metabolic diseases

1. 厚 德 博 爱 精 医 卓 越
INBORN ERRORS OF
METABOLISM
• Inborn errors of metabolism are conditions due to a
genetic defect related to synthesis, metabolism,
transport or storage of biochemical compounds.
• The metabolic error is due to deficiency of one or
more enzymes required for the formation or
transport of protein

2. 厚 德 博 爱 精 医 卓 越
CLASSIFICATION
• Disturbances in the synthesis or catabolism of
complex molecules
• Disorders of intermediary metabolism leading to
recurrent acute or chronic intoxication due to
accumulation of toxic compounds. Eg :
aminoacidopathies, urea cycle defects and sugar
intolerance. Clinical manifestations are metabolic
acidosis, vomiting and lethargy

3. 厚 德 博 爱 精 医 卓 越
• Energy deficiency disease. Includes glycogen storage
disease, mitochondrial disease and fatty acid
oxidation defects. Symptoms include hypoglycemia,
hypotonia, myopathy, cardiomyopathy, failure to
thrive etc.

4. 厚 德 博 爱 精 医 卓 越
WHEN TO SUSPECT??
• Great mimicker
• Physician has to pick up important clues in history ,
physical examination and routine laboratory
investigations to suspect IEM
• It should be suspected in a previously well newborn
presenting with lethargy, poor feeding, persistent
vomiting, intractable seizures, tachypnea, floppiness,
unusual body/urine odor, failure to thrive, etc where other
common problem like sepsis, HIE, hypoglycemia has
been ruled out.
• History of previous unexplained neonatal death and
consanguinity are important clues

5. 厚 德 博 爱 精 医 卓 越
Phenylketonuria
(PKU)

6. 厚 德 博 爱 精 医 卓 越
Purpose and requirement
• To master the definition of PKU
• To master the clinical manifestation of
Classic PKU

7. 厚 德 博 爱 精 医 卓 越
Metabolic Errors
• Amino acid metabolism
• Carbohydrate metabolism
• Lipid metabolism
• Mucopolysaccharidosis (粘多糖)
• Purine and pyrimidine metabolism（嘌呤
和嘧啶）
• ......

8. 厚 德 博 爱 精 医 卓 越
Phenylalanine
• An essential amino acid
• Must obtain through diet
• Exist in all proteins and some artifical
sweetners

9. 厚 德 博 爱 精 医 卓 越
PKU Definition
Phenylketonuria is a group of heritable
disorders of the phenylalanine hydroxylase
system, associated with elevation of the
blood phenylalanine level.

10. 厚 德 博 爱 精 医 卓 越
• Autosomal recessive genetic disorder
• Enzyme（PHA or its cofactor BH4）
deficiency
• Excess Phenylalanine and metabolites
accumulation in body
• Disrupt normal metabolism and cause brain
damage
• Increased urinary levels of metabolites of
phenylketone

11. 厚 德 博 爱 精 医 卓 越
Incidence and genetics
• About 1 in 15,000 births,
• Different countries, different incidence
• North Ireland 1/4,404，German 1/6,971，US
1/10,059，Japan 1/73,000
• China 1/11,000 .
• Genetics: inherited as autosomal recessives.

12. 厚 德 博 爱 精 医 卓 越
Pathogenesis
• What is the pathogenesis of PKU？

13. 厚 德 博 爱 精 医 卓 越
Phe metabolic pathway
Phe tyrosine DOPA
Phenylpyruvate
Phenylacetate
Phenylacetylglutamine
Phenyllactate
Thyroxine
eumelamin
Dopamine
Norepinephrine
Epinephrine
PHA
TYA
BH4
BH4
Protein synthesis

14. 厚 德 博 爱 精 医 卓 越
Classification of PKU
• Classic PKU ( 99%)
• BH4 deficient PKU(1%)

15. 厚 德 博 爱 精 医 卓 越
Classic PKU-
Deficiency of phenylalanine hydroxylase
phenylalanine tyrosine
phenylalanine
Phenylethylamine
Phenylpyruvate
Phenyllactate
Phenylacetate
4-OH-phenylacetate
urine
Thyroxine
Epinephrine
Eumelanin
Cerebral injury
PHA

16. 厚 德 博 爱 精 医 卓 越
BH4 deficiency PKU
phenylalanine tyrosine
Deficiency of
BH4
phenylalanine
Phenylethylamine
Phenylpyruvate
Pheyllactate
Phenylacetate
4-OH-phenylacetate
urine
Thyroxine
Epinephrine
eumelanin
Cerebral injury
dopamine
Deficiency
of BH4
Nerve system
functional
injury

17. 厚 德 博 爱 精 医 卓 越
Clinical manifestation-
Classic phenylketonuria
• The affected infant is normal at birth
• Mental retardation may develop gradually
and may not be evident for a few months
(age is less than 3months)
• Mental retadation: usually severe(60% IQ‹50)
• Hyperactive with purposeless movements,
rhythmic rocking, and athetosis
• Convulsion: seizure occur before 18months
of age

18. 厚 德 博 爱 精 医 卓 越

19. 厚 德 博 爱 精 医 卓 越

20. 厚 德 博 爱 精 医 卓 越
Clinical manifestation
• Vomiting : sometimes severe
(misdiagnosed to pyloric stenosis)

21. 厚 德 博 爱 精 医 卓 越
Clinical manifestation
Physical examination:
• Affected infants are blonder than unaffected
siblings.
• Have fair skin and blue eye
• Have seborrheic and eczematoid rash
• Unpleasant odor of phenylacetic acid,
described as musty or mousey

22. 厚 德 博 爱 精 医 卓 越

23. 厚 德 博 爱 精 医 卓 越
Clinical manifestation
• Hypertonic with hyperactive deep tendon
reflexes
• Seizure, abnormal EEG (50% )
• Microcephaly, prominent maxilla with
widely spaced teeth, enamel hypoplasia
and growth retadation

24. 厚 德 博 爱 精 医 卓 越
Clinical manifestation
CT and MRI scanning:
diffuse cerebral cortex atrophy

25. 厚 德 博 爱 精 医 卓 越

26. 厚 德 博 爱 精 医 卓 越

27. 厚 德 博 爱 精 医 卓 越
Diagnosis of Classic PKU
• Depends on measuring blood levels of
phenylalanine
• the bacterial inhibition assay method of
Guthrie: the blood for screening be
obtained after 48-72hr of life and
preferably after feeding proteins.
• PA is more than 4mg/dl(0.24mmol/L),
result is positive.

28. 厚 德 博 爱 精 医 卓 越
Diagnosis of Classic PKU
• screening test：the bacterial inhibition
assay method of Guthrie:

29. 厚 德 博 爱 精 医 卓 越

30. 厚 德 博 爱 精 医 卓 越
Diagnosis of Classic PKU
The laboratory criteria:
• a plasma phenylalanine level above
20mg/dl(normal range:1-3mg/dl)
• A normal plasma tyrosine level
• increased urinary levels of metabolites of
phenylalamine(phenylpyruvic and
hydroxyphenylacetic acids)
• A normal concentration of the cofactor
tetrahydrobiopterin（BH4)

31. 厚 德 博 爱 精 医 卓 越
Treatment of Classic PKU
• GOAL of therapy is to reduce phenylalanine
and its metabolites in body fluids in order to
prevent or minimize brain damage.
• A optimal serum level lies between 3mg/dl and
15mg/dl( 4mg/dl and 10mg/dl in china)
• A low Phe in dietary
• Dietary treatment should be started as soon
after birth as the diagnosis is established.
• Adequate calories, nutrients, and vitamins

32. 厚 德 博 爱 精 医 卓 越
Treatment of Classic PKU
• ammount of phenylalanine origined from
food:
• 50-70mg/kg/d age is less than 2 months
• 40mg/kg/d 3-6months
• 25-30mg/kg/d 2yrs
• 10-30mg/kg/d more than 4yrs

33. 厚 德 博 爱 精 医 卓 越
Treatment of Classic PKU
The duration of diet therapy:
Rigid diet control may be relaxed after 6 yr
of age.

34. 厚 德 博 爱 精 医 卓 越
Symptoms can be changed
After dietary treatment, most is reversible
For example：seizure can be controlled.
EEG can change into normal. Special
odor can disappear but mental retardation
can not improve

35. 厚 德 博 爱 精 医 卓 越
early

36. 厚 德 博 爱 精 医 卓 越
overtreatment
• particular notice:
In rapidly growing infants, may lead to
phenylalanine deficiency, manifested by
lethargy, anorexia, anemia, rashes,
diarrhea, and even death

37. 厚 德 博 爱 精 医 卓 越
Manifestation of BH4 deficiency
• Due to defficiency of cofactor
tetrahydrobiopterin(BH4), Malignant
hyperphenylalaninemia:
• The resulting signs and symptoms range from
mild to serve。
• The symptoms and signs are similar and
indistinguishable from those of classic PKU.
• neurologic errors is often obvious , such as
loss of head control, hypertonia, drooling,
swallowing difficulties, and myoclonic seizure,
develop after 3 mo of age despite adequate
dietary therapy.

38. 厚 德 博 爱 精 医 卓 越
Diagnosis of deficent-BH4 PKU
• Screening program is positive
• Evidence of hyperphenylalaninemia
• Obvious neurologic manifestation
• Some other tests

39. 厚 德 博 爱 精 医 卓 越
Diagnosis of BH4 deficiency
• Measurement of neopterin and biopterin in
body fluid, especially urine.
• BH4 loading test: an oral or intravenous dose of
BH4 normalizes plasma phenylalanine in
patients with BH4 deficiency within 4-6hours.
• Enzyme assay: the activity of dihydropteridine
reductase, 6-pyruvoyltetrahydropterin synthase,
and GTP cyclohydrolase can be measured.
• Gene study: gene for dihydropteridine reductuse
and carbinolamine dehydratase have been
identified.

40. 厚 德 博 爱 精 医 卓 越
Treatment of BH4 deficiency
• BH4 Supplementation
• Low phe diet
• Replacement therapy with
neurotransmitters precursors （L-dopa
and 5-HT）
• supplements of folinic acid in DHPR
deficiency

41. 厚 德 博 爱 精 医 卓 越
treatment
• L-dopa orally administered at a dose of
30-50mg/kg/d
• 5- hydroxytryptophan（5-HT) at a dose of
3-8mg/kg/d

42. 厚 德 博 爱 精 医 卓 越
Prevention of PKU
• Avoiding inbreeding
• Neonatal screening of PKU
• Prenatal diagnosis and carrier detection

43. 厚 德 博 爱 精 医 卓 越
summary
• Autosomal recessive inheritance.
• Deficiency of the enzyme phenylalanine
hydroxylase, or cofactor of this enzyme
（BH4).
• Excsess Phenylalanine and subsquent
metabolities acculation in body fluids，
disrupt normal metabolism and cause brain
damage
• fair skin, light hair、musty odour、
neurological manifestation、Growth
retardation 、Newborn screening ：
• Dietary restriction and some therapy

44. 厚 德 博 爱 精 医 卓 越
E N D

45. 厚 德 博 爱 精 医 卓 越
Thank you
!