Post on 25-Dec-2015
Inborn Errors of Metabolism
Michael Marble, MD
Professor of Clinical Pediatrics
Division of Clinical Genetics
Department of Pediatrics, LSUHSC
and Children’s Hospital
A 3 day old male is brought to the emergency room with a history of lethargy progressing to unresponsiveness. You take an initial history which reveals that the baby had been feeding normally for 24 hours but thereafter became irritable and lost interest in feeding. On exam, you notice that he is breathing fast and deep and is unresponsive. Along with other possible diagnoses, you suspect metabolic disease.
(4) Plasma ammonia result is 1400 micromole/L (0-80). What is the most likely diagnosis? Which tests would you send to confirm a specific metabolic disorder?
Ornithine transcarbamylase deficiency. Plasma amino acids, urine orotic acid
(2) You obtain a complete metabolic profile which shows a normal result. Urinalysis shows elevated specific gravity but is otherwise normal. Capillary blood gas shows respiratory alkalosis: 7.53/ pCO2 20/HCO3 nl, BE nl
(1) Which laboratory studies would you order to obtain quick evidence for or against metabolic disease?
(3) Based on these results, what type of metabolic disease is most likely? Which test would you order next?
Urea cycle disease; plasma ammonia
(5) You confirm that the patient has ornithine transcarbamylase deficiency. What is the recurrence risk in the next pregnancy? Who else in the family should be tested?
X-linked inheritance therefore 50% recurrence risk if mother is a carrier. (6) What is the treatment?
Hemodialysis, low protein diet, arginine, phenylbutyrate
Urea Cycle Disorders DIET
Protein NH4+ + HCO3Carbamoyl Phosphate
OrnithineCitrulline
Argininosuccinic Acid
Arginine
urea(2N)
UREA
CYCLE Asp (N)
OTC
Urea cycle disorders:•Ornithine transcarbamylase deficiency (X-linked)
•Carbamoyl phosphate synthase deficiency (AR)
•Citrullinemia (AR)
•Argininosuccinic acidemia (AR)
•Argininemia (AR)
Hyperammonemia without metabolic acidosis (usually have respiratory alkalosis)
OTC deficiency is the most common and is X-
linked
X-linked inheritance, partially affected female
Headaches, recurrent vomiting, avoids meat
A 3 day old male is brought to the emergency room with a history of lethargy progressing to unresponsiveness. You take an initial history which reveals that the baby had been feeding normally for 24 hours but thereafter became irritable and progressively less interested in feeding. On exam, you notice immediately that he is breathing fast and deep and is unresponsive. Along with other possible diagnoses, you suspect metabolic disease.
(2) You obtain a blood gas, basic metabolic profile, urinalysis and plasma ammonia which show the following:
(1) Which laboratory studies would you order to obtain quick evidence for or against metabolic disease?
(3) Based on these results, what type of metabolic disease is most likely?
Organic acidemias (this patient has propionic acidemia)
136
104.8
101 26
0.796 UA 3+ ketones Ammonia 646
(0-36)Capillary blood gas:
7.11/CO2 19, HCO3 9, BE - 11
(4) How would you confirm a specific metabolic disorder in this case?
Urine organic acids, plasma acylcarnitine profile
Isoleucine
Valine
Methionine
Cholesterol
Odd chain fatty acids
leucine Isovaleryl CoA HMG CoA Acetyl CoA
Krebs Cycle
Methylmalonyl CoAPropionyl CoA Succinyl CoAbiotin B12
Lysine
Tryptophan Glutaryl CoA Crotonyl CoA
3MCC
Acetyl CoA
Bicarb is used to buffer the propionic acid, leading to increased anion gap
methylmalonic acidemia
propionic acidemia
isovaleric acidemia
glutaric acidemia
ETS
ATP
Even chain fatty acids
Anabolic CatabolicATP
Organic Acids
Organic acids are the intermediates in the catabolism of amino acids, lipids and other compounds; specific enzyme deficiencies lead to characteristic urine organic acid profiles
Long chain fatty acid
Fatty acid
Fatty acyl-CoA
Fatty acyl-carnitine
Fatty acyl-carnitine
Fatty acyl-CoA
acetyl CoA
ketones
Free carnitine
Plasma CytoplasmMitochondrion
Krebs
Free carnitine
Detected by acylcarnitine profile
Propionyl CoA
propionylcarnitine
Fatty acid oxidation
Organic acids are metabolized in the mitochondria; blocks in their metabolism lead to elevation of specific acylcarnitines which are identified by plasma acylcarnitine profile
CoA
Selected Organic Acidemias
Propionic
Methylmalonic
Isovaleric
Glutaric
Maple syrup urine
biotin
B12
riboflavin
riboflavin
thiamine
Usually severe
Some respond to B12
Sweaty foot odor to urine
Macrocephaly, dystonia,
Maple syrup odor, elevated branched chain amino acids
Disease Cofactor Other features
Abnormal MRI
Wide anion gap ketoacidosis
+
+
+
+
+
Glutaric Acidemia Type 1
Severe movement disorder
•Intercurrent illnesses (usually viral) greatly increase the risk of metabolic encephalopathy and long term disability; therefore preventive measures against catabolism are critical
•The parents of organic acidemia patients should be given emergency protocols for management during intercurrent illnesses
D10 + ¼ NS at 1.5 maintenance volume;
IV carnitine
Glutaric acidemia type 1(patient with viral illness)
Urea cycle disease versus organic acidemias
lethargy/coma
vomiting
hyperammonemia
metabolic ketoacidosis
primary respiratory alkalosis
UCD OA
+ +/-
+
+
+
+
+ +
-
-
+
You are called to the newborn nursery regarding an 8 hour old female who is listless and not interested in feeding. The baby is severely hypotonic and lethargic but no other obvious abnormalities are noted. Accucheck shows normal glucose. Blood gas, complete metabolic profile, CBC, plasma ammonia, lactate and urinalysis all show normal results. Chest X-ray comes back normal. Along with other possibilities, you suspect a neuromuscular disorder and consult neurology. Maintenance IVFs are started. Pregnancy history is significant for decreased fetal movements. While awaiting neurology consult, the baby has apnea spells and develops myoclonic jerks. and is intubated. An EEG shows a “burst suppression” pattern.
(2) How would you confirm the diagnosis?
CSF/plasma glycine ratio
(3) What is the prognosis?
Very poor, despite treatment
(1) What is the most likely diagnosis?Nonketotic hyperglycinemia
Nonketotic hyperglycinemia
*Defect in glycine catabolism
•autosomal recessive
•symptoms in first 24 hours
•hypotonia/encephalopathy, seizures, burst suppression EEG
•increased CSF/plasma glycine
•Tx: benzoate, dextramethorphan
•poor prognosis, diet ineffective
Glycine NH3 + CO2
*Diagnosis based on elevated CSF/Plasma glycine ratio
A 15 month old female, previously healthy, was brought to the emergency room after the mother had difficulty arousing her in the morning. Over the past 2 days, the child had had a low grade fever, cough, mild diarrhea and 3 episodes of vomiting. Due to poor appetite, the patient did not eat very much for dinner and missed her ususal bedtime snack the night before presentation. In the ER, she was noted to have a depressed mental status but was partially responsive. Exam was otherwise normal. Initial lab testing showed the following:
The ER physician starts an IV and gives a bolus of glucose to correct hypoglycemia. The physician also gives normal saline boluses for rehydration. Then IVFs with D5 ¼ normal saline is started at 1.5 maintenance fluids. Followup labs show normal serum glucose but no change in acid-base status. The patient’s mental status worsens and she becomes comatose. She is transferred to the PICU. Plasma ammonia level is found to be mildly elevated at 101 micromoles/L .
CBC: WBC mildly elevated
CMP shows sodium 139, Cl 104, CO2 13 BUN 28 Cre 0.6, glucose 37, mild elevation of ALT and AST
Urinalysis negative for reducing substances and ketones, specific gravity is elevated
Based on the above presentation and lab results, the patient most likely has a disorder within which category of inborn error of metabolism?
Fatty acid oxidation defects (specifically MCAD in this patient)How would you confirm a specific diagnosis?
Plasma acylcarnitine profile
Patient who presented with hypoglycemia and altered
mental status
Diagnosis of fatty acid oxidation disorders by acylcarnitine analysis
Long chain fatty acid
Fatty acid
Fatty acyl-CoA
Fatty acyl-carnitine
Fatty acyl-carnitine
Fatty acyl-CoA
MCAD
SCAD
acetyl CoA
ketones
Free carnitine
Plasma CytoplasmMitochondrion
18 16 14 12 8 6 4
fatty acyl CoAs
+ Fatty acyl-carnitine
(C6-C12)(C6-C12)
Detected by acylcarnitine analysis
MCAD deficiency
Fatty acids
fasting
ketones
acetyl CoA
Krebs cycle
*key pathway for adaptation to fasting
VLCAD LCHAD MCAD SCAD
CPT1/CPT2
+
Brain
Fatty acid oxidation
•Distinguishing feature of FAOD is hypoketotic hypoglycemia
•Medium chain acyl CoA dehydrogenase deficiency(MCAD) is most common and has a 25% risk of death with first episode
•LCHAD, VLCAD and carnitine uptake disorder are variably associated with, hepatomegaly, liver disease, hypertrophic cardiomyopathy and potential arrythmias
•All are autosomal recessive
LCHAD deficiencyHypoketotic hyoglycemia, hypotonia, failure to thrive
At diagnosis
On dietary
treatment
Variable Clinical presentations of fatty acid oxidation
•Hyoketotic hypoglycemia in neonatal period
•Later onset hypoketotic hypoglycemia
•Sudden infant death syndrome
•Hypertrophic cardiomyopathy, arrythmias
•Liver disease
•Adolescent or adult onset myopathy
•Acute rhabdomyolysis
•Asymptomatic
DiseaseTypical
presentation Comments
Probably benign
Most common FAOD, may be associated with “SIDS”
SCAD
MCAD
VLCAD
Hypoketotic hypoglycemia
N/A
Variable: hypoketotic hypoglycemia, hypertrophic
cardiomyopathy, myopathy, liver dz
Extemely variable ranging from neonatal to adult onset
LCHAD Variable: hypoketotic hypoglycemia, hypertrophic
cardiomyopathy, myopathy, liver dz
Extremely variable, need low fat diet
Fatty acid oxidation disorders
Diagnosis is based on the specific pattern of acylcarnitine elevations
Disorders of carnitine metabolism
(1) Carnitine transports long chain fatty acids into the mitochondria
(2) Carnitine deficiency can be primary or secondary
(3) Primary carnitine deficiency is caused by abnormal transport of carnitine itself into the cells (carnitine uptake disorder, AKA “systemic carnitine deficiency”)
(4) Secondary carnitine deficiency is caused by other metabolic disorders through the formation of carnitine esters (acylcarnitines) by abnormal organic/fatty acids
Decreased total carnitine
Decreased free carnitine
Normal acyl/free ratio
Normal total carnitine
Normal or increased free carnitine
Normal acyl/free ratio
Plasma:
Urine:
Primary (CUD)
Decreased/normal total carnitine
Decreased free carnitine
Increased acyl/free ratio
Decreased/normal total carnitine
Decreased free carnitine
Increased acyl/free ratio
Plasma:
Urine:
MCAD, organic acidemias etc
A 6 day old female who is breast fed is brought to the emergency room due to poor feeding, vomiting and jaundice? Initial laboratory studies show the following:
136
104.8
115 26
0.773
Total Bilirubin 19
Direct bilirubin 5.2
AST 987
ALT 767
Which metabolic disorder do you suspect?
galactosemia
Which other routine tests should you order?
PT, PTT, urine reducing substances How would you confirm the diagnosis?
Enzyme assay, DNA
How would you treat this patient?
Galactose free diet
What are the acute and long term complications of this disorder?
Liver disease, E coli sepsis, cataracts, MR, speech delay, ovarian failure
Lactose Galactose
glucose
Gal-1-Pgalactokinase
(galactose-glucose)
Glucose-1-P
glycolysis
galactose-1-P uridyltransferase
UDP galactose
UDP glucose
pyruvate
epimerase
(cataracts)
(classical)(benign)
Breast milk, cow’s milk
Glucose-6-P
Galactose Metabolism
Treatment: galactose free diet, ophthalmology and developmental followup
A 9 year old male is brought to the emergency room due to acute vomiting and lethargy shortly after a birthday party. Past medical history is significant for failure to thrive in late infancy which resolved without determination of a diagnosis. He had had several bouts of vomiting in the past, usually after consuming candy or soft drinks at parties. He has had no dental cavities. Laboratory results in the ER are as follows:
136
104.8
115 26
0.773
Total Bilirubin
6.4
Direct bilirubin 5.2
AST 767
ALT 987
What is the most likely metabolic diagnosis?
Hereditary fructose intolerance
A 3 month old female is found to have hepatomegaly on routine exam. She is asymptomatic. Lab testing shows hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and elevated AST and ALT.
What is the most likely diagnosis?
Glycogen storage disease
How would you confirm the diagnosis?
DNA, liver biopsy
What is the treatment?
dietary
Glycogen Storage Disease 1a
“Von Gierke disease”
weakness
hepatomegalyfacial features
Hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia,
neutropenia
Glycogen Storage Disease 1b
Sibling with same disorder
Autosomal recessive
Glycogen
Glucose – 1- P
Glucose – 6- P
Glucose-6-phosphataseGlucose
Glut 2
glucose
cytoplasm
plasma
pyruvate
Lactic acidosis
gluconeogenesis
glycolysis
Pentose phosphate
shunt(hyperuricemia)
GSD types 1a and 1b
ER
Glycogen is a storage form of glucose:
•Liver glycogen releases glucose into the circulation
•Muscle glycogen is used locally
Krebs cycle
Acetyl CoA
Malonyl CoA
Stimulates fatty acid synthesis and inhibits fatty acid breakdown
(Hyperlipidemia)
DiseaseTypical
presentation Other features
Hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia
Puffy cheeks, neutropenia
Von Gierke (GSDIa)
GSDIb
Pompei (GSD II)
Puffy cheeks
Weakness, hypotonia, cardiomyopathy
EKG: short PR intervals, wide QRS
Similar to Von Gierke but milder, normal
lactate
Muscle, including cardiac may be
involved
Hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia
Debrancher deficiency (GSD III)
McCardle disease (GSD VI)
Only muscle involvement Risk of rhabdomyolysis
Brancher deficiency (GSD IV)
Fatal liver disease (amylopectinosis)
Other organ involvement
Selected glycogen storage diseases
Treatment
Nocturnal NG feedings, avoid fasting
Nocturnal NG feedings, avoid fasting, neutropenia precautions
Enzyme replacement
Similar to GSD1a
? transplant
Avoid excess excercise
Apparently normal development for the first 6 months but begins to slow down. She was able to sit unassisted by 1 year. She was very socially interactive and could grasp objects. Gradually lost her ability to sit and grasp objects. Became less and less interactive, and lost interest in eating and became emaciated. She had splenomegaly. Ophthalmology exam revealed a cherry red spot macula:
•What type of disorder do you suspect?
Lysosomal storage disease
•How would you confirm a diagnosis?
Enzyme assay
•What is the differential diagnosis of cherry red macula?
Patient with developmental regression
Lysosomal lipid storage disorders associated with cherry red macula:•Niemann-Pick A
•Tay-Sachs disease
•GM1 gangliosidosis
•Sandhoff disease
•Farber lipogranulomatosis
•Sialidosis
Lysosomal storage disease: ocular features
Mucoploysaccharides (glycosaminoglycans)
Bone, connective tissue, skin,
cornea,joints etc
Cell membranes, organelles
Bacteria, viruses
Lysosome
Sphingolipids, glycolipids etc
Food particles
Glycoproteins
Acid hydrolases
“The cells wrecking crew”
Glycogen
Abnormal lysosomal storage leads to developmental regression
Metachromatic Leukodystrophy
•Rapid developmental regression starting in late infancy
•Lysosomal accumulation of sulfatides
GM1 Gangliosidosis
Neonatal presentation: hypotonia, ascites
A 14 month old female presented with developmental delay to your clinic. She was reportedly normal at birth but at 8 months was noted to have mild kyphosis when sitting. She had chronic rhinorrhea. Late in infancy, the parents noticed gradual changes in craniofacial features including thickening of the eyebrows, large tongue, prominence of forehead. The patient hand been pulling to stand but lost this ability and seemed to be regressing in overall development. On exam, you notice a scaphocephalic head shape, frontal bossing, relatively thick eyebrows, cloudy cornea and stiff elbows.
The patient most likely has a disorder within which category of inborn error of metabolism?
Lysosomal storage disease (mucopolysaccharidosis)
How would you confirm a specific diagnosis?
Enzyme assay, urine mucopolysaccharies (glycosaminoglycans), skeletal survey
Mucopolysaccharidosis• Hurler Syndrome: comparison with sibs
Hurler syndrome
Mucopolysaccharidosis
• Hurler syndrome – alpha L-iduronidase def.
organomegaly
Sanfilipo Syndrome (MPS 3)
• facial features
•Sanfilipo (MPS III)
•Less severe somatic features
•Developmental delay
•Behavioral problems
•Neurological regression
Maroteaux-Lamy (MPS VI)
Maroteaux-Lamy syndrome
(MPS6)
Morquio (MPS IV)
Lysosomal storage disease: laboratory diagnosis
•Urine mucopolysaccharides
•Urine oligosaccharide
•Enzyme assay
•DNA (for genetic counseling and to rule out pseudoalleles)
DiseaseTypical
presentation Inheritance
Developmental regression, dysosotosis multiplex, cloudy cornea, organomegaly, cardiac valve disease
Hurler (MPS1)
Hunter (MPS2)
San Filippo (MPS3)
Autosomal recessive
Later onset, mild somatic features
Mainly skeletal involvement
Similar to Hurler but no cloudy cornea
Morquio (MPS4)
Maroteaux-Lamy (MPS6)
Similar to Hurler but “CNS sparing”
Treatment
X-linked
Autosomal recessive
Autosomal recessive
Autosomal recessive
BMT/ERT
BMT/ERT
BMT/ERT
?ERT
One year old female with failure to thrive, developmental delay and hypotonia, MRI showed basal ganglia abnormalities. Labs show mild elevation of lactate.
Mitochondrial genome sequencing: mutation m.8993T>G in a subunit of ATP synthase
Mitochondrial genome disorders•Maternal
inheritance
•Heteroplasmy
•Replicative segregation
Mitochondrial genome disorders
•Myoclonic epilepsy, lactic acidosis, stroke-like episodes (MELAS)
•Myoclonic epilepsy ragged red fibers (MERRF)
•Neuropathy, ataxia, retinintis pigmentosa (NARP)
•Nonsyndromic deafness/diabetes
•Kearn Sayres: sporadic giant deletions
•Pearson syndrome: sporadic giant deletions
•Leigh syndrome
•other
PKU Adult with Mental Retardation: born before
newborn screening era
Severe mental retardation,
microcephaly, behavioural
problems
•Phenylalanine hydroxylase defect
•Autosomal recessive
•Normal infant at birth
Phe TyrDietary protein
PAH
Neurotransmitters, melanin etc
PKU: Clinical Problems if Untreated
• mental retardation
• seizures
• hypopigmentation
• rash
Tx: low phenylalanine diet
*Due to newborn screening, the above problems rarely occur.
Heel stick:
•Obtain at about 48 hours
•If obtained too early, false
negative
Filter paper with blood spots and
demographic information
“Guthrie cards”
Patients with PKU: low Phe diet, frequent monitoring of Phe, dietary counseling
Normal growth and development
•Studies have shown that NBS has virtually eliminated mental
retardation due to PKU
Phenylketonuria
HYPERCHLOREMICMETABOLIC ACIDOSIS
LIVER DISEASECATARACTS
HYPERBILIRUBINEMIAREDUCING SUBSTANCES
Selected Presentations/Diagnostic Considerations
INFANT/CHILD WITH SUSPECTED
METABOLIC DISEASE
KETONES NEGATIVE ENCEPHALOPATY < 24 HRS OLD, BURST SUPPRESSION EEG
METABOLIC ACIDOSIS
HYPOGLYCEMIAINAPPROPRIATELY LOW KETONES
RESPIRATORY ALKALOSIS
HYPERAMMONEMIA
FATTY ACID OXIDATION
DEFECT
ORGANIC ACIDEMIA
UREA CYCLE DISEASE
GALACTOSEMIA
NON KETOTIC HYPERGLYCINEMIA
HYPOGLYCEMIAHEPATOMEGALY
GLYCOGENSTORAGEDISEASE (LIVER)
DEVELOPMENTALREGRESSION
SKELETAL DYSPLASIAORGANOMEGALY
VARIABLE CLOUDY CORNEA
Lysosomal storage (MPS)
WIDE ANION GAP METABOLIC ACIDOSIS, KETONURIA, HYPERAMMONEMIA
DEVELOPMENTALREGRESSION
ORGANOMEGALY CHERRY RED MACULA
Lysosomal storage (glycolpids))
WEAKNESSRHABDOMYOLYSIS
GLYCOGENSTORAGEDISEASE (MUSCLE)Or FAOD