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