolism PDF

Neurogenetics Questions A pathogenic variant in the RYR1 gene is observed. ◦ What condition is this associated with? (LO3/LO6) ◦ If this variant is a biallelic change that causes a nonsense mutation, which inheritance pattern is expected? (LO6) ◦ Severe forms of this mutation are linked with w...

Neurogenetics Questions A pathogenic variant in the RYR1 gene is observed. ◦ What condition is this associated with? (LO3/LO6) ◦ If this variant is a biallelic change that causes a nonsense mutation, which inheritance pattern is expected? (LO6) ◦ Severe forms of this mutation are linked with which clinical features in addition to the myopathy? (LO4/LO5) Inborn Errors of Metabolism N OW K N OW N A S : CO M M O N M E TA BO LI C DI S OR D ERS BM S 5 3 2 BLO C K 4 L EC T UR E 5 Objectives 1. Define the terms genetic and inherited and explain the similarities and differences between genetic and inherited disorders 2. Describe what is meant by inborn errors in metabolism/common metabolic disorders and explain how they relate to biochemistry 3. Summarize the broad spectrum of consequences for IEM based on tissue involvement 4. Describe physical abnormalities and odors that are possible with IEM 5. Describe the clinical features and identify the associated genes for the following conditions: MSUD, PKU, Galactosemia, and Fructosemia 6. Differentiate between the conditions using the general classification system, connect inheritance with the disease presentation, and identify the gene involved in generating the condition LO1 Genetic vs. Inherited GENETIC INHERITED Involves changes in genes Involves genetic changes Change may occur during mitosis during Change occurs or is observed in past embryogenesis rather than due to gametic generations or from parental gametes changes (familial) May be a new version or new change but overall condition will be observed in the family or gametes LO2 Inborn Error of Metabolism a.k.a. Common Metabolic Disorders Enzyme defects in biochemical and metabolic pathways Highly complex and present with several organ systems involved RARE individually but collectively common ◦ Overall incidence of the group = greater than 1 in 1,000 Majority = Autosomal Recessive Require specialized training: American Board of Medical Genetics and Genomics (ABMGG) certification ◦ There are specific guidelines for considering IEMs including consideration of familial factors LO3 Classification Onset Predominant signs/symptoms Main organs/systems affected Acuity or Chronicity of Presentations ◦ Acute or chronic LO3 Spectrum of Consequences Phenotypic Normalcy to Distinct Dysmorphic Features Most = Normal at birth with significant non-specific signs and symptoms ◦ Many of the non-specific signs and symptoms are common with other serious medical conditions Wide tissue presentation depending on the specific condition and age of onset ◦ Dermatologic: alopecia or brittle hair, ichthyosis, vesicular or bullous lesions, skin appearance/elasticity ◦ Opthalmologic: cataracts, corneal clouding, impaired vision ◦ Cardiac: cardiomyopathies, cardiac failure ◦ Hepatic: organomegaly, jaundice, fibrosis/cirrhosis, etc.. ◦ Musculoskeletal: hypotonia, muscle weakness, progressive myopathy, etc.. ◦ Neurologic: decreased consciousness, seizures, mental status changes, progressive neurologic disability, etc… LO3, LO4 Broad Categories and Examples Category Examples Urea cycle disorders Ornithine transcarbamylase deficiency, citrullinemia, argininosuccinic aciduria, argininemia Organic acidemias Propionic acidemia, methylmalonic aciduria, isovaleric acidemia, glutaric acidemia, maple syrup urine disease Fatty acid oxidation defects Medium chain acyl-CoA dehydrogenase deficiency, carnitine palmitoyl transferase 1 deficiency, long chain hydroxyacyl-CoA dehydrogenase deficiency Amino acidopathies Tyrosinemia, phenylketonuria, homocysteinuria Carbohydrate disorders Galactosemia, fructosemia Mitochondrial disorders MELAS, MERFF, pyruvate dehydrogenase deficiency  IEM and Structural Abnormalities Disorder Abnormality Observed Zellweger syndrome (absence of Large fontanelle, prominent forehead, flattened peroxisomes) nasal bridge (a.k.a. low nasal bridge), epicanthal folds and hypoplastic supraorbital ridge Pyruvate dehydrogenase Epicanthal folds, flattened nasal bridge, petite deficiency nose with anteverted alae nasi, long philtrum Glutaric aciduria type II Macrocephaly, high forehead, flattened nasal bridge, short anteverted nose; genitourinary abnormality of hypospadias in males, aural anomalies and rocker bottom feet Smith-Lemli-Opitz syndrome Epicanthal folds, flat nasal bridge, syndactyly, (cholesterol biosynthetic defect) cataracts and genital abnormalities Congenital glycosylation Inverted nipples and lipodystrophy disorders Lysosomal storage disorders, Coarse facies Mucopolysaccharidoses LO4  Odor as an IEM Indicator Disorder Potential Odor Maple syrup urine disease (MSUD) Maple Syrup Isovaleric acidemia or glutaric acidemia type II Sweaty Feet Cystinuria and tyrosinemia type I Sulfur Tyrosinemia type I Boiled Cabbage Trimethylaminuria or dimethylglycine Old Fishy dehydrogenase deficiency Multiple carboxylase deficiency (MCD) Cat’s Urine Phenylketonuria (PKU) Mousy LO4 Biochemistry Introduction FED/Absorptive State Biochemistry Introduction Overnight Fasting State/ Post-absorptive State LO5, LO6 Fructosemia (a.k.a. Hereditary Fructose Intolerance) Cannot breakdown Fructose Autosomal Recessive Mutations in ALDOB (Aldolase B) ◦ 9q31.1 Onset = early infancy ◦ Newborns may exhibit changes in behavior as well as hepatosplenomegaly and jaundice Additional Information: ◦ Aldolase B has been shown to be regulatory for the pentose phosphate pathway generally and glucose- 6-phosphate dehydrogenase specifically LO5, LO6 Fructosemia Pathway Connections (Biochemistry Introduction) LO5, LO6 Galactosemia Autosomal Recessive Failure to properly process galactose ◦ Excess build-up of Gal-1-P ◦ Too much galactose results in conversion into toxic galacitol via Aldose Reductase ◦ ONLY galactosemia results in galacitol Several types exist: Classic/Type I (most severe), Type II (galactokinase deficiency), and Type III (galactose epimerase deficiency) Onset = infancy with type I being life-threatening and requiring immediate intervention Types II and III = more mild with few long-term consequences Mutations in GALT (type I), GALK1 (type II), and GALE (type III) ◦ GALT = galactose-1-phosphate uridylyltransferase 9p13.3 ◦ GALK1 = galactokinase 1 deficiency 17q25.1 ◦ GALE = UDP-galactose-4-epimerase 1p36.11 LO5, LO6 Galactose Metabolism Simplified  Biochemistry Introduction: Amino Acid Degradation Glucogenic = can produce glucose in liver Fumarate Group = produces cytoplasmic fumarate Ketogenic = produce ketone bodies or acetyl CoA Adapted From: Lieberman and Peet. Basic Medical Biochemistry (2018) LO5, LO6 PKU Autosomal Recessive Toxic build-up of phenylalanine in blood ◦ Lead to build-up in the brain and damage ◦ Variable symptoms with classic form considered most severe ◦ Skin presentations including eczema are also expected Onset = infancy Mutations in PAH (phenylalanine hydroxylase) ◦ Pathogenic mutations can vary ◦ If some enzyme function is retained, the phenotypes are more mild (variant PKU) ◦ Other mild forms of the condition are known as non-PKU hyperphenylalanemia Additional Information ◦ Maternal consumption of phenylalanine particularly if the mother also has the condition can begin the damage process and cause microencephaly LO5, LO6 MSUD Autosomal Recessive Reduced ability to process amino acids Mutations in BCKDHA, BCKDHB, and DBT ◦ BCKDHA = branched chain keto acid dehydrogenase E1 subunit alpha 19q13.2 ◦ BCKDHB = branched chain keto acid dehydrogenase E1 subunit beta 6q14.1 ◦ DBT = dihydrolipoamide branched chain transacylase E2 1p21.2 ◦ Form a complex for breaking down leucine, isoleucine, and valine Onset = infancy with potential lethality if not treated Branched Chain Amino Acid Degradation This slide is intended to put the activity of genes into context; you are not expected to memorize or utilize the figure Branched-chain alpha keto acid dehydrogenase is a multi-subunit complex where mutations in any component can lead to reduced function and disease manifestation for MSUD ◦ Inability to breakdown and properly utilize isoleucine, valine, and leucine  Questions What is the relationship between metabolic disorders and clinical presentation based on tissues? (LO3 and LO4) A disorder that affects catabolic breakdown of amino acids is most likely to result in what? (LO3, LO5, LO6) Milder PKU could also be thought of as what? (LO5, LO6) Fill in the following chart: (LO5, LO6) Disorder Gene(s) Onset and Noteworthy or Expected Presentation Fructosemia Galatosemia PKU MSUD