INBORN ERRORS OF METABOLISM

February 26, 2014

Dr. Jessica Joy Ramolete

eramae.sibayan

1
INBORN ERRORS OF METABOLISM

Inherited defect in the structure or function of key
proteins in the metabolic pathway
Inheritance
o Rare
o 1:2500 births or a few or single case report
o Autosomal recessive disease due to a single
gene defect
o Some X-linked
o Alterations in mitochondrial DNA inherited
from the maternal lineage

Newborn Screening
PKU
Hypothyroidism
Homocystinuria
Maple Syrup Urine Disease
Galactosemia
Biotinidase Deficiency
Congenital Adrenal Hyperplasia
Middle Chain Acyl CoA Dehydrogenase Deficiency
(MCADD)
*In the Philippines: we only screen for 5 of these

Signs and Symptoms
Catastrophic illness following a period of normal
behavior or feeding session
Unexplained lethargy, coma, recurrent seizures,
persistent or recurrent vomiting, jaundice, failure to
thrive, unusual body odor
Developmental delay
Hyperammonemia, Hypoglycemia
o Pedia:
Unrelieved hypoglycemia:
massive convulsions without a
neurologic etiology
Metabolic acidosis
Family history of unexplained death and recurrent
illnesses

Usual Cause of Consult
US: inborn errors of metabolism
o more common
Phil and Asian countries: more on infectious causes

Treatment
Emerging therapy for suspected inborn errors of
metabolism
o To current and on-going disease
Nutritional therapy utilizing synthetic medical forms
o Once etiology of IEOM is known
Other nutritional therapy
o Vitamin and Co factors
Other Therapeutic Modalities
o Replacement therapies
Digestive enzymes
o Organ transplantation
o Replacement of a mutant gene

Inborn Errors of
Metabolism
Modify or
Restrict
Vitamin or
Co factor
Other
therapies

Phenylketonuria Phenylalanin
e
<1% of
cases due
to
Biopterin
synthetic
effect

Supplementa
l tyrosine
Tyrosinemia type
1
Phenylalanin
e, tyrosine,
methionine
No NTBC 4
hydroxy
phenylpyruv
ate
dioxygenase
inhibitor

Tyrosinemia type
2
Phenylalanin
e
Tyrosine

No
Maple syrup
urine disease
Leucine
Valine
Isoleucine
Some are
thiamine
responsive


Isovaleric
acidemia
Leucine No Supplementa
l carnitine
and glycine

Propionic
acidemia
Isoleucine
Valine
Methionine
Threonine

Possible
role for
biotin
Supplementa
l carnitine
Homocystinuria Methionine 50%
pyridoxine
responsive
Supplementa
l folate
Betaine

Ornithine trans
carbamylase
deficiency
Protein No Supplementa
l citrulline,
benzoate,
phenylbutyra
te

Citrulinemia Protein No Supplementa
l arginine,
benzoate,
phenyl
acetate,
phenyl
butyrate

Glutaric acidemia
type 1
Lysine
Tryptophan
Possible
role of
Riboflavin
Supplementa
l carnitine

Biotinidase None Biotin


Familial
Hypophosphatem
ic rickets
None 1,25
Dihydroxy
vitamin D

Phosphorus
Acrodermatitis
enteropathica

None Zinc
INBORN ERRORS OF METABOLISM
February 26, 2014
Dr. Jessica Joy Ramolete

eramae.sibayan

2
Pyruvate
Dehydrogenase
deficiency
Low CHO,
High fat diet
Possible
thiamine
response

Alkali
therapy
Galactosemia
transferase
deficiency

Galactose
lactose
Lactose free
infant
formula

Conclusion
Family education
o Genetic counselling
Nutritional therapy
o Remains to be the cornerstone of therapy

1) Phenylketonuria (PKU)
Incidence
o 1:11,000 Caucasian
o Autosomal recessive gene
Biochemical defect
o Phenylalanine hydroxylase is absent
Testing for PKU
o Normal value: less than 2 mg/dl
o Abnormal:
Above 2 mg/dl at 12 24 hours
Above 4 mg/dl at 3 days or more
Clinical changes
o Mental retardation
IQ below 50
o Decreased production of tyrosine
Blond, blue eyes, fair skin
o Hyperactive
o Poor coordination
o Immature
o Over dependent
o Seizures- MC manifestation of inborn error
Treatment
o Early diagnosis: PKU part of Newborn
Screening
o Restriction of phenylalanine intake to
maintain an acceptable range of
phenylalanine (< 2 mgs)
o Nutritionally adequate diet adjusted from
time to time to meet the requirements for
normal growth and development
o Continuing clinical and biochemical
monitoring
o Comprehensive program of education of
parents
o Modification diet
Phenylalanine needs to be
restricted but it cannot be totally
eliminated from the diet
Protein contain 4-6%
phenylalanine which is excessive
for a child with PKU
Lofenalac: milk formula
95% of phenylalanine
has been removed
Phenyl-free or PKU-AID
Used in older children
Contains no
phenylalanine
Treatment of choice:
Low phenylalanine
diet and oral
supplementation of
BH4
(Tetrahydrobiopterin)







2) Tyrosinemia
Features
o Autosomal recessive
o Deficiency of parahydroxypyruvic acid
oxidase
o Newborn infants may have transient
tyrosinemia
3-5 days: tyrosine not readily
available
Dietary modification
o Hydrolysate low in phenylalanine and
tyrosine
Treatment of choice
o Nitisinone (NTBC)
Inhibits tyrosine degradation at 4
HPPD (4 hydroxy phenylpyruvate
dioxygenase)
Prevents hepatic and neurologic
crisis
Slows down disease progression

3) Maple Syrup Urine Disease
Biochemical defect:
o Unable to breakdown branched chain
amino acids
Leucine
Isoleucine
Valine
o Leads to build up of these in the blood
o Misdiagnosed as neonatal sepsis
Clinical changes
o Poor suck
o Irregular respiration
o Rigidity and flaccidity
o Grand mal seizures
o Hypoglycemia
o Frequent infections
o Urine
Sweet-smelling urine similar to
that of maple syrup
Dietary treatment
o Diet restricted in isoleucine, leucine, and
valine
o Milk formula
GIBCO amino acid mix
INBORN ERRORS OF METABOLISM
February 26, 2014
Dr. Jessica Joy Ramolete

eramae.sibayan

3
Special milk formula
Synthetic formulas devoid of:
Leucine
Isoleucine
Valine
o Fruits, vegetables, and cereals low in
protein

4) Homocystinuria
Biochemical findings
o Lack of cystathionine synthetase
Clinical findings
o Autosomal recessive
o Mental retardation
o Dislocated lens
o Skeletal deformities
o Thromboembolism
o Early atherosclerosis
Treatment
o Pyridoxine
o Folic acid
o Betaine
o Choline
Dietary modification
o Normal and excessive intake or protein for
those unresponsive to pyridoxine
o Unresponsive to pyridoxine
Low methionine diet
supplemented with cysteine
o Low methionine diet powder

5) Galactosemia
Treatment
o Nutramigen
o Prosobee
o Meat based formula

6) Familial Hypercholesterolemia
Children dying of heart attack
Genetic defect in the metabolism of LDL
Diets containing less than 150 mg of cholesterol daily

7) Celiac disease
Gluten-sensitive enteropathy
Hallmark of malabsorption syndrome*
Abnormal mucosal response to the protein fraction in
grain gliadin
Elimination of food containing-gluten
o Reversal of signs and symptoms
o Permits normal GIT absorption
Give calcium (1,200 mg) and Vitamin D (400 IU)
supplementation
o To restore bone density in patients whose
axial bone density is decreased
Principles:
o Toxic grain products
Glutens are a family of proteins
found in many grains
Corn and rice are safe in patients
with celiac disease
Wheat, rye, barley and
buckwheat
Produce symptoms
Oats: questionable as cause
However, still
omitted in gluten free
diet
o Substitutes
Corn
Rice
Potato flour
Soy bean flour
Tapioca
Arrow root: found in Korea and
Japan, parang kamote
o Wheat products are used as filters in many
processed foods
o Duration of diet: lifelong
Gluten-restricted diet
o Foods containing gluten
Avoid
ALFALFA
Barley
Buckwheat
Oats
Rye
Wheat
o Gluten-free grain and flour substitute
Use
Corn flour
Corn starch
Lima bean flour
Potato flour
Rice
Rice flour
Soy flour
Arrow root
o *Gluten free food
Fresh meats
Milk
Fish eggs
Fresh vegetables
Fruits

8) Malabsorption Syndrome
Defect in
o Intestinal lumen resulting to the inadequate
fat hydrolysis or altered bile salt
metabolism
o Mucosal epithelial cells
Affect absorbing surfaces
Interferes with transport
function
o Intestinal lymphatics
o Vit ADEK cant be absorbed!
Signs and symptoms
o Pale, bulky, offensive stools
Due to abnormal high fat
INBORN ERRORS OF METABOLISM
February 26, 2014
Dr. Jessica Joy Ramolete

eramae.sibayan

4
content
Immediately after intake
o Muscle wasting and progressive weight loss
Due to diarrhea, steatorrhea,
and anorexia
o Abdominal distension in children
o Vitamin and mineral deficiency
Diagnosis
o Fecal fat
NV: <7 g/24 hours
o Serum triglycerides and chylomicrons
o Fecal radioactivity
o Serum carotene
o Lactose intolerance test
o Breath hydrogen test
o Schilling test
o Folic acid test

Treatment
o Dietary modification
Diet high in proteins and calories
Modification of fat intake
Vitamin and mineral
supplementation

o Fat malabsorption
DOC: Medium Chain
Triglycerides (MCT)
Hydrolysed much
more rapidly
Transported to portal
veins as free fatty
acids bound to
albumin
Fractionated coconut
oil, Potagen
o 50-70% supplied as MCT
Remainder from LCT
Meat
Fish
Poultry
Butter
25 g or long chain
triglycerides (LCT) per
day

9) CHO Malabsorption
Clinical
o Sour smelling stools
o Perianal area is erythematous with satellites
o MC malabsorbed- glucose; in infants-
lactose; older- lactose, maltodextrin (OT)
Diagnostics
o Clinitest tablets
Result: ++++ brown orange
Treatment
o Maltodextrin (DOC)
Low osmolality
Well digested and absorbed
Enhance calcium absorption
Shortened diarrheal duration
Faster intestinal recovery
Seen in milk of preterms

10) Protein intolerance
Clinical
o Family history of atopy
o Allergic march: atopy allergic
rhinitisbronchial asthma(OT)
Diagnostics
o Endoscopy with biopsy
Gross nodularities
Treatment
o Hydrolysate (Whey)
Pre-digested and readily
absorbed for immediate
utilization
Decreased antigenicity
Rapid return to normal growth
o Whey
Higher percentage found in
breast milk


Thoughts:
Dont just wear clothes that will make you look good
Wear those that you are comfortable with
Same with friends
Go not with people that will make you famous
But with people that you can smile with without pretentions

Plant seeds of happiness, hop, success, and love
It will come back to you in abundance
Such is the law of nature

Put love into your heart so nothing would be heavy
Put understanding in your mind so nothing would be difficult
And put God into your whole being so nothing is impossible

Enjoy and use every moment of life
Dont save it for some other day
Because there is no courtesy desk for us to go and get a refund on unused
life
Good luck.. God bless
-jjram