Genetics Cases and Resources Webinar Slides - November 8, 2022

- 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

THE BODY’S RESPONSE TO FASTING

Energy
source
Time after eating
Meal
Food

Energy
source
Time after eating
Meal
Glycogen

Energy
source
Time after eating
Meal
Gluconeogenesis
Muscle
RBCs
Fatty acid oxidation

Energy
source
Time after eating
Meal
RBCs
Gluconeogenesis

Energy
source
Time after eating
Meal
Food
Glycogen
Gluconeogenesis
Muscle
RBCs

LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
© Copyright 2022 VMP Genetics. All rights reserved

LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE

LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE

LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE
Carnitine palmitoyltransferase (CPT) II

LONG CHAIN FATTY
ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY
ACYL CoA
CARNITINE Carnitine palmitoyltransferase (CPT) II

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
CARNITINE

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETYL CoA

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETYL CoA
ACETYL CoA

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
ACETOACETATE

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
KETONE BODY

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
Long chain hydroxyacyl CoA
dehydrogenase (LCHAD)

Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
ACETYL CoA

Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
MEDIUM CHAIN
β-OXIDATION
ENZYMES

Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
ACETYL CoA

Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
SHORT CHAIN
β-OXIDATION
ENZYMES

Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
ACETYL CoA
ACETYL CoA

Mitochondrial
Membrane
SHORT CHAIN FATTY
ACYL CoA
SHORT CHAIN
β-OXIDATION
ENZYMES SHORT CHAIN FAO DEFECTS
• No (few?) symptoms
• Brain – HAPPY
• Muscles - HAPPY

Mitochondrial
Membrane
MEDIUM CHAIN FATTY
ACYL CoA
MEDIUM CHAIN
β-OXIDATION
ENZYMES MEDIUM CHAIN FAO DEFECTS
• Symptoms!
• Brain – UNHAPPY
• Muscles - HAPPY

Mitochondrial
Membrane
LONG CHAIN FATTY
ACYL CoA
LONG CHAIN
β-OXIDATION
ENZYMES
LONG CHAIN FAO DEFECTS
• Symptoms!
• Brain – UNHAPPY
• Muscles - UNHAPPY

CLASSIFICATION
Disorders of
Intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
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
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
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
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
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

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

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

PROTEIN DISORDERS
CARBOHYDRATE
DISORDERS
FATTY ACID
OXIDATION DEFECTS
Metabolic
differential dx
SUDDEN INFANT DEATH SYNDROME

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

Hypoglycemia
Inadequate ketosis for the glucose
or duration of fasting
Pathological!
PATHOBIOCHEMISTRY

Glucose
Electrolytes, bicarbonate
Liver functions (AST, ALT)
CK (creatine kinase)
Supportive
DIAGNOSIS

Glucose
Supportive
DIAGNOSIS
Metabolic Acylcarnitines

L-carnitine Organic acyl CoA
Fatty acyl CoA
Organic acylcarnitine
Fatty acylcarnitine
Glycine
Organic acylglycine
Fatty acylglycine

Glucose
Supportive
DIAGNOSIS
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
Maple syrup urine
disease
CPS I/OTC def’y
Citrullinemia I, II
Arginase deficiency
Galactosemia
Propionic acidemia
Isovaleric acidemia
Malonic acidemia
MCAD deficiency
CACT deficiency
SCAD deficiency
SCHAD/MCHAD def’y
MCKAT deficiency
VLCAD deficiency
OTHER DISORDERS:
Hemoglobinopathies
Cystic fibrosis
Pompe 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
Maple syrup urine
disease
CPS I/OTC def’y
Citrullinemia I, II
Arginase deficiency
Galactosemia
Propionic acidemia
Isovaleric acidemia
Malonic acidemia
MCAD deficiency
CACT deficiency
SCAD deficiency
SCHAD/MCHAD def’y
MCKAT deficiency
VLCAD deficiency
OTHER DISORDERS:
Hemoglobinopathies
Cystic fibrosis
Hearing loss
NEWBORN SCREENING
IN MASSACHUSETTS
Pompe disease

MANAGEMENT
Eating regimen Avoid prolonged fasting
Fasting duration depends on age
Develop a routine eating regimen
? Bed-time / overnight snack

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

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?

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

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

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

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

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

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

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

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.

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.

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)

DIAGNOSIS
Enzyme assay ⍺-glucosidase
DNA testing GAA gene

TREATMENT
Symptomatic Treat cardiac failure
Respiratory support
Nutritional and feeding support
Physical therapy
Surgery for contractures
Definitive Enzyme replacement therapy

TREATMENT
Prevention Infections
Aggressive treatment
Immunizations
RSV prophylaxis (<2 years)
Avoid general anesthesia, if possible

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

PROGNOSIS on Rx - LATE ONSET
ERT Improved motor strength
Improved respiratory function

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

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

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

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

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)

FEMALES
Symptomatic When chromosome abnormalities
are also present
When biochemical abnormalities
are present

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

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

TREATMENT
Neutropenia G-CSF
Prophylactic antibiotics
Nasogastric/gastrostomy feeding
Prevent hypoglycemia (corn starch, IV)
Cardiac Prevent/treat congestive heart failure
Aspirin prophylaxis
Transplantation
Feeding

TREATMENT
Support Barth Syndrome Foundation
Patient advocacy organizations
(RNE, NORD)
Development Services

CLINICAL STUDIES
Other Resistance exercise training
Patient
Registry/
Biorepository
North American Mitochondrial Disease
Consortium (NAMDC)

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

Genetics Cases and Resources Webinar Slides - November 8, 2022

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