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- 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
Long chain hydroxyacyl CoA
dehydrogenase (LCHAD) deficiency
CLASSIFICATION
Disorders of
intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
From Jean-Marie Saudubray, MD
CLASSIFICATION
Disorders of
intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
From Jean-Marie Saudubray, MD
THE BODY’S RESPONSE TO FASTING
© Copyright 2022. VMP Genetics. All rights reserved
Energy
source
Time after eating
Meal
Food
THE BODY’S RESPONSE TO FASTING
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Energy
source
Time after eating
Meal
Glycogen
THE BODY’S RESPONSE TO FASTING
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Energy
source
Time after eating
Meal
Gluconeogenesis
Muscle
RBCs
THE BODY’S RESPONSE TO FASTING
Fatty acid oxidation
© Copyright 2022. VMP Genetics. All rights reserved
Energy
source
Time after eating
Meal
THE BODY’S RESPONSE TO FASTING
RBCs
Gluconeogenesis
Fatty acid oxidation
© Copyright 2022. VMP Genetics. All rights reserved
Energy
source
Time after eating
Meal
Food
Glycogen
Fatty acid oxidation
THE BODY’S RESPONSE TO FASTING
Gluconeogenesis
Muscle
RBCs
© Copyright 2022. VMP Genetics. All rights reserved
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
© Copyright 2022 VMP Genetics. All rights reserved
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
© Copyright 2022 VMP Genetics. All rights reserved
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
© Copyright 2022 VMP Genetics. All rights reserved
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE
© Copyright 2022 VMP Genetics. All rights reserved
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE
© Copyright 2022 VMP Genetics. All rights reserved
Carnitine palmitoyltransferase (CPT) II
LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE Carnitine palmitoyltransferase (CPT) II
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
CARNITINE
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Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
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Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETOACETATE
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Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
KETONE BODY
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Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Long chain hydroxyacyl CoA
dehydrogenase (LCHAD)
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
MEDIUM CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
MEDIUM CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
SHORT CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
SHORT CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
ACETYL CoA
ACETYL CoA
© Copyright 2022 VMP Genetics. All rights reserved
Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
SHORT CHAIN
β-OXIDATION
ENZYMES SHORT CHAIN FAO DEFECTS
• No (few?) symptoms
• Brain – HAPPY
• Muscles - HAPPY
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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
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
CLASSIFICATION
Disorders of
intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
From Jean-Marie Saudubray, MD
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
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
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
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
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
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
Hypoglycemia
Reduced ketogenesis
Increased medium and long chain
fatty acid intermediates
Metabolic acidosis
Causes
ENCEPHALOPATHY IN FAO DEFECTS
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Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
© Copyright 2022 VMP Genetics. All rights reserved
Long chain hydroxyacyl CoA
dehydrogenase (LCHAD)
Introducing…
Michelle and Jake
https://ultrarareadvocacy.com/patient-story/michelle-and-jake/
Fasting intolerance
Encephalopathy – coma, seizures
Liver dysfunction
Episodic
decompensation
SYMPTOMS OF FAO DEFECTS
© Copyright 2022 VMP Genetics. All rights reserved
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
PROTEIN DISORDERS
CARBOHYDRATE
DISORDERS
FATTY ACID
OXIDATION DEFECTS
Metabolic
differential dx
SUDDEN INFANT DEATH SYNDROME
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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
Hypoglycemia
Inadequate ketosis for the glucose
or duration of fasting
Pathological!
PATHOBIOCHEMISTRY
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Glucose
Electrolytes, bicarbonate
Liver functions (AST, ALT)
CK (creatine kinase)
Supportive
DIAGNOSIS
© Copyright 2022 VMP Genetics. All rights reserved
Glucose
Electrolytes, bicarbonate
Liver functions (AST, ALT)
CK (creatine kinase)
Supportive
DIAGNOSIS
© Copyright 2022 VMP Genetics. All rights reserved
Metabolic Acylcarnitines
L-carnitine Organic acyl CoA
Fatty acyl CoA
Organic acylcarnitine
Fatty acylcarnitine
Glycine
Organic acylglycine
Fatty acylglycine
© Copyright 2022 VMP Genetics. All rights reserved
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
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
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
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
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
MANAGEMENT
Eating regimen Avoid prolonged fasting
Fasting duration depends on age
Develop a routine eating regimen
? Bed-time / overnight snack
© Copyright 2022. VMP Genetics. All rights reserved
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
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
Pompe disease
(late-onset)
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
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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
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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
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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
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
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CARDIAC FAILURE
THE POMPE EKG – A BIG HINT
High QRS voltage + short PR interval + WPW
© 2008-2018 Society for Inherited Metabolic Disorders www.simd.org
Muscle biopsy
 Glycogen accumulation
Lynch. J Histochem Cytochem (2005) 53:63
https://www.youtube.com/watch?v=iaMSnqfd4h0&t=1s
Introducing…
Shaylee & Jared
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
Introducing…
Shaylee & Jared
https://www.youtube.com/watch?v=DPJT-GTFslU
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
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
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
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
DIAGNOSIS
Enzyme assay ⍺-glucosidase
DNA testing GAA gene
© Copyright 2022. VMP Genetics. All rights reserved
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
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
TREATMENT
Prevention Infections
Aggressive treatment
Immunizations
RSV prophylaxis (<2 years)
Avoid general anesthesia, if possible
© Copyright 2022. VMP Genetics. All rights reserved
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
PROGNOSIS on Rx - LATE ONSET
ERT Improved motor strength
Improved respiratory function
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Barth Syndrome
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
Introducing…
Barth Syndrome Foundation
https://youtu.be/pKILh10xHbY
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
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
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
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
FEMALES
Symptomatic When chromosome abnormalities
are also present
When biochemical abnormalities
are present
© Copyright 2022. VMP Genetics. All rights reserved
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
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
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
TREATMENT
Support Barth Syndrome Foundation
Patient advocacy organizations
(RNE, NORD)
Development Services
© Copyright 2022. VMP Genetics. All rights reserved
CLINICAL STUDIES
Other Resistance exercise training
Patient
Registry/
Biorepository
North American Mitochondrial Disease
Consortium (NAMDC)
© Copyright 2022. VMP Genetics. All rights reserved
Genetic and Rare Diseases (GARD) Information Center
(for providers)
RESOURCES
Medline Plus
(for the public)
RESOURCES
National Organization
for Rare Disorders
(NORD)
RESOURCES
RESOURCES
GeneReviews
https://www.ncbi.nlm.nih.gov/books/NBK1116/
Inborn Metabolic Diseases, 7th Edition.
Saudubray JM, et al. Springer, 2022.
RESOURCES
IEMBase (online app – “IEMBase”)
Vademecum Metabolicum (online app – “eVM”)
Thank you for participating today!
Questions?
mkorson@vmpgenetics.com
www.vmpgenetics.com

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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
  • 4. CLASSIFICATION Disorders of intoxication Metabolic disease Disorders of energy metabolism Disorders of complex molecules From Jean-Marie Saudubray, MD
  • 5. THE BODY’S RESPONSE TO FASTING © Copyright 2022. VMP Genetics. All rights reserved
  • 6. Energy source Time after eating Meal Food THE BODY’S RESPONSE TO FASTING © Copyright 2022. VMP Genetics. All rights reserved
  • 7. Energy source Time after eating Meal Glycogen THE BODY’S RESPONSE TO FASTING © Copyright 2022. VMP Genetics. All rights reserved
  • 8. Energy source Time after eating Meal Gluconeogenesis Muscle RBCs THE BODY’S RESPONSE TO FASTING Fatty acid oxidation © Copyright 2022. VMP Genetics. All rights reserved
  • 9. Energy source Time after eating Meal THE BODY’S RESPONSE TO FASTING RBCs Gluconeogenesis Fatty acid oxidation © Copyright 2022. VMP Genetics. All rights reserved
  • 10. Energy source Time after eating Meal Food Glycogen Fatty acid oxidation THE BODY’S RESPONSE TO FASTING Gluconeogenesis Muscle RBCs © Copyright 2022. VMP Genetics. All rights reserved
  • 11. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane © Copyright 2022 VMP Genetics. All rights reserved
  • 12. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane © Copyright 2022 VMP Genetics. All rights reserved
  • 13. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane CARNITINE © Copyright 2022 VMP Genetics. All rights reserved
  • 14. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane CARNITINE LONG CHAIN FATTY ACYL CoA CARNITINE © Copyright 2022 VMP Genetics. All rights reserved
  • 15. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane CARNITINE LONG CHAIN FATTY ACYL CoA CARNITINE © Copyright 2022 VMP Genetics. All rights reserved Carnitine palmitoyltransferase (CPT) II
  • 16. LONG CHAIN FATTY ACYL CoA Mitochondrial Membrane CARNITINE LONG CHAIN FATTY ACYL CoA CARNITINE Carnitine palmitoyltransferase (CPT) II © Copyright 2022 VMP Genetics. All rights reserved
  • 17. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA CARNITINE © Copyright 2022 VMP Genetics. All rights reserved
  • 18. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 19. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA LONG CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 20. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 21. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA ACETYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 22. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA ACETOACETATE © Copyright 2022 VMP Genetics. All rights reserved
  • 23. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA KETONE BODY © Copyright 2022 VMP Genetics. All rights reserved
  • 24. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA LONG CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved Long chain hydroxyacyl CoA dehydrogenase (LCHAD)
  • 25. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 26. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA LONG CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 27. Mitochondrial Membrane MEDIUM CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 28. Mitochondrial Membrane MEDIUM CHAIN FATTY ACYL CoA MEDIUM CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 29. Mitochondrial Membrane MEDIUM CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 30. Mitochondrial Membrane MEDIUM CHAIN FATTY ACYL CoA MEDIUM CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 31. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 32. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA SHORT CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 33. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 34. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA SHORT CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved
  • 35. Mitochondrial Membrane SHORT CHAIN FATTY ACYL CoA ACETYL CoA ACETYL CoA © Copyright 2022 VMP Genetics. All rights reserved
  • 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
  • 39. CLASSIFICATION Disorders of intoxication Metabolic disease Disorders of energy metabolism Disorders of complex molecules From Jean-Marie Saudubray, MD
  • 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
  • 46. Hypoglycemia Reduced ketogenesis Increased medium and long chain fatty acid intermediates Metabolic acidosis Causes ENCEPHALOPATHY IN FAO DEFECTS © Copyright 2022 VMP Genetics. All rights reserved
  • 47. Mitochondrial Membrane LONG CHAIN FATTY ACYL CoA LONG CHAIN β-OXIDATION ENZYMES © Copyright 2022 VMP Genetics. All rights reserved Long chain hydroxyacyl CoA dehydrogenase (LCHAD)
  • 49. Fasting intolerance Encephalopathy – coma, seizures Liver dysfunction Episodic decompensation SYMPTOMS OF FAO DEFECTS © Copyright 2022 VMP Genetics. All rights reserved
  • 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
  • 51. PROTEIN DISORDERS CARBOHYDRATE DISORDERS FATTY ACID OXIDATION DEFECTS Metabolic differential dx SUDDEN INFANT DEATH SYNDROME © 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
  • 53. Hypoglycemia Inadequate ketosis for the glucose or duration of fasting Pathological! PATHOBIOCHEMISTRY © Copyright 2022 VMP Genetics. All rights reserved
  • 54. Glucose Electrolytes, bicarbonate Liver functions (AST, ALT) CK (creatine kinase) Supportive DIAGNOSIS © Copyright 2022 VMP Genetics. All rights reserved
  • 55. Glucose Electrolytes, bicarbonate Liver functions (AST, ALT) CK (creatine kinase) Supportive DIAGNOSIS © Copyright 2022 VMP Genetics. All rights reserved Metabolic Acylcarnitines
  • 56. L-carnitine Organic acyl CoA Fatty acyl CoA Organic acylcarnitine Fatty acylcarnitine Glycine Organic acylglycine Fatty acylglycine © 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.
  • 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
  • 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 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
  • 62. 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 Eating regimen Avoid prolonged fasting Fasting duration depends on age Develop a routine eating regimen ? Bed-time / overnight snack © Copyright 2022. VMP Genetics. All rights reserved
  • 64. 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
  • 65. 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
  • 67. 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
  • 68. 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
  • 69. 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
  • 70. 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
  • 71. 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
  • 73. THE POMPE EKG – A BIG HINT High QRS voltage + short PR interval + WPW
  • 74. © 2008-2018 Society for Inherited Metabolic Disorders www.simd.org Muscle biopsy  Glycogen accumulation Lynch. J Histochem Cytochem (2005) 53:63
  • 76. 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
  • 78. 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
  • 79. 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
  • 80. 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
  • 81. 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. DIAGNOSIS Enzyme assay ⍺-glucosidase DNA testing GAA gene © Copyright 2022. VMP Genetics. All rights reserved
  • 83. 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
  • 84. 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. TREATMENT Prevention Infections Aggressive treatment Immunizations RSV prophylaxis (<2 years) Avoid general anesthesia, if possible © Copyright 2022. VMP Genetics. All rights reserved
  • 86. 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. PROGNOSIS on Rx - LATE ONSET ERT Improved motor strength Improved respiratory function © Copyright 2022. VMP Genetics. All rights reserved
  • 89. 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
  • 91. 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
  • 92. 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
  • 93. 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
  • 94. 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. FEMALES Symptomatic When chromosome abnormalities are also present When biochemical abnormalities are present © Copyright 2022. VMP Genetics. All rights reserved
  • 96. 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
  • 97. 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
  • 98. 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
  • 99. TREATMENT Support Barth Syndrome Foundation Patient advocacy organizations (RNE, NORD) Development Services © Copyright 2022. VMP Genetics. All rights reserved
  • 100. CLINICAL STUDIES Other Resistance exercise training Patient Registry/ Biorepository North American Mitochondrial Disease Consortium (NAMDC) © Copyright 2022. VMP Genetics. All rights reserved
  • 101. Genetic and Rare Diseases (GARD) Information Center (for providers) RESOURCES
  • 102. Medline Plus (for the public) RESOURCES
  • 103. National Organization for Rare Disorders (NORD) RESOURCES
  • 105. RESOURCES IEMBase (online app – “IEMBase”) Vademecum Metabolicum (online app – “eVM”)
  • 106. Thank you for participating today! Questions? mkorson@vmpgenetics.com www.vmpgenetics.com