This document summarizes various inborn errors of amino acid metabolism, including: - Phenylketonuria (PKU), which results from a defect in the enzyme phenylalanine hydroxylase and can cause intellectual disability if left untreated; - Tyrosinemias, including types 1, 2, and 3, which are caused by defects in tyrosine catabolism and can lead to liver or neurological complications; - Alkaptonuria, which results from homogentisic acid dioxygenase deficiency and causes dark urine; and - Maple syrup urine disease, caused by a branched-chain keto acid dehydrogenase complex defect leading to accumulation of leucine, isoleucine

1. Inborn errors
of Amino Acid
Metabolism

2. •Garrod first proposed
the concept of
“inborn errors of
metabolism” in 1909
•More than 1000 IEM
discovered thereafter

3. Metabolic disorders which impair the synthesis and
degradation of amino acids.
Caused by inherited enzyme defects of catabolic pathways or
intracellular transport of amino acids.
accumulation of (1) the parent amino acid, (2) its by-products
or (3) the catabolic products (organic acids), depending on the
location of the enzyme block.

4. Aminoacidopathies — a group of rare and diverse disorders,
caused by the deficiency of an enzyme or transporter involved in
amino acid metabolism
Organic acidemias — products in the catabolic pathway of
certain amino acids accumulate.
Urea cycle defects — defciency of enzymes or transporter in the
urea cycle

5. Epidemiology
• The incidence of IEMs, collectively,
is estimated to be as high as 1 in
800 live births
• Phenylketonuria (PKU) with
incidence of 1 in 10,000 is among
the most prevalent.
• Pattern of inheritance mostly
autosomal recessive with male:
female ratio 1:1

6. Amino
Acidopathies
Phenylketonuria (PKU)
Tyrosinemia
Alkaptonuria
Maple Syrup Urine Disease (MSUD)

7. Disorders of Phenyalanine and Tyrosine

8. Phenylketonuria (PKU)
• Hyperphenylalaninaemia (HPA):
• Mutations within the gene for the hepatic enzyme
phenylalanine hydroxylase (PAH)
• Mutations within those genes involving production or
recycling of tetrahydrobiopterin metabolism

9. Clinical Presentation
• Autosomal Recessive
• Highest incidence in Turkish population (1:2600)
and 1:10000 in European and Asian
• Untreated PKU leads to intellectual disability,
seizures, “mousy” odour, hypopigmentation

11. Defects of biopterin
• A deficiency of BH4 results in
hyperphenylalaninaemia, and affects
tyrosine hydroxylase, tryptophan
hydroxylase, as well as nitric oxide synthases
• Defects of biopterin metabolism result in
severe encephalopathies.

12. Diagnosis
• Phenylalanine level >20 mg/dl
• Tandem mass spectrometry
• Guthrie test
• Ferric chloride
• DNA analysis

14. Diagnosis of biopterin disorders
Urinary biopterin and
neopterin values are low
High Urinary neopterin
values and low biopterin
Neopterin : normal
Biopterin :Very high

15. Maternal PKU
• Offspring of women with untreated classical PKU suffer developmental delay,
microcephaly, cardiac defects, low birth weight and dysmorphic features.
• The risk of CHD increases with increasing PHE exposure.
• Strict dietary control for pregnant women with PKU and, preferably before conception
and throughout pregnancy is associated with normal outcomes

16. Treatment
• Most important therapeutic intervention in PKU is phenylalanine-restricted dietary
treatment.
• Guanosine triphosphate cyclohydrolase deficiency and 6-pyruvoyltetrahydrobiopterin
deficiency: administration of BH4
• Dihydropteridine reductase deficiency: low-phenylalanine diet, neurotransmitter
precursors and folinic acid

17. Tyrosinaemia type 1 (fumarylacetoacetase
deficiency)
• Presents acutely in the early weeks of life with failure to thrive,
vomiting, hepatomegaly, fever, oedema, and epistaxis;
• Death from hepatic failure often occurs in infancy.
• Chronic presentation:
chronic liver disease,
a renal tubular Fanconi syndrome with hypophosphataemic
rickets, and
episodic abdominal pain and neuropathy suggestive of acute
porphyria.
• The most serious complication is hepatocellular carcinoma
• Hepatorenal Tyrosinemia
• Autosomal Recessive
• Incidence 1.5:1000

18. Diagnosis
• Urine –
• Tyrosine
• Parahydroxy phenyl pyruvic acid
• Hydroxyphenyl lactic acid
• Serum –
• Tyrosine
• Succinylacetone

19. Treatment
• Restricted intake of tyrosine and
phenylalanine
• Nitisinone  blocks 4-
hydroxyphenylpyruvate dioxygenase 
turning tyrosinaemia type 1 into
tyrosinaemia type 3 and reducing the
production of toxic metabolites.
• Liver Transplant if not responding to
nitisinone

20. Tyrosinaemia type 2
(tyrosine
aminotransferase
deficiency)
• Oculocutaneous/Richner-
Hanhart Syndrome
• Incidence - less than 1/250,000
• Diagnosis: There is increased
excretion of tyrosine, and
tyramine,; there is no Fanconi
syndrome and no increase in
succinylacetone.
• Treatment – Restricted Phe, Tyr
diet

21. Tyrosinaemia type 3 (4-Hydroxyphenylpyruvate
dioxygenase deficiency)
• Very rare; may be associated with learning difficulties and possibly other
neurological complications.
• Biochemical findings similar to Tyrosinaemia type 2, but the plasma values of
tyrosine are usually less.
• Enzyme and molecular genetic studies can prove the diagnosis.
• Treatment: low-tyrosine, low-phenylalanine diet.

22. Albinism (type 1)
• Congenital disorder
• 1 in 20,000 worldwide
• Partial or complete elimination of Tyrosinase
activity
• Types
• Oculocutaneous type 1A
• Oculocutaneous type 1B
• Clinical features white hair, light-colored eyes, and
pale skin along with photophobia and functional
blindness

23. Alkaptonuria
• 1st IEM described by
Garrod.
• Caused by
deficiency of
homogentisate
dioxygenase
• 1 in 250,000

24. Diagnosis and Treatment
• Homogentisic acid : urinary organic acid analysis.
• Homogentisic acid can be decreased by a low-protein diet.
• Nitisinone reduces overproduction of homogentisic acid in
alkaptonuria.

25. Maple Syrup Urine Disease
• Prevalence of approximately 1 in 200 000 newborns
• Deficiency of the thiamine-dependent branched chain α-keto acid
dehydrogenase complex
• The branched chain amino acids leucine, isoleucine, and valine, their
corresponding α-keto acids and hydroxy acid derivatives as well as L-
alloisoleucine are increased in physiological fluids.

26. Clinical Presentation
• Classic MSUD -
• Presents in the first few days of life
• lethargy, irritability, poor feeding, and neurological deterioration.
• Intermediate MSUD -
• Late onset,
• failure to thrive,
• developmental delay, and seizures
• Intermittent MSUD -
• Normal growth and intellectual development
• Infections or physiological stress leads to clinical and biochemical features of classic MSUD

27. Diagnosis
• Odour of maple syrup
• Confirmation - increased plasma concentrations of leucine,
isoleucine, and valine and/or by increased urinary excretion of α-
keto and hydroxy acids.
• Rothera positive

28. Treatment
•Diet low in BCAA
•Thiamine
•Liver transplantation

29. Treatment
• Currently no highly effective treatment
• Low-protein diets have only a limited effect on decreasing plasma
glycine concentrations.
• Sodium benzoate to increase glycine excretion has lowered plasma
and cerebrospinal fluid levels of glycine and reduced seizures.
• Dextromethorphan is commonly used to reduce seizures and
improve alertness

30. Thank you