Metabolic Disorders
Inborn Errors Of Metabolism
DR. ABDULLAH ALOMAIR
MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)
Associate Professor of Pediatrics
Consultant Pediatrician
Department of Pediatrics
PRESIDENT
SAUDI PEDIATRIC ASSOCIATION
1
Metabolic Disorders
Inborn Errors Of Metabolism
Inborn Errors Of Metabolism (IEM)
- A large group of hereditary biochemical
diseases
- Specific gene mutation cause abnormal
or missing proteins that lead to altered
function.
2
Pathophysiology

SINGLE GENE DEFECTS in synthesis
or catabolism of proteins, carbohydrates,
or fats.

Defect in an ENZYME or TRANSPORT
PROTEIN , which results in a block in a
metabolic pathway.
Pathophysiology

EFFECTS :
- toxic ACCUMULATION of substrates before the block,
- intermediates from ALTERNATIVE pathways
- defects in ENERGY production and utilization caused
by a deficiency of products beyond the BLOCK.

Every metabolic disease has several forms that vary in AGE
OF ONSET , clinical severity and, often, MODE OF
INHERITANCE.
Metabolic Disorders
Features suggestive of metabolic disorder :
From history:
Parental history :
Consanguineous parents
Previous unexplained neonatal deaths
Particular ethnic group (in certain diseases)
7
Metabolic Disorders
Features suggestive of metabolic disorder :
Examination findings:
Organomegaly (e.g. hepatomegaly)
Cardiac disease
Ocular involvement (e.g. cherry red spot)
Skin manifestations
Unusual odour
Non-specific neurological findings
Neonatal and Post Neonatal Presentation
Neonatal presentation
Normal-appearing child at birth (some
conditions are associated with dysmorphic
features)
•
•
•
•
•
•
•
poor feeding
lethargy
vomiting
seizures
coma
unusual odour
hypoglycaemia, acidosis (in some defects)
9
Neonatal and Post Neonatal Presentation
Post neonatal presentation
•
•
•
•
•
•
Encephalopathy
Developmental regression
Reye syndrome
Motor deficits
Seizures
Intermittent episodes of vomiting, acidosis,
hypoglycaemia and/or coma triggered by
stress e.g. infections, surgery.
Newborn Screening






PKU - in NICU even if not advanced to full feeds
Galactosemia
Hypothyroidism
Hemoglobinopathies
Biotinidase defic, CAH (21-OH’ase def),
Maple syrup urine disease ( MSUD )
- GUTHRIE TEST
PROCEDURES FOR DIAGNOSIC CONFIRMATION
Non – Specific Tests:
Specific Tests:
•
•
•
•
Blood glucose,
ammonia, bicarbonate
and PH
Peripheral Blood smear
– WBC or bone marrow
vacuolization , foam
cells or granules.
C.S.F. glycine , other
amino acids , lactate.
Direct
biochemical
assays of metabolites
or their metabolic
by-products, or of an
enzyme’s function.
•
DNA studies
•
Neuro-radiology
12
INBORN ERRORS OF AMINO ACID METABOLISM
ASSOSIATED WITH ABNORMAL ODOR
Inborn Error of
Metabolism
Urine Odor
Gultaric Acidemia
Sweaty feet
Maple Syrup urine disease
Maple syrup
Hypermethioninemia
Boiled cabbage
Phenylketonuria
Mousy or musty
Trimethylaminuria
Rotten fish
13
MANAGEMENT OF IEM
Genetic:
Establish diagnosis.
Carrier testing.
Pedigree analysis, risk counseling.
Consideration of Prenatal diagnosis for
pregnancies at risk.
25
MANAGEMENT OF IEM
PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL

Family counseling and support.

Education
to
promote
increased
compliance with special form of therapy
such as Protein – restricted diet.

Assessment of community resources
and support groups.
26
TREATMENT OF GENETIC DISEASES

Modify environment, e.g., diet, drugs

Avoid known environmental triggers

BMT


Surgical, correct or repair defect or organ
transplantation
Modify or replace defective gene product, megadose
vitamin therapy or enzyme replacement

Replace defective gene

Correct altered DNA in defective gene
Galactosemia
28
Carbohydrates :
Galactosemia
Enzyme deficiency:
Galactose-1-phosphate uridyl transferase deficiency.
Rare . Autosomal recessive
●
●
●
●
●
Follows feeding with lactose containing (breastmilk / formula)
Patient feeds poorly , have vomiting, jaundice, hepatomegaly
and hepatic failure
Chronic liver disease
Cataracts
Developmental delay develop if condition is untreated.
29
CYSTIC FIBROSIS
Cause : Loss of 3 DNA bases in a gene for the protein
that transports Cl ions so salt balance is upset. Causes a
build up of thick mucus in lungs and digestive organs.
AMINO ACID DISORDERS
Phenyl Ketonuria (PKU)
Phenylalanine
Phenylalanine
Hydroxylase
Phenyl ethylamine
Tyrosine
Phenyl pyruvic acid
31
Phenylketonuria PKU
32
PKU
CLINICAL FEATURES

Hyperactivity, athetosis, vomiting.

Blond.

Seborric dermatitis or eczema skin.

Hypertonia.

Seizures.

Severe mental retardation.

Unpleasant odor of phenyl acetic acid.
DIAGNOSIS
•
Screening : Guthrie Test.
•
High Phenylalanine > 20
mg/dl.
•
High Phenyl pyruvic acid.
TREATMENT
•
DIET.
•
BH4 (Tetrahydrobiopterin).
•
L – dopa and 5hydroxytryptophan.
33
PKU
34
Albinism
35
Homocystinuria
Elevated homocystine levels affect collagen , result in a Marfanoid
habitus, ectopia lentis, mental retardation and strokes
38
Homocystinuria
METHIONINE
Cysathionine
CYSTATHIONINE
Synthatase
DIAGNOSIS:
High methionine and homocystine.
TREATMENT:
•High dose of B6 and Folic Acid.
•Low methionine and high cystine diet,
•Betain (trimethylglycine)
39
Homocystinuria
40
Amino acid disorders :
Urea cycle defects and hyperammonemia
All present with lethargy, seizures, ketoacidosis, neutropenia, and
hyperammonemia

Ornithine carbamyl transferase (OTC) deficiency

Carbamyl phosphate synthetase deficiency

Citrullinemia

Arginosuccinic Aciduria

Argininemia

Transient tyrosinemia of prematurity
First Steps in Metabolic Therapy for IEM

Reduce precursor substrate load

Provide caloric support

Provide fluid support

Remove metabolites via dialysis

Divert metabolites

Supplement with cofactor(s)
CARNITINE METABOLISM



An essential nutrient found in highest
concentration in red meat.
Primary function : Transport long-chain
fatty acids into mitochondria for oxidation.
Carnitine supplementation in fatty acid
oxidation disorders and organic acidosis may
augment excretion of accumulated
metabolites , but may not prevent metabolic
crises in such patients .
Important IEM Treatment supplements:

Carnitine for elimination of Organic Acid through
creation of carnitine esters.

Sodium Benzoate, phenylacetate and
phenylbutyrate for Hyperammonemia
elimination.
Therapeutic Measures for IEM
•
•
•
•
•
•
D/C oral intake temporarily
Usually IVF’s with glucose to give 12-15
mg/kg/min glu and at least 60 kcal/kg to
prevent catabolism (may worsen PDH)
Bicarb/citrate
Carnitine/glycine
Na Benzoate/arginine/citrulline
Dialysis--not exchange transfusion
Vitamins--often given in cocktails after labs
drawn before dx is known
• Biotin, B6, B12, riboflavin, thiamine, folate
ORGANIC ACIDEMIA
Disorder
Enzyme
•
Methyl malonic
Acidemia.
•
Methyl malonyl COA
mutase.
•
Propionic Acidemia.
•
Propionyl COA
Carboxylase.
•
Multiple carboxylase
deficiency.
•
Malfunction of all
carboxylase.
•
Ketothiolase deficiency .
•
2 methylacetyl COA thiolase
def.
46
ORGANIC ACIDEMIA
Treatment
Clinical Features


Vomiting, ketosis.

Thrombocytopenia ,
neutropenia.


Osteoporosis.

Mental retardation.


Hydration / alkali.
Calories to 
catabolic state.
Exchange
transfusion.
Low protein diet.
47
ORGANIC ACIDEMIA
48
LYSOSOMAL STORAGE
DISORDERS

Glycogen Storage Diseases

Sphingolipidoses
(Lipidoses And Mucolipidoses)

Mucopolysaccharidoses
49
Lysosomal Storage Disease
Disease
Enzyme Defiency
Major Accumulating
Metabolite
Glucosidase
Glycogen
GM1 gangliosidoses
β-galactosidase
GM1 gangliosides,
galactose-containing
oligosaccharides
GM2 gangliosidoses
Tay-Sachs disease
Gaucher disease
Niemann-Pick disease
Hexosaminidase A
Glucocerebrosidase
Sphingomyelinase
GM2 ganglioside
Glucocerebroside
Sphingomyelin
MPS I H (Hurler)
α-L-Iduronidase
Heparan sulfate
Dermatan sulfate
MPS II (Hunter)
(X-linked recessive)
L-Iduronosulfate
sulfatase
Heparan sulfate
Dermatan sulfate
Glycogenosis
Type II (Pompe disease)
Sphingolipidoses
Mucopolysaccharidoses
50
Glycogen Storage Diseases
Name
Type O
von Gierke
(Type IA)
Type IB
Pompe
(Type II)
Forbe (Cori)
(Type III)
Andersen
(Type IV)
McArdle's
(Type V)
Her
(Type VI)
Tarui
(Type VII)
Type VIII
Type IX
Type X
Type XI
Enzyme
Glycogen synthetase
Glucose-6-phosphatase
Symptoms
Enlarged, fatty liver; hypoglycemia when fasting
Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia
G-6-P translocase
Acid maltase
Same as in von Gierke's disease but may be less severe; neutropenia
Enlarged liver and heart, muscle weakness
Glycogen debrancher
Enlarged liver or cirrhosis; low blood sugar levels; muscle damage
and heart damage in some people
Cirrhosis in juvenile type; muscle damage and CHF
Glycogen branching enzyme
Muscle glycogen
phosphorylase
Liver glycogen phosphorlyase
Muscle cramps or weakness during physical activity
Muscle phosphofructokinase
Muscle cramps during physical activity; hemolysis
Unknown
Liver phosphorylase kinase
Cyclic 3-5 dependent kinase
Unknown
Hepatomegaly; ataxia, nystagmus
Hepatomegaly; Often no symptoms
Hepatomegaly, muscle pain (1 patient)
Hepatomegaly. Stunted growth, acidosis, Rickets
Enlarged liver; often no symptoms
Principle Groups of
Glycogen Storage Diseases
53
Von Gierke Disease
54
LYSOSOMAL STORAGE
DISORDERS
Lipidoses And Mucolipidoses
55
Gauch. cell
56
Sandhoff - Dense thalam
58
Leucodys..
59
Lipid-retina
60
LYSOSOMAL STORAGE
DISORDERS
Mucopolysaccharidoses
61
Clinical And Pathological Ultra
structure Of
Mucopolysaccharidoses
Disease
Clinical Manifestation
Ultrastructure of Stored
Material
MPS type I
Earliest, most severe developmental
regression
coarse facial features
Hepatosplenomegaly
dystosis of bone
cardiac involvement
corneal clouding
Fibrillogranular mucopolysaccharides
in cells of viscera and brain
MPS type II
Later developmental regression
Hunter
coarse facial features
Fibrillogranular mucopolysaccharides
in cells of viscera and brain
X-linked
dystosis of bone cardiac involvement
Hurler
hepatosplenomegaly
minimal corneal clouding
62
Hurler’s
63
Hurler’s
64
65
Mcopolysacch. Morquio
66
PEROXISOMAL DISORDERS

Due to dysfunction of a single or multiple
peroxisomal enzymes, or to failure to form or
maintain a normal number of functional
peroxisomes.

Peroxisomes
=
Subcellular organelles
involved in various essential anabolic or catabolic
processes, biosynthesis of Plasmalogens and bile
acids.
67
PEROXISOMAL DISORDERS
Clinical Manifestations:

Hypotonia.

Dysmorphia.

Psychomotor delay and seizures.

Hepatomegaly.

Abnormal eye findings such as retinitis pigmentosa
or cataract.

Hearing impairment.
68
Peroxisomal Disorders

Zellweger Syndrome
(Cerebro-hepato-renal
syndrome)

Typical and easily recognized
dysmorphic facies.

Progressive degeneration of
Brain/Liver/Kidney, with
death ~6 mo after onset.

When screening for PDs.
obtain serum Very Long
Chain Fatty Acids- VLCFAs
Zellweger
70
Chond punct
71
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THANK YOU
73
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Metabolic Disorders



75
Due to inherited reduced activities of proteins
involved in the synthesis, breakdown or transport of
amino acids, organic acids, fats, carbohydrates and
complex macromolecules.
Most are autosomal recessive due to mutations that
result in reduced enzyme activity or reduced amount
of enzyme.
Pathogenesis may include: accumulation of a toxic
intermediate, reduced amount of a necessary end
product or activation of an alternate pathway.
Inborn Errors of Metabolism of Acute Onset: Nonacidotic,
Nonhyperammonemic Features
Neurologic Features Predominant (Seizures, Hypotonia, Optic
Abnormality)
Glycine encephalopathy (nonketotic hyperglycinemia)
Pyridoxine-responsive seizures
Sulfite oxidase/santhine oxidase deficiency
Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile refsum disease)
Jaundice Prominent
Galactosemia
Hereditary fructose intolerance
Menkes kinky hair syndrome
1-antitrypsin deficiency
Hypoglycemia (Nonketotic): Fatty acid oxidation defects (MCAD, LCAD,
carnitine palmityl transferase, infantile form)
Cardiomegaly
Glycogen storage disease (type II phosphorylase kinase b deficiency 18)
Fatty acid oxidation defects (LCAD)
Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD)
Skeletal Muscle Weakness : Fatty acid oxidation defects (LCAD, SCAD,
multiple acyl-CoA dehydrogenase
Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the
Neonate or Infant
Symptoms indicating possibility of an IEM (one or all)
Infant becomes acutely ill after period of normal behavior and feeding;
this may occur within hours or weeks
Neonate or infant with seizures and/or hypotonia, especially if seizures
are intractable
Neonate or infant with an unusual odor
Symptoms indicating strong possibility of an IEM, particularly when coupled
with the above symptoms
Persistent or recurrent vomiting
Failure to thrive (failure to gain weight or weight loss)
Apnea or respiratory distress (tachypnea)
Jaundice or hepatomegaly
Lethargy
Coma (particularly intermittent)
Unexplained hemorrhage
Family history of neonatal deaths, or of similar illness, especially in
siblings
Parental consanguinity
Sepsis (particularly Escherichia coli)
Laboratory Assessment of Neonates
Suspected of Having an
Inborn Error of Metabolism
Routine Studies
Blood lactate and
pyruvate
Complete blood count
and differential
Plasma ammonia
Plasma glucose
Plasma electrolytes and
blood pH
Urine ketones
Urine-reducing
substances
Special Studies
Plasma amino acids
Plasma carnitine
Urine amino acids
Urine organic acids
Classification


Transient Hyperammonemia
of Newborn
Inborn Errors of Metab:
•
•
•
•
•

Molybdenum Cofactor
Deficiency
•



Organic Acidemias
Fatty Acid Oxidation def
Urea Cycle Defects
Amino Acidurias
Non-ketotic Hyperglycinemia
Sulfite Oxidase Deficiency
Metal Storage Disorders:
Cholesterol Disorders:
Leukodystrophies, other…
•
Krabbe disease





Mitochondrial Disorders
Glycogen Storage Disorders
Hyperinsulinism
Carbohydrate Disorders
Lysosomal Disorders
•
•
•

Mucopolysaccharidoses (Xlinked Hunter’s, Hurler’s)
Gaucher disease
Tay-Sachs Disease
Peroxisomal Disorders
•
•
Zellwegger’s (CerebroHepato-renal)
X-linked
Adrenoleukodystrophy
PEROXISOMAL DISORDERS
Diagnosis:

Immunochemical studies for Peroxisomes.

 V. Long Chain FA ( VLCFA ) level.

Chor. Vill. Samp. or/ amniocytes culture 
 Plasmalogens
synthesis.
Treatment:

Supportive, multidisciplinary interventions.

Diet:  VLCFA,  phytanic acid.

Organ transplantation.
81
Peroxisomal Disorders
GROUP I : BIOGENSIS OF PEROXISOME
Zellweger syndrome
(cerebrohepatorenal syndrome).
Neonatal adrenoleukodystrophy.
Infantile Refsum disease.
Hyperpipecolic acidemia.
GROUP II : PERSOXISOMAL
ENZYME DEFECTS
GROUP III : POSITIVE PEROXISOMES BUT
MULTIPLE DEFECTIVE ENZYME
Zellweger – Like.
Pseudo – infantile Refsum disease.
Rhizomelic chondro-dysplasia
punctata
Refsum disease.
X - linked Adreno-Leuko-Dystrophy.
Pseudo – Zellweger syndrome.
Hyperoxaluria….etc.
82
Syndrome
83
Mitochondrial Syndromes
Presenting in Childhood to Adult
Most Common
Clinical
Presentation
Other Cliical
Features
Mt DNA Defect
MELAS: myopathy,
encephalopathy, lactic
acidosis and stroke-like
episodes
Stroke-like episodes in
the first and second
decade of life often
associated with
migraine headache,
blood lactate
Deafness, myopathy,
diabetes mellitus
mtDNA mutations at
3243, 3271
tRNA mutations
MERRF: Myoclonic
epilepsy with ragged
red fibers
Progressive myoclonic
epilepsy
Ataxia, myopathy
deafness, short stature
MtDNA A8344G
tRNA mutation
NARP: Neurogenic
weakness, ataxia and
retinitis pigmentosa
Peripheral neuropathy,
myopathy, seizures
Leigh syndrome
MtDNA 8993
Complex V deficiency
84
Clinical Presentation of Amino Acid Disorders
Clinical Abnormality
Abnormal Amino Acid
Presumptive Diagnosis
Acute neonatal
presentation with
ketoacidosis
Leucine, isoleucine,
valine
Organic Acid Disorders
Maple syrup urine disease
Methylmalonic acidemia
Propionic acidemia
Isovaleric acidemia
85
Acute neonatal
presentation with
hyperammonemia
Arginine, Citrulline
Marfanoid, strokes,
ectopia lentis,
mental retardation
Homocystine &
methionine
Urea cycle disorders
Ornithine transcarbamylase deficiency
Argininosuccinate synthase deficiency
Argininosuccinate lyase deficiency
Severe
Phenylalanine
developmental delay
Homocystinuria
Phenylketonuria
Mitochondrial
Disorders

Classically involve mutations in
mitochondrial DNA

Follow a maternal pattern of inheritance

Highly variable with regard to penetrance and
expressivity based on the variability in tissue
distribution of abnormal mitochondria
86
Metabolic Profiles
Organic and Amino Acid Disorders
Predominanat
Biochemical
Clinical Findings
KetoAcidosis
Lethargy
Odor
Acidosis
Lethargy
Odor
Lactic Acidosis
Lethargy
Hypoglycemia
Lethargy
Hyperammonemia
Lethargy
Other
Most Common Diagnosis
Ammonia: Normal or slightly
elevated Ketones: Elevated
Glucose: Normal
Maple syrup urine disease
Ammonia: Elevated
Glucose: Normal or decreased
Ketones: May be elevated
Lactate: Slightly elevated
Methylmalonic acidemia
Propionic acidemia
Isolvaleric acidemia
Acidosis: Usually present
Ammonia: Normal or slightly
elevated
Ketones: May be elevated
Pyruvate dehydrogenase
Pyruvate carboxylase deficiency
Respiratory chain disorder
Ammonia: Lactate Acidosis
Ketones: Absent or inappropriately
low
Fatty acid oxidation defects
Acidosis: Absent
Respiratory Alkalosis
Urea cycle disorders
Newborn screening is available dependent on population frequency for some
Expanded newborn screening for fatty acid defects recently offered
87
CHILDREN AFTER THE NEONATAL
PERIOD Clinical Manifestation
Mental retardation, Macro/Microcephaly.
Coarse facial features/dysmorphia.
Developmental regression.
Convulsion.
Myopathy / cardiomyopathy.
Recurrent emesis with coma and hepatic dysfunction.
Hypertonia / hypotonia.
Failure to thrive.
Ophthalmic – related problems : e.g. cataract, corneal cloudiness,
cherry red spot, optic atrophy.
Renal failure or renal tubular acidosis.
88
CARNITINE METABOLISM




An essential nutrient found in highest concentration in red
meat.
Primary function : Transport long-chain fatty acids into
mitochondria for oxidation.
Primary defects of carnitine transport manifest as Reye
syndrome , cardiomyopathy or skeletal myopathy with
hypotonia
Secondary carnitine deficiency is due to diet
( esp. I.V alimentation or ketogenic diet ) , renal losses ,
drug therapy ( esp. valproic acid) and other metabolic
disorders ( esp. disorders of fatty acid oxidation and
organic acidemias )
89
CARNITINE METABOLISM




Prognosis depends on the cause of the carnitine
abnormality.
Free and esterified carnitine can be measured in
blood.
Oral or I.V. L-carnitine is used in carnitine
deficiency or lnsufficiency in doses of 25100mg/kgm/day or higher.
Carnitine supplementation in fatty acid oxidation
disorders and organic acidosis may augment
excretion of accumulated metabolites , but may not
prevent metabolic crises in such patients .
90
Management of IEM - NICU
•
•
•
•
•
•
•
•
Stop nutrient triggering disorder e.g. protein, galactose
Give high-energy intake
NICU care to correct tissue perfusion, dehydration,
acidosis
Hyperammonemia Rx with Na benzoate, Na
phenylbutyrate, arginine
Dialysis
Insulin to control hyperglycemia and reduce catabolism
Vitamins e.g Biotin, B6, B12
Specific therapy e.g. carnitine, glycine
Pathophysiology

SINGLE GENE DEFECTS in synthesis or catabolism of proteins,
carbohydrates, or fats.

Defect in an ENZYME or TRANSPORT PROTEIN , which results in a
block in a metabolic pathway.

EFFECTS :
- toxic ACCUMULATION of substrates before the block,
- intermediates from ALTERNATIVE pathways
- defects in ENERGY production and utilization caused by a
deficiency of products beyond the BLOCK.

Every metabolic disease has several forms that vary in AGE OF ONSET ,
clinical severity and, often, MODE OF INHERITANCE.
MEDICAL
Dependent on diagnosis and severity:
Dietary or vitamin therapy
Drug therapy
BMT
Avoid known environmental triggers
Surgery
93
Transient Hyperammonemia of
Newborn:





Markedly high NH4 in an infant less than 24 HOL, or first 1-2 DOL
before protein intake occurs.
Often in context of large, premature infant with symptomatic
pulmonary disease.
Very sick infant.
Unknown precipitant, unknown etiology (possible slow delayed
urea cycle initiation), with potential for severe sequelae (20-30%
death, 30-40% abnl dev.) if not treated.
Does not recur after being treated.