1. 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

2. Inborn Errors Of Metabolism
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.

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.
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.

6. 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

7. 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.

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

9. 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.

10. Neonatal and Post 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)

11. Neonatal and 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.

12. 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.

13. 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. Amino acids shouldn’t be present in the CSF if its there it indicates a metabolic disorder.
Specific Tests:
Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function.
DNA studies
Neuro-radiology
Bone marrow transplantation is a treatment of both inborn errors of metabolism

14. Urine Odor Inborn Error of Metabolism
INBORN ERRORS OF AMINO ACID METABOLISM
ASSOSIATED WITH ABNORMAL ODOR
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

16. They may come with flattened mid-face, indistinct philtrum, low nasal bridge and single palmar crease.
Small chin is called micrognathia

18. 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.

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

20. PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL
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.

21. 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

22. Galactosemia

23. : 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.

24. 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

25. Phenyl Ketonuria (PKU)
AMINO ACID DISORDERS
Phenyl Ketonuria (PKU)
Phenylalanine
Phenylalanine
Tyrosine
Hydroxylase
Phenyl ethylamine Phenyl pyruvic acid
Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.

26. Phenylketonuria PKU

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

28. PKU

29. Albinism

30. Iris had fibrous tissue, and it’s colourless and is red due to vessels.

31. Homocystinuria
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.

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

33. Homocystinuria

34. 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

35. 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)

36. Therapeutic Measures for IEM
D/C oral intake temporarily
Usually IVF’s with glucose to give 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

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

38. 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.

39. 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 mg/kgm/day or higher.

40. ORGANIC ACIDEMIA Disorder Enzyme 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.

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

42. ORGANIC ACIDEMIA

43. LYSOSOMAL STORAGE DISORDERS
Glycogen Storage Diseases
Sphingolipidoses common in eastern jews
(Lipidoses And Mucolipidoses)
Mucopolysaccharidoses

44. Lysosomal Storage 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

45. Glycogen Storage Diseases

47. Principle Groups of Glycogen Storage Diseases

48. Von Gierke Disease

49. LYSOSOMAL STORAGE DISORDERS
Lipidoses And Mucolipidoses

50. In gaucher liver is enlarged but the rest of the body is very thin
Gauch. cell

51. In gaucher you see the cherry red spot appearance in the macula

52. Sandhoff - Dense thalam

53. Cerebral palsy --- scissoring of the legs
Lipid accumalation around the retinal arteries and veins
Lipid-retina

54. LYSOSOMAL STORAGE DISORDERS
Mucopolysaccharidoses

55. 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 present in hurler but absent in hunter
Fibrillogranular mucopolysaccharides in cells of viscera and brain
MPS type II
Hunter
X-linked
Later developmental regression
hepatosplenomegaly
minimal corneal clouding

56. Hurler’s

57. In hurler :
Nasal bridge is depressed , increase distance of philthrum , epicanthal folds, bossing of the head , thick eyebrows , upturn nostrils
Hurler’s

59. Mcopolysacch. Morquio

60. 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.

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

62. 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 Acids- VLCFAs

63. Zellweger

64. 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.

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

66. 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

67. Mitochondrial Syndromes Presenting in Childhood to Adult
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, 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 Complex V deficiency

69. 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.

70. 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
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

71. Organic and Amino Acid Disorders
Metabolic Profiles
Organic and Amino Acid Disorders
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
Ammonia: Elevated Glucose: Normal or decreased Ketones: May be elevated Lactate: Slightly elevated
Methylmalonic acidemia Propionic acidemia Isolvaleric acidemia
Lactic Acidosis
Acidosis: Usually present Ammonia: Normal or slightly elevated Ketones: May be elevated
Pyruvate dehydrogenase Pyruvate carboxylase deficiency Respiratory chain disorder
Hypoglycemia
Ammonia: Lactate Acidosis Ketones: Absent or inappropriately low
Fatty acid oxidation defects
Hyperammonemia
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

72. 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.

76. 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

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