Genetics Cases and Resources Webinar Slides - November 8, 2022

1. - METABOLISM CASES - Mark S. Korson, MD VMP Genetics Metabolic diseases that cause muscle symptoms: LCHAD deficiency, Pompe disease, Barth syndrome © Copyright 2022. VMP Genetics. All rights reserved

2. Long chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency

3. CLASSIFICATION Disorders of intoxication Metabolic disease Disorders of energy metabolism Disorders of complex molecules From Jean-Marie Saudubray, MD

36. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA SHORT CHAIN β-OXIDATION ENZYMES SHORT CHAIN FAO DEFECTS • No (few?) symptoms • Brain – HAPPY • Muscles - HAPPY © Copyright 2022 VMP Genetics. All rights reserved

37. Mitochondrial Membrane MEDIUM CHAIN FATTY ACYL CoA MEDIUM CHAIN β-OXIDATION ENZYMES MEDIUM CHAIN FAO DEFECTS • Symptoms! • Brain – UNHAPPY • Muscles - HAPPY © Copyright 2022 VMP Genetics. All rights reserved

38. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA LONG CHAIN β-OXIDATION ENZYMES LONG CHAIN FAO DEFECTS • Symptoms! • Brain – UNHAPPY • Muscles - UNHAPPY © Copyright 2022 VMP Genetics. All rights reserved

40. CLASSIFICATION Disorders of Intoxication Metabolic disease Disorders of energy metabolism Disorders of complex molecules © Copyright 2021 VMP Genetics. All rights reserved From Jean-Marie Saudubray, MD

41. Free Fatty Acids, Ketones, mM Hours of Fasting Glucose, mg/dL 8 12 16 20 24 28 32 20 40 60 80 100 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 (Stanley et al, 1990) MCAD Deficiency

42. Free Fatty Acids, Ketones, mM Hours of Fasting Glucose, mg/dL 8 12 16 20 24 28 32 20 40 60 80 100 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 (Stanley et al, 1990) Free Fatty Acids MCAD Deficiency

43. Free Fatty Acids, Ketones, mM Hours of Fasting Glucose, mg/dL 8 12 16 20 24 28 32 20 40 60 80 100 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Ketones (Stanley et al, 1990) Free Fatty Acids MCAD Deficiency

44. Free Fatty Acids, Ketones, mM Hours of Fasting Glucose, mg/dL 8 12 16 20 24 28 32 20 40 60 80 100 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Glucose Ketones (Stanley et al, 1990) Free Fatty Acids MCAD Deficiency

45. Free Fatty Acids, Ketones, mM Hours of Fasting Glucose, mg/dL 8 12 16 20 24 28 32 20 40 60 80 100 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Glucose Ketones (Stanley et al, 1990) Free Fatty Acids MCAD Deficiency SYMPTOM ONSET

48. Introducing… Michelle and Jake https://ultrarareadvocacy.com/patient-story/michelle-and-jake/

50. Fasting intolerance Encephalopathy – coma, seizures Liver dysfunction Episodic decompensation SYMPTOMS OF LONG-CHAIN FAO DEFECTS Muscle pain and weakness Rhabdomyolysis  myoglobinuria • Creatine kinase (CK) elevations Cardiomyopathy Myopathy © Copyright 2022 VMP Genetics. All rights reserved

52. PROTEIN DISORDERS CARBOHYDRATE DISORDERS FATTY ACID OXIDATION DEFECTS Metabolic differential dx SUDDEN INFANT DEATH SYNDROME • Urea cycle defects • Organic acidemias • Glucose production/ metabolism defects • Disorders of pyruvate metabolism • Mitochondrial disorders • Ketone production defects • Disorders of carnitine metabolism © Copyright 2022. VMP Genetics. All rights reserved

57. Glucose Electrolytes, bicarbonate Liver functions (AST, ALT) CK (creatine kinase) Supportive DIAGNOSIS © Copyright 2022 VMP Genetics. All rights reserved Metabolic Acylcarnitines Molecular DNA testing Confirmation

58. PKU Biopterin defects Homocystinuria Hypermethioninemia HHH syndrome Tyrosinemia I, II, III Maple syrup urine disease CPS I/OTC def’y Citrullinemia I, II Arg-succinic aciduria Arginase deficiency Galactosemia Galactokinase def’y Gal-epimerase def’y Biotinidase deficiency Multiple carboxylase def’y Propionic acidemia Methylmalonic acidemia MMA/Cobalamin defects Isovaleric acidemia b-ketothiolase deficiency HMG-CoA lyase def’y Glutaric acidemia I, II Malonic acidemia Ethylmalonic encephalopathy 3-me-CoA carboxylase def’y 3-me-glutaconic aciduria 2-me-3-OHbutyric academia 2-me-butyrylglycinuria Isobutyrylglycinuria MCAD deficiency CACT deficiency CPT I, II deficiency Carnitine uptake defect SCAD deficiency SCHAD/MCHAD def’y MCKAT deficiency VLCAD deficiency LCHAD/TFP deficiency Dienoyl CoA red def’y OTHER DISORDERS: Congenital hypothyroidism Congenital adrenal hyperplasia Congenital toxoplasmosis Hemoglobinopathies Cystic fibrosis Severe combined immunodeficiency Pompe disease Hurler disease (MPS I) X-linked adrenoleukodystrophy Spinal muscular atrophy Critical congenital heart disease Hearing loss NEWBORN SCREENING IN MASSACHUSETTS

59. PKU Biopterin defects Homocystinuria Hypermethioninemia HHH syndrome Tyrosinemia I, II, III Maple syrup urine disease CPS I/OTC def’y Citrullinemia I, II Arg-succinic aciduria Arginase deficiency Galactosemia Galactokinase def’y Gal-epimerase def’y Biotinidase deficiency Multiple carboxylase def’y Propionic acidemia Methylmalonic acidemia MMA/Cobalamin defects Isovaleric acidemia b-ketothiolase deficiency HMG-CoA lyase def’y Glutaric acidemia I, II Malonic acidemia Ethylmalonic encephalopathy 3-me-CoA carboxylase def’y 3-me-glutaconic aciduria 2-me-3-OHbutyric academia 2-me-butyrylglycinuria Isobutyrylglycinuria MCAD deficiency CACT deficiency CPT I, II deficiency Carnitine uptake defect SCAD deficiency SCHAD/MCHAD def’y MCKAT deficiency VLCAD deficiency LCHAD/TFP deficiency Dienoyl CoA red def’y OTHER DISORDERS: Congenital hypothyroidism Congenital adrenal hyperplasia Congenital toxoplasmosis Hemoglobinopathies Cystic fibrosis Severe combined immunodeficiency Pompe disease Hurler disease (MPS I) X-linked adrenoleukodystrophy Spinal muscular atrophy Critical congenital heart disease Hearing loss NEWBORN SCREENING IN MASSACHUSETTS

60. PKU Biopterin defects Homocystinuria Hypermethioninemia HHH syndrome Tyrosinemia I, II, III Maple syrup urine disease CPS I/OTC def’y Citrullinemia I, II Arg-succinic aciduria Arginase deficiency Galactosemia Galactokinase def’y Gal-epimerase def’y Biotinidase deficiency Multiple carboxylase def’y Propionic acidemia Methylmalonic acidemia MMA/Cobalamin defects Isovaleric acidemia b-ketothiolase deficiency HMG-CoA lyase def’y Glutaric acidemia I, II Malonic acidemia Ethylmalonic encephalopathy 3-me-CoA carboxylase def’y 3-me-glutaconic aciduria 2-me-3-OHbutyric academia 2-me-butyrylglycinuria Isobutyrylglycinuria MCAD deficiency CACT deficiency CPT I, II deficiency Carnitine uptake defect SCAD deficiency SCHAD/MCHAD def’y MCKAT deficiency VLCAD deficiency LCHAD/TFP deficiency Dienoyl CoA red def’y OTHER DISORDERS: Congenital hypothyroidism Congenital adrenal hyperplasia Congenital toxoplasmosis Hemoglobinopathies Cystic fibrosis Severe combined immunodeficiency Pompe disease Hurler disease (MPS I) X-linked adrenoleukodystrophy Spinal muscular atrophy Critical congenital heart disease Hearing loss NEWBORN SCREENING IN MASSACHUSETTS AMINO ACID DISORDERS ORGANIC ACID DISORDERS FATTY ACID OXIDATION DEFECTS GALACTOSE DISORDERS OTHER DISORDERS

61. PKU Biopterin defects Homocystinuria Hypermethioninemia HHH syndrome Tyrosinemia I, II, III Maple syrup urine disease CPS I/OTC def’y Citrullinemia I, II Arg-succinic aciduria Arginase deficiency Galactosemia Galactokinase def’y Gal-epimerase def’y Biotinidase deficiency Multiple carboxylase def’y Propionic acidemia Methylmalonic acidemia MMA/Cobalamin defects Isovaleric acidemia b-ketothiolase deficiency HMG-CoA lyase def’y Glutaric acidemia I, II Malonic acidemia Ethylmalonic encephalopathy 3-me-CoA carboxylase def’y 3-me-glutaconic aciduria 2-me-3-OHbutyric academia 2-me-butyrylglycinuria Isobutyrylglycinuria MCAD deficiency CACT deficiency CPT I, II deficiency Carnitine uptake defect SCAD deficiency SCHAD/MCHAD def’y MCKAT deficiency VLCAD deficiency LCHAD/TFP deficiency Dienoyl CoA red def’y OTHER DISORDERS: Congenital hypothyroidism Congenital adrenal hyperplasia Congenital toxoplasmosis Hemoglobinopathies Cystic fibrosis Severe combined immunodeficiency Spinal muscular atrophy Critical congenital heart disease Hearing loss NEWBORN SCREENING IN MASSACHUSETTS Pompe disease Hurler disease (MPS I) X-linked adrenoleukodystrophy

63. MANAGEMENT Diet Heart-healthy diet Restrict fat? (esp. during infections or stresses) Medium chain triglycerides (MCT, C6-C8-C10) in LC FAODs Triheptanoin (C7) in LC-FAODs © Copyright 2022. VMP Genetics. All rights reserved

64. MANAGEMENT Screen For systemic disease (heart, muscle, nerves, eyes) Developmental impact Screen siblings Who is not at risk? Who is asymptomatic? Who is pre-symptomatic? © Copyright 2022. VMP Genetics. All rights reserved

65. Pompe disease (late-onset)

66. POMPE DISEASE Defect ⍺-glucosidase deficiency (<1% activity Early Onset, 2-40% Late Onset) Males = females Male : Female Autosomal recessive Inheritance 1:40,000 in the US Higher incidence in African-Americans Incidence © Copyright 2022. VMP Genetics. All rights reserved

67. MAJOR TYPES Early Onset Onset before 12 months • Cardiomyopathy • Myopathy • Feeding problems  failure to thrive • Weakness, breathing difficulties Prognosis Death from heart failure and/or respiratory failure © Copyright 2022. VMP Genetics. All rights reserved

68. MAJOR TYPES (continued) Late Onset Onset before 12 months: • No cardiomyopathy Onset after 12 months: • No cardiomyopathy • Muscle weakness - respiratory, skeletal Prognosis Respiratory disease is the major cause of morbidity and mortality © Copyright 2022. VMP Genetics. All rights reserved

69. SYMPTOMS Early onset Poor feeding  failure to thrive Muscle weakness  Motor delays Respiratory compromise Cardiac failure Late onset Muscle weakness, gait abnormalities Respiratory muscle weakness © Copyright 2022. VMP Genetics. All rights reserved

70. BIOCHEMISTRY Creatine kinase (CK) Elevated in Early Onset (up to ~2000) May/may not be elevated in Late Onset Urine oligosaccharides Tetrasaccharide: • Elevated in Early Onset • +/- Elevated in Late Onset © Copyright 2022. VMP Genetics. All rights reserved

71. CARDIAC FAILURE

72. THE POMPE EKG – A BIG HINT High QRS voltage + short PR interval + WPW

74. https://www.youtube.com/watch?v=iaMSnqfd4h0&t=1s Introducing… Shaylee & Jared

75. LIVER TESTING ”Liver functions” Hepatotoxicity – AST, ALT Biliary function (cholestasis) – bilirubin, alkaline phosphatase, GGTP Synthetic function – PT, albumin © Copyright 2022. VMP Genetics. All rights reserved

76. Introducing… Shaylee & Jared https://www.youtube.com/watch?v=DPJT-GTFslU

77. WHILE WE’RE ON THE SUBJECT OF LIVER FUNCTION TESTS Lab tests: • ESR 11 mm/hr (NL=0-10) • CRP 0.2 mg/L (NL=0.2-9.7) • AST 1174 IU/L (NL=8-33) • ALT 588 IU/L (NL<25) • Lactate 2.1 mmol/L (NL=1.0-2.2) • Other routine chemistry tests normal Adapted from SIMD-NAMA

78. WHILE WE’RE ON THE SUBJECT OF LIVER FUNCTION TESTS Previously healthy 2-year-old boy. Parents are worried because he “seems weak” following an episode of roseola 3 months ago and a recent episode of acute gastroenteritis. Also complaining that his legs hurt. Weakness began about 3 weeks after most recent illness, and has progressed; now unable to stand from a sit, can no longer run, and seems clumsy. Normal development. Adapted from SIMD-NAMA

79. WHILE WE’RE ON THE SUBJECT OF LIVER FUNCTION TESTS On examination, he is not jaundiced and there is no liver enlargement. Head lag, symmetric hypotonia with variable muscle atrophy, diminished reflexes. When trying to stand from a sitting position, he requires assistance. He cruises holding on to the furniture. Bilateral calf hypertrophy, firm on palpation. Adapted from SIMD-NAMA

80. WHILE WE’RE ON THE SUBJECT OF LIVER FUNCTION TESTS Lab tests: • ESR 11 mm/hr (NL=0-10) • CRP 0.2 mg/L (NL=0.2-9.7) • AST 1174 IU/L (NL=8-33) • ALT 588 IU/L (NL<25) • Lactate 2.1 mmol/L (NL=1.0-2.2) • Other routine chemistry tests normal • CK > 32,000 (NL=39-308) Adapted from SIMD-NAMA

82. PKU Biopterin defects Homocystinuria Hypermethioninemia HHH syndrome Tyrosinemia I, II, III Maple syrup urine disease CPS I/OTC def’y Citrullinemia I, II Arg-succinic aciduria Arginase deficiency Galactosemia Galactokinase def’y Gal-epimerase def’y Biotinidase deficiency Multiple carboxylase def’y Propionic acidemia Methylmalonic acidemia MMA/Cobalamin defects Isovaleric acidemia b-ketothiolase deficiency HMG-CoA lyase def’y Glutaric acidemia I, II Malonic acidemia Ethylmalonic encephalopathy 3-me-CoA carboxylase def’y 3-me-glutaconic aciduria 2-me-3-OHbutyric academia 2-me-butyrylglycinuria Isobutyrylglycinuria MCAD deficiency CACT deficiency CPT I, II deficiency Carnitine uptake defect SCAD deficiency SCHAD/MCHAD def’y MCKAT deficiency VLCAD deficiency LCHAD/TFP deficiency Dienoyl CoA red def’y OTHER DISORDERS: Congenital hypothyroidism Congenital adrenal hyperplasia Congenital toxoplasmosis Hemoglobinopathies Cystic fibrosis Severe combined immunodeficiency Spinal muscular atrophy Critical congenital heart disease Hearing loss NEWBORN SCREENING IN MASSACHUSETTS Pompe disease Hurler disease (MPS I) X-linked adrenoleukodystrophy

83. TREATMENT Symptomatic Treat cardiac failure Respiratory support Nutritional and feeding support Physical therapy Surgery for contractures Definitive Enzyme replacement therapy © Copyright 2022. VMP Genetics. All rights reserved

85. PROGNOSIS on Rx - EARLY ONSET ERT Dx <6 months (before ventilator dependence) • Improved survival • Improved chance of ventilator- independence • Improved motor development Dx <2 weeks • Improved motor development first 2 years © Copyright 2022. VMP Genetics. All rights reserved

87. Barth Syndrome

88. BARTH SYNDROME Incidence 1/300,000 – 1/400,000 (US) 1/140,000 (SW England) 1-9/1,000,000 (Orphanet) Males > Females Male : Female Infancy Age of onset x-linked Inheritance © Copyright 2022. VMP Genetics. All rights reserved

89. Introducing… Barth Syndrome Foundation https://youtu.be/pKILh10xHbY

90. SYMPTOMS (in affected males) Any combination of Cardiomyopathy Skeletal myopathy/hypotonia Neutropenia Growth delays (pre-pubertal) Dysmorphic features Family history of x-linked inheritance © Copyright 2022. VMP Genetics. All rights reserved

91. SYMPTOMS (in affected males) Cardiomyopathy Onset under 5 years Presenting feature in ~73% of cases Risk of arrhythmias, stroke Skeletal myopathy Proximal > distal, with hypotonia Not progressive Developmental delays (motor, 40-50%) Exercise intolerance © Copyright 2022. VMP Genetics. All rights reserved

92. SYMPTOMS (in affected males) Neutropenia Present in up to 69% of cases Presenting feature in ~18% Infection risk: • Oral ulcerations (~60%) • Sepsis, pneumonia uncommon • Compensatory monocytosis Growth Feeding problems, diarrhea/constipation Delay before puberty, with improved growth afterward © Copyright 2022. VMP Genetics. All rights reserved

93. SYMPTOMS (in affected males) Development Motor delays Vocabulary and reading – age appropriate Math, visuospatial skills challenged Sensory issues to feeding/eating (limited with preference for cheesy, salty and spicy) © Copyright 2022. VMP Genetics. All rights reserved

95. PATHOLOGY Cardiolipin Tafazzin (TAZ) Necessary for maintaining mitochondrial shape, energy production, and protein transport within cells Taz1p acyltransferase Adds linoleic acid to the cardiolipin molecule (remodeling) so cardiolipin can perform © Copyright 2022. VMP Genetics. All rights reserved

96. DIAGNOSIS Biochemical testing Definitive testing CBC and differential count Urine organic acids • 3-methylglutaconic acid • 3-methylglutaric acid • 2-ethylhydracrylic acid Increased monolysocardiolipin/ cardiolipin ratio (males) DNA testing (TAZ), Xq28 © Copyright 2022. VMP Genetics. All rights reserved

97. TREATMENT Neutropenia G-CSF Prophylactic antibiotics Nasogastric/gastrostomy feeding Prevent hypoglycemia (corn starch, IV) Cardiac Prevent/treat congestive heart failure Aspirin prophylaxis Transplantation Feeding © Copyright 2022. VMP Genetics. All rights reserved

100. Genetic and Rare Diseases (GARD) Information Center (for providers) RESOURCES

101. Medline Plus (for the public) RESOURCES

102. National Organization for Rare Disorders (NORD) RESOURCES

103. RESOURCES GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1116/ Inborn Metabolic Diseases, 7th Edition. Saudubray JM, et al. Springer, 2022.

104. RESOURCES IEMBase (online app – “IEMBase”) Vademecum Metabolicum (online app – “eVM”)

105. Thank you for participating today! Questions? mkorson@vmpgenetics.com www.vmpgenetics.com

Genetics Cases and Resources Webinar Slides - November 8, 2022

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