Awesome

1. Metabolic Disorders
Inborn Errors Of Metabolism
1
DR. ABDULLAH ALOMAIR
MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)
Associate Professor of Pediatrics
Consultant Pediatrician
Department of Pediatrics
PRESIDENT
SAUDI PEDIATRIC ASSOCIATION

2. 2
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.
Metabolic Disorders
Inborn Errors Of Metabolism

3. 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.

4. 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.

7. Metabolic Disorders
From history:
Parental history :
Consanguineous parents
Previous unexplained neonatal deaths
Particular ethnic group (in certain diseases)
7
Features suggestive of metabolic disorder :

8. Features suggestive of metabolic disorder :
Metabolic Disorders
Examination findings:
Organomegaly (e.g. hepatomegaly)
Cardiac disease
Ocular involvement (e.g. cherry red spot)
Skin manifestations
Unusual odour
Non-specific neurological findings

9. 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

10. 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.

11. 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

12. Specific Tests:
• Direct biochemical
assays of metabolites
or their metabolic
by-products, or of an
enzyme’s function.
• DNA studies
• Neuro-radiology
12
PROCEDURES FOR DIAGNOSIC CONFIRMATION
Non – 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.

13. Urine Odor
Inborn Error of
Metabolism
Sweaty feet
Gultaric Acidemia
Maple syrup
Maple Syrup urine disease
Boiled cabbage
Hypermethioninemia
Mousy or musty
Phenylketonuria
Rotten fish
Trimethylaminuria
13
INBORN ERRORS OF AMINO ACID METABOLISM
ASSOSIATED WITH ABNORMAL ODOR

25. Genetic:
Establish diagnosis.
Carrier testing.
Pedigree analysis, risk counseling.
Consideration of Prenatal diagnosis for
pregnancies at risk.
25
MANAGEMENT OF IEM

26.  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
PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL
MANAGEMENT OF IEM

27. 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

28. Galactosemia
28

29. :
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

30. 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.

31. AMINO ACID DISORDERS
Phenyl Ketonuria (PKU)
31
Phenylalanine Tyrosine
Hydroxylase
Phenylalanine
Phenyl ethylamine Phenyl pyruvic acid

32. Phenylketonuria PKU
32

33.  Hyperactivity, athetosis, vomiting.
 Blond.
 Seborric dermatitis or eczema skin.
 Hypertonia.
 Seizures.
 Severe mental retardation.
 Unpleasant odor of phenyl acetic acid.
33
PKU
DIAGNOSIS
• Screening : Guthrie Test.
• High Phenylalanine > 20
mg/dl.
• High Phenyl pyruvic acid.
TREATMENT
• DIET.
• BH4 (Tetrahydrobiopterin).
• L – dopa and 5-
hydroxytryptophan.
CLINICAL FEATURES

34. 34
PKU

35. Albinism
35

38. Homocystinuria
Elevated homocystine levels affect collagen , result in a Marfanoid
habitus, ectopia lentis, mental retardation and strokes
38

39. METHIONINE CYSTATHIONINE
39
Homocystinuria
Cysathionine
Synthatase
DIAGNOSIS:
High methionine and homocystine.
TREATMENT:
•High dose of B6 and Folic Acid.
•Low methionine and high cystine diet,
•Betain (trimethylglycine)

40. Homocystinuria
40

41. 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

42. 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)

43.  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 METABOLISM

44. Important IEM Treatment supplements:
 Carnitine for elimination of Organic Acid through
creation of carnitine esters.
 Sodium Benzoate, phenylacetate and
phenylbutyrate for Hyperammonemia
elimination.

45. 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

46. ORGANIC ACIDEMIA
Disorder
• Methyl malonic
Acidemia.
• Propionic Acidemia.
• Multiple carboxylase
deficiency.
• Ketothiolase deficiency .
Enzyme
• Methyl malonyl COA
mutase.
• Propionyl COA
Carboxylase.
• Malfunction of all
carboxylase.
• 2 methylacetyl COA thiolase
def.
46

47. ORGANIC ACIDEMIA
Clinical Features
 Vomiting, ketosis.
 Thrombocytopenia ,
neutropenia.
 Osteoporosis.
 Mental retardation.
Treatment
 Hydration / alkali.
 Calories to 
catabolic state.
 Exchange
transfusion.
 Low protein diet.
47

48. ORGANIC ACIDEMIA
48

49. LYSOSOMAL STORAGE
DISORDERS
 Glycogen Storage Diseases
 Sphingolipidoses
(Lipidoses And Mucolipidoses)
 Mucopolysaccharidoses
49

50. 50
Lysosomal Storage Disease
Disease Enzyme Defiency Major Accumulating
Metabolite
Glycogenosis
Type II (Pompe disease) Glucosidase Glycogen
Sphingolipidoses
GM1 gangliosidoses
GM2 gangliosidoses
Tay-Sachs disease
Gaucher disease
Niemann-Pick disease
β-galactosidase
Hexosaminidase A
Glucocerebrosidase
Sphingomyelinase
GM1 gangliosides,
galactose-containing
oligosaccharides
GM2 ganglioside
Glucocerebroside
Sphingomyelin
Mucopolysaccharidoses
MPS I H (Hurler)
MPS II (Hunter)
(X-linked recessive)
α-L-Iduronidase
L-Iduronosulfate
sulfatase
Heparan sulfate
Dermatan sulfate
Heparan sulfate
Dermatan sulfate

51. Glycogen Storage Diseases

52. Name Enzyme Symptoms
Type O Glycogen synthetase Enlarged, fatty liver; hypoglycemia when fasting
von Gierke
(Type IA)
Glucose-6-phosphatase Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia
Type IB G-6-P translocase Same as in von Gierke's disease but may be less severe; neutropenia
Pompe
(Type II)
Acid maltase Enlarged liver and heart, muscle weakness
Forbe (Cori)
(Type III)
Glycogen debrancher Enlarged liver or cirrhosis; low blood sugar levels; muscle damage
and heart damage in some people
Andersen
(Type IV)
Glycogen branching enzyme Cirrhosis in juvenile type; muscle damage and CHF
McArdle's
(Type V)
Muscle glycogen
phosphorylase
Muscle cramps or weakness during physical activity
Her
(Type VI)
Liver glycogen phosphorlyase Enlarged liver; often no symptoms
Tarui
(Type VII)
Muscle phosphofructokinase Muscle cramps during physical activity; hemolysis
Type VIII Unknown Hepatomegaly; ataxia, nystagmus
Type IX Liver phosphorylase kinase Hepatomegaly; Often no symptoms
Type X Cyclic 3-5 dependent kinase Hepatomegaly, muscle pain (1 patient)
Type XI Unknown Hepatomegaly. Stunted growth, acidosis, Rickets

53. Principle Groups of
Glycogen Storage Diseases
53

54. 54
Von Gierke Disease

55. LYSOSOMAL STORAGE
DISORDERS
Lipidoses And Mucolipidoses
55

56. 56
Gauch. cell

58. 58
Sandhoff - Dense thalam

59. 59
Leucodys..

60. 60
Lipid-retina

61. LYSOSOMAL STORAGE
DISORDERS
Mucopolysaccharidoses
61

62. Clinical And Pathological Ultra
structure Of
Mucopolysaccharidoses
Disease Clinical Manifestation Ultrastructure of Stored
Material
MPS type I
Hurler
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
Hunter
X-linked
Later developmental regression
coarse facial features
hepatosplenomegaly
dystosis of bone cardiac involvement
minimal corneal clouding
Fibrillogranular mucopolysaccharides
in cells of viscera and brain
62

63. 63
Hurler’s

64. 64
Hurler’s

65. 65

66. 66
Mcopolysacch. Morquio

67.  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

68.  Hypotonia.
 Dysmorphia.
 Psychomotor delay and seizures.
 Hepatomegaly.
 Abnormal eye findings such as retinitis pigmentosa
or cataract.
 Hearing impairment.
68
PEROXISOMAL DISORDERS
Clinical Manifestations:

69. 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

70. 70
Zellweger

71. 71
Chond punct

72. 72

73. 73
THANK YOU

74. 74

75. 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.
75

77. 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
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 deficiency18
)
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

78. 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)

79. Laboratory Assessment of Neonates
Suspected of Having an
Inborn Error of Metabolism
Routine Studies Special Studies
Blood lactate and
pyruvate
Complete blood count
and differential Plasma amino acids
Plasma ammonia Plasma carnitine
Plasma glucose Urine amino acids
Plasma electrolytes and
blood pH Urine organic acids
Urine ketones
Urine-reducing
substances

80. Classification
 Transient Hyperammonemia
of Newborn
 Inborn Errors of Metab:
• Organic Acidemias
• Fatty Acid Oxidation def
• Urea Cycle Defects
• Amino Acidurias
• Non-ketotic Hyperglycinemia
 Molybdenum Cofactor
Deficiency
• Sulfite Oxidase Deficiency
 Metal Storage Disorders:
 Cholesterol Disorders:
 Leukodystrophies, other…
• Krabbe disease
 Mitochondrial Disorders
 Glycogen Storage Disorders
 Hyperinsulinism
 Carbohydrate Disorders
 Lysosomal Disorders
• Mucopolysaccharidoses (X-
linked Hunter’s, Hurler’s)
• Gaucher disease
• Tay-Sachs Disease
 Peroxisomal Disorders
• Zellwegger’s (Cerebro-
Hepato-renal)
• X-linked
Adrenoleukodystrophy

81. Diagnosis:
 Immunochemical studies for Peroxisomes.
  V. Long Chain FA ( VLCFA ) level.
 Chor. Vill. Samp. or/ amniocytes culture   Plasmalogens
synthesis.
81
PEROXISOMAL DISORDERS
Treatment:
 Supportive, multidisciplinary interventions.
 Diet:  VLCFA,  phytanic acid.
 Organ transplantation.

82. Peroxisomal Disorders
GROUP II : PERSOXISOMAL
ENZYME DEFECTS
82
GROUP I : BIOGENSIS OF PEROXISOME
GROUP III : POSITIVE PEROXISOMES BUT
MULTIPLE DEFECTIVE ENZYME
Zellweger syndrome
(cerebrohepatorenal syndrome).
Neonatal adrenoleukodystrophy.
Infantile Refsum disease.
Hyperpipecolic acidemia.
Refsum disease.
X - linked Adreno-Leuko-Dystrophy.
Pseudo – Zellweger syndrome.
Hyperoxaluria….etc.
Zellweger – Like.
Pseudo – infantile Refsum disease.
Rhizomelic chondro-dysplasia
punctata

83. Mitochondrial Syndromes
Presenting in Childhood to Adult
Syndrome 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
83

84. 84

85. 85
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 Urea cycle disorders
Ornithine transcarbamylase deficiency
Argininosuccinate synthase deficiency
Argininosuccinate lyase deficiency
Marfanoid, strokes,
ectopia lentis,
mental retardation
Homocystine &
methionine
Homocystinuria
Severe
developmental delay
Phenylalanine Phenylketonuria
Clinical Presentation of Amino Acid Disorders

86. 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

87. 87
Predominanat
Biochemical
Clinical Findings
Other Most Common Diagnosis
KetoAcidosis
Lethargy
Odor
Ammonia: Normal or slightly
elevated Ketones: Elevated
Glucose: Normal
Maple syrup urine disease
Acidosis
Lethargy
Odor
Ammonia: Elevated
Glucose: Normal or decreased
Ketones: May be elevated
Lactate: Slightly elevated
Methylmalonic acidemia
Propionic acidemia
Isolvaleric acidemia
Lactic Acidosis
Lethargy
Acidosis: Usually present
Ammonia: Normal or slightly
elevated
Ketones: May be elevated
Pyruvate dehydrogenase
Pyruvate carboxylase deficiency
Respiratory chain disorder
Hypoglycemia
Lethargy
Ammonia: Lactate Acidosis
Ketones: Absent or inappropriately
low
Fatty acid oxidation defects
Hyperammonemia
Lethargy
Acidosis: Absent
Respiratory Alkalosis
Urea cycle disorders
Metabolic Profiles
Organic and Amino Acid Disorders
Newborn screening is available dependent on population frequency for some
Expanded newborn screening for fatty acid defects recently offered

88. CHILDREN AFTER THE NEONATAL
PERIOD
88
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.

89. 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

90. 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 25-
100mg/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

91. 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

92.  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.
Pathophysiology

93. Dependent on diagnosis and severity:
Dietary or vitamin therapy
Drug therapy
BMT
Avoid known environmental triggers
Surgery
93
MEDICAL

94. 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.