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.
-In autosomal dominant disorders, the structural abnormality
dominates over the chemical abnormality.
-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.

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.
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
Metabolic Disorders
• 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.
7
Metabolic Disorders
Features suggestive of metabolic disorder :
From history:
Parental history :
Consanguineous parents
Previous unexplained neonatal deaths
Particular ethnic group (in certain diseases)
8
Metabolic Disorders
Features suggestive of metabolic disorder :
Examination findings:
Organomegaly (e.g. hepatomegaly) in the absence of viral
infection.
Cardiac disease
Ocular involvement (e.g. cherry red spot)
Skin manifestations e.g. pigmentations.
Unusual odour. Due to change in the chemicals of the urine.
Non-specific neurological findings. In a non-meningitis child you
have to think of metabolic disorders.
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 is very dangerous, acidosis (in some
defects)
10
Neonatal and Post Neonatal Presentation
Post neonatal presentation
•
•
•
•
•
•
Encephalopathy without the presence of
infection.
Developmental regression
Reye syndrome ( damage of the brain and
liver eventually leading to
encephalopathy).
Motor deficits
Seizures
Intermittent episodes of vomiting, acidosis,
hypoglycaemia and/or coma triggered by
stress e.g. infections, surgery.
Newborn Screening
the earlier its detected the fewer the complications






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: it’s a cheap test that requires
only one drop of blood to check for multiple
metabolic disorders.
PROCEDURES FOR DIAGNOSIC CONFIRMATION
Non – Specific Tests:
Specific Tests:
•
•
Direct biochemical assays of
metabolites or their metabolic byproducts, or of an enzyme’s function.
•
DNA studies
•
Neuro-radiology
•
•
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. Amino acids shouldn’t
be present in the CSF if its there it
indicates a metabolic disorder.
Bone marrow transplantation is a treatment of both inborn errors of
metabolism
13
INBORN ERRORS OF AMINO ACID METABOLISM
ASSOSIATED WITH ABNORMAL ODOR
Inborn Error of Metabolism
Gultaric Acidemia
Sweaty feet
Maple Syrup urine disease
Maple syrup
Hypermethioninemia
Boiled cabbage
Phenylketonuria
Mousy or musty
Trimethylaminuria
Rotten fish
Urine Odor
14
They may come with flattened mid-face, indistinct philtrum, low
nasal bridge and single palmar crease.
Small chin is
called
micrognathia
Low-set ears: >1/3rd of the ears lower than the line connecting
the 2 pupils.
Low nasal bridge: common sign, which is also seen in Down.
MANAGEMENT OF IEM
Genetic:
Establish diagnosis.
Carrier testing.
Pedigree analysis, risk counseling.
Consideration of Prenatal diagnosis for pregnancies at
risk.
19
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.
20
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
22
:
Carbohydrates
Galactosemia
Enzyme deficiency:
Galactose-1-phosphate uridyl transferase deficiency.
It is a rare autosomal recessive.
● Follows feeding with lactose containing (breast milk / formula)
● Patient feeds poorly , have vomiting, jaundice, hepatomegaly and
hepatic failure
● Chronic liver disease
● Cataracts
● Developmental delay develop if condition is untreated., if they
were given galactose free diet you will avoid the social and mental
damage but they might complain of dyslexia.
23
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. It is diagnosed by sweat test: measuring the chloride
concentration in the sweat
AMINO ACID DISORDERS
Phenyl Ketonuria (PKU)
Phenylalanine
Phenylalanine
Hydroxylase
Phenyl ethylamine
Tyrosine
Phenyl pyruvic acid
Phenyl pyruvic acid is what gives the urine its smell because its
ketonic and acidic.
25
Phenylketonuria PKU
26
PKU
DIAGNOSIS
CLINICAL FEATURES
•
Screening : Guthrie
Test.
•
High Phenylalanine >
20 mg/dl.
•
High Phenyl pyruvic
acid.
1. Hyperactivity, athetosis, vomiting.
2. Blond.
3. Seborric dermatitis or eczema skin.
4. Hypertonia.
5. Seizures.
6. Severe mental retardation.
7. Unpleasant odor of phenyl acetic acid.
TREATMENT
•
DIET.
•
BH4 (Tetrahydrobiopterin).
•
L – dopa and 5hydroxytryptophan.
27
PKU
28
Albinism
29
Iris had fibrous tissue, and it’s colourless and is
red due to vessels.
Homocystinuria
31
Elevated homocystine levels affect collagen , result in a Marfanoid habitus,
ectopia lentis but lens dislocation in homocystinemia is downward unlike in
marfan its upward, mental retardation and strokes, its harmful to the bones
and body. Araachnodyctly.
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)
32
Homocystinuria
33
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)
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 pyruvate
dehydrogenase deficiency)
• 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
Important IEM Treatment supplements:
• Carnitine for elimination of Organic Acid through
creation of carnitine esters.
• Sodium Benzoate, phenylacetate and
phenylbutyrate for Hyperammonemia
elimination.
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 .
• Carnitine is an endogenous metabolite but can be
given as supplementations.
CARNITINE METABOLISM
• 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 )
• 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 25-100mg/kgm/day or higher.
39
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.
40
ORGANIC ACIDEMIA
Clinical Features
Treatment
 Vomiting, ketosis.
 Hydration / alkali.
 Thrombocytopenia ,
neutropenia.
 Calories to  catabolic
state.
 Osteoporosis.
 Mental retardation.
 Exchange transfusion.
 Low protein diet.
41
ORGANIC ACIDEMIA
42
LYSOSOMAL STORAGE
DISORDERS
•
Glycogen Storage Diseases
•
Sphingolipidoses common in
eastern jews
(Lipidoses And Mucolipidoses)
•
Mucopolysaccharidoses
43
Lysosomal Storage Disease
Disease
Enzyme Defiency
Major Accumulating
Metabolite
Glucosidase
Glycogen
β-galactosidase
GM1 gangliosides,
galactose-containing
oligosaccharides
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
GM1 gangliosidoses
GM2 gangliosidoses
Tay-Sachs disease
Gaucher disease
Niemann-Pick disease
Mucopolysaccharidoses
44
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
47
Von Gierke Disease
48
LYSOSOMAL STORAGE
DISORDERS
Lipidoses And Mucolipidoses
49
In gaucher liver is enlarged but
the rest of the body is very thin
Gauch. cell
50
In gaucher you see the
cherry red spot appearance
in the macula
Sandhoff - Dense thalam
52
Cerebral palsy -- scissoring of
the legs
Lipid accumalation
around the retinal
arteries and veins
Lipid-retina
53
LYSOSOMAL STORAGE DISORDERS
Mucopolysaccharidoses
54
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 present in hurler but
absent in hunter
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
Hurler
hepatosplenomegaly
cardiac involvement
55
minimal corneal clouding
Hurler’s
56
In hurler :
Nasal bridge is depressed , increase distance of
philthrum , epicanthal folds, bossing of the head ,
thick eyebrows , upturn nostrils
Hurler’s
57
58
Mcopolysacch. Morquio
59
PEROXISOMAL DISORDERS


Peroxisomes = Subcellular organelles involved
in various essential anabolic or catabolic
processes, biosynthesis of Plasmalogens and bile
acids.
Due to dysfunction of a single or multiple
peroxisomal enzymes, or to failure to form or
maintain a normal number of functional
peroxisomes.
60
PEROXISOMAL DISORDERS
Clinical Manifestations:

Hypotonia.

Dysmorphia.

Psychomotor delay and seizures.

Hepatomegaly.

Abnormal eye findings such as retinitis pigmentosa
or cataract.

Hearing impairment.
61
Peroxisomal Disorders
•
Zellweger Syndrome is
autosomal recessive
disorder.
(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 AcidsVLCFAs
Zellweger
63
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.
64
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.
65
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
66
Mitochondrial Syndromes Presenting
in Childhood to Adult
67
Syndrome
Most Common
Clinical
Presentation
Other Clinical
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
68
Transient Hyperammonemia of Newborn:
 Markedly high NH4 in an infant less than 24 HOL (hours of life),
or first 1-2 DOL (day of life) 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.
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
Acute neonatal
presentation with
hyperammonemia
Arginine, Citrulline
Marfanoid, strokes,
ectopia lentis,
mental retardation
Homocystine &
methionine
Ornithine transcarbamylase deficiency
Argininosuccinate synthase deficiency
Argininosuccinate lyase deficiency
Severe
Phenylalanine
developmental delay
70
Urea cycle disorders
Homocystinuria
Phenylketonuria
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
71
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.
72
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 r ecurrent 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 simila r 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
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 adrenoleuko
dystrophy, infantile refsum disease)
-
Jaundice Prominent
Galactosemia
Hereditary fructose intolerance
Menkes kinky hair syndrome
a1-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
Fatty acid oxidation def ects (LCAD)
Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD)
Skeletal Muscle Weakness : Fatty acid oxidation defects (LCAD, SCAD,
multiple acyl -CoA dehydrogenase
18
)
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
MEDICAL
Dependent on diagnosis and severity:
Dietary or vitamin therapy
Drug therapy
BMT
Avoid known environmental triggers
Surgery
77