1. به نام خدا

2. Metabolic Disorders Noushin Rostampour
Assistant professor of pediatric endocrinology and metabolism

3. Metabolic Disease
Many childhood conditions are caused by single gene mutations
These mutations can result in the alteration of primary protein structure or the amount of protein synthesized.
These hereditary biochemical disorders are also termed inborn errors of metabolism or inherited metabolic disorders

4. Metabolic disorder
Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite

5. COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM
The affected infant is normal at birth and becomes symptomatic later on in life.

6. COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM
In general, the earlier the appearance of clinical symptoms the more severe is the disease.
The majority of conditions are inherited as autosomal recessive

7. COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM
A history of consanguinity in the parents
Unexplained death in the neonatal period
Question of an inherited metabolic disease in the sick infant?

8. COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM
Most of the genetic metabolic conditions can be controlled successfully by some form of therapy
These patients can have a normal life if diagnosed and treated early, before irreversible damage to organs

9. COMMON CHARACTERISTICS OF GENETIC DISORDERS OF METABOLISM
This underlines the importance of early diagnosis, which can be achieved through screening of all newborn infants

11. CLINICAL MANIFESTATIONS
In the newborn period, the clinical findings are usually nonspecific and similar to those seen in infants with sepsis.

12. CLINICAL MANIFESTATIONS
Lethargy
Poor feeding
Convulsions
Vomiting

13. CLINICAL MANIFESTATIONS
Children :
Mental retardation
Motor deficits
Developmental regression
Convulsions
Myopathy
Recurrent emesis
Cardiomyopathy

14. CLINICAL MANIFESTATIONS
Developmental delay
Unusual odor
Acidosis
Coma
Hepatomegaly
Renal stones

16. Laboratory studies
Measurements of ammonia, bicarbonate, and pH are often very helpful initially

18. INITIAL EVALUATION Testing should be performed:
At the time of presentation
When symptoms are most pronounced
Laboratory values may be normal when the patient is well.

19. INITIAL EVALUATION CBC diff Arterial blood gas Blood glucose
Serum ammonia
Electrolytes
BUN/ Cr

20. INITIAL EVALUATION
Urine (color, odor, dipstick, ketones)

21. Treatment Special diets Peritoneal dialysis or hemodialysis
Administration of the deficient metabolite
Administration of the deficient enzyme
Administration of the cofactor
Bone marrow transplantation
Liver transplantation

22. CLASSIFICATION Amino acid disorders Organic acidemias
Urea cycle defects
Disorders of carbohydrate metabolism
Fatty acid oxidation defects
Mitochondrial disorders
Peroxisomal disorders
Lysosomal storage diseases

23. Organic acidemia

24. Organic acidemia
Organic acidemias are a group of disorders characterized by increased excretion of organic acids in urine.
They result from deficiencies of specific enzymes in the breakdown pathways of amino acids.

25. Classification Branched-chain organic acidemias MMA PA IVA
Multiple carboxylase deficiency
Glutaric acidemia type 1

26. Clinical presentation
Newborns typically present during the first one to two weeks after birth
Poor feeding
Vomiting
Floppiness
Muscular hypotonia
Lethargy
Coma

27. Clinical presentation
Pregnancy and perinatal history frequently are uncomplicated.
Family history may reveal consanguinity and/or siblings who died during the neonatal period

28. Clinical presentation
The initial presentation in older infants, children:
Lethargy
Vomiting
FTT
Seizures
Acute decompensation
Pancytopenia

29. Management Intravenous hydration Correction of metabolic acidosis
Hyperammonemia TX
Hypoglycemia TX
Correction of electrolyte abnormalities
Treatment of infections

30. Urea cycle disorders

31. Urea cycle disorders
The urea cycle is the metabolic pathway that transforms nitrogen to urea
Deficiency of any of the enzymes in the pathway causes a UCD.
Examples of UCDs include ornithine transcarbamylase deficiency and citrullinemia.

33. Urea cycle disorders
UCDs often present in newborns who are initially well and become hyperammonemic after a period of protein feeding
However, patients with partial enzyme activity may present later

34. CLINICAL FEATURES Initial signs: Somnolence Poor feeding Vomiting
Lethargy
Coma

35. Lab Data
Hyperammonemia
Respiratory alkalosis

36. Ammonia Newborn: mean plasma ammonia :45 ± 9 micromol/L
Upper limit of normal : 80 to 90 micromol/L

37. Ammonia Children older than one month : 50 micromol/L
Plasma ammonia greater than 100 to 150 micromol/L: further testing

38. Treatment
Treatment should be initiated as soon as UCD is suspected

39. Phenylketonuria

40. PKU
Deficiency of phenylalanine hydroxylase or its cofactor tetrahydrobiopterin : accumulation of phenylalanine in body fluids and the CNS

41. PHENYLALANINE HYDROXYLASE
The normal metabolism of phenylalanine
(pathways a and b)
BREAKDOWN
Dietry sources, particularly plant proteins
PHENYLALANINE HYDROXYLASE
PHENYLALANINE
TYROSINE
(b)
(a)
BODY PROTEINS
© 2008 Paul Billiet ODWS

42. Genetic
PKU is inherited as an autosomal recessive trait

43. PKU
The prevalence of PKU in the United States :1/14,000 to 1/20,000

44. Clinical presentation
Newborn infants are asymptomatic prior to the initiation of feeds
In untreated patients, the hallmark of the disease is intellectual disability

45. Clinical presentation
MR may develop gradually and may not be evident for the 1st few months
Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom

46. Clinical presentation
Older untreated children become hyperactive, with purposeless movements, rhythmic rocking, and athetosis
These infants are lighter
Some may have a seborrheic or eczematoid rash

47. Clinical presentation
These children have an unpleasant odor of phenylacetic acid(musty or mousey)

48. Clinical presentation
Most infants are hypertonic with hyperactive DTR.
About 25% of children have seizures
More than 50% have EEG abnormalities

49. Clinical presentation
Microcephaly
Prominent maxilla
Enamel hypoplasia
Growth retardation

51. Diagnosis
Early diagnosis can only be achieved by mass screening of all newborn infants
Elevated serum phenylalanine
Classic PKU: >20 mg/dL(1200 micromol/L)

52. Treatment The goal of therapy is to reduce phenylalanine in the body
The diet should be started as soon as diagnosis is established.

53. Treatment Overtreatment may lead to phenylalanine deficiency Lethargy
Failure to thrive
Anorexia
Anemia
Rash
Diarrhea
Death

54. Treatment
Treatment is designed to maintain plasma phenylalanine:2-6 mg/dl using a diet
Treatment is lifelong

55. Galactosemia

56. Galactose
Milk and dairy products contain lactose, the major dietary source of galactose.
Lactose  Glucose + Galactose
The metabolism of galactose produces fuel for cellular metabolism through its conversion to glucose-1-phosphate.

57. Galactose
Galactose also plays an important role in the formation of galactosides, which include glycoproteins, glycolipids, and glycosaminoglycans.

58. Galactosemia
Denotes the elevated level of galactose in the blood and is found in three distinct disorders of galactose metabolism defective in one of the following enzymes
Galactose-1-phosphate uridyl transferase
Galactokinase
Uridine diphosphate galactose-4-epimerase.

59. Galactosemia Autosomal recessive disease.
It affects the body’s ability to use or metabolize galactose resulting in the accumulation of galactose 1-phosphate in the body.

60. Galactosemia
Galactosemia is a serious disease with early onset of symptoms; the incidence is 1/60,000.
The infants is unable to metabolize galactose-1-phosphate: the accumulation of which results in injury to kidney, liver, eyes and brain.

61. Clinical features Jaundice Hepatomegaly Vomiting Hypoglycemia
Convulsions
Lethargy
Irritability
Feeding difficulties

62. Clinical features Poor weight gain Aminoaciduria Cataracts
Vitreous hemorrhage
Hepatic cirrhosis
Ascites
Splenomegaly
Mental retardation.

63. Clinical features
Patients with galactosemia are at increased risk for E.coli neonatal sepsis
The onset of sepsis often precedes the diagnosis of galactosemia.
When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (mental retardation) becomes increasingly severe and irreversible.

64. Clinical features
Galactosemia should be considered for the newborn or young infant who is not thriving or who has any of the preceding findings.

65. Diagnosis
Reducing substance in several urine specimens collected while the patient is receiving human milk, cow's milk, or another formula containing lactose.
Deficient activity of GALT is demonstrable in hemolysates of erythrocytes, which also exhibit increased concentrations of galactose-1-phosphate.

66. Treatment
The only treatment for galactosemia is eliminating lactose and galactose from the diet
There is no definite cure for Galactosemia, the condition is life long and it can only be controlled
Calcium supplement

67. Prognosis
Elimination of galactose from diet reverses growth failure and renal and hepatic dysfunction.
Cataracts regress, and most patients have no impairment of eyesight
Early diagnosis and treatment have improved the prognosis of galactosemia

68. Prognosis
On long-term follow-up, patients still manifest ovarian failure , developmental delay, and learning disabilities that increase in severity with age
Most manifest speech disorders, whereas a smaller number demonstrate poor growth and impaired motor function and balance

69. Tyrosinemia

70. Tyrosinemia Inborn error in the degradation of the amino acid tyrosine
Genetic: Autosomal recessive
Three types (type I, type II, type III).

71. Type I Tyrosinemia Most common type of tyrosinemia
Caused by a mutation in the FAH gene that encodes for the FAH enzyme.

72. Symptoms of Type I Tyrosinemia
Failture to gain weight
Diarrhea and vomiting
Jaundice
Cabbage-like odor
Increased tendency to bleed
PNS involvement
kidney and liver failure
Liver cirrhosis
Hepatocellular carcinoma

73. http://www. childrenshospital

74. Type II Tyrosinemia
Mutation in the TAT gene that encodes for the hepatic TAT enzyme.
Autosomally recessive
Also known as “Richner-Hanhard syndrome”

75. Symptoms of Type II Tyrosinemia
Elevated plasma tyrosine
Lesions of skin and eyes
Due to clumping of cellular tyrosine crystals
Excessive tearing and photophobia
Mental retardation (elevated blood tyrosine levels)
Symptoms often begin in early childhood.

76. Treatments
Dietary restriction of tyrosine and phenylalanine. (aim Tyrosine below 500 μmol/L)
NTBC (2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione) to block metabolism.
Protects patients from fatal, end stages of disease
However, increases plasma tyrosine and requires several follow-ups.
Liver transplant

77. Thanks for your attention