Lecture 59 - Diseases Of Amino Acid Metabolism

Front 1

General features of inborn errors of metabolism

Back 1

- Patients may appear normal at birth

- mainly recessive inheritance

-diagnosed by laboratory testing

Front 2

What are the categories for inherited metabolic disease?

Back 2

1. Deficiency of enzyme activity

2. Deficiency of enzyme protein

3. Cofactor abnormalities

4. Transport defects

5. Defects in structural proteins

Front 3

Cross-reactive material (CRM)

Back 3

Defined as a protein produced by a mutant gene that reacts antigenically with antibody against the normal protein

Front 4

CRM+

Back 4

Deficiency of enzyme activity

(residual enzymatic activity and clinically milder)

Front 5

CRM-

Back 5

Deficiency of enzyme protein

(no residual activity and clinically more severe)

Front 6

Phenotypic heterogeneity

Back 6

Different patients with the same disorder expressing the trait differently

Front 7

Biochemical heterogeneity

Back 7

Different patients with blocks in the same metabolic pathway having different accumulations of metabolites

Front 8

Molecular heterogeneity

Back 8

Different patients with different mutations in the same gene

Front 9

Locus/Genetic heterogeneity

Back 9

Different patients with different mutations in different genes but with same phenotype

Front 10

Amino acids usually limited to deficiencies in enzyme activities affecting the first (or second) catabolic step

Back 10

True

Front 11

Where does amino acid accumulation are usually found?

Back 11

Plasma, Urine, CSF, amniotic fluid (less frequent)

Front 12

Who needs amino acids analysis?

Back 12

- Life-threatening illness in neonatal period

- Unexplained systemic findings compatible with one of the aminoacidopathies

- Infantile Seizures

- Unexplained mental retardation or developmental delay

- Abnormal newborn screen

Front 13

What does the interpretation of results depends on?

Back 13

- Age of patient

- Diet

- Medications

- Knowledge of clinical history

Front 14

How are aminoacidopathies diagnosed in the laboratory?

Back 14

1. Separation of individual amino acids by chromatographic techniques (TLC, HPLC)

2. Staining with ninhydrin (form color products like Ruhemann's purple)

Front 15

What are Urea cycles defects?

Back 15

5 inborn errors

1. Carbamyphosphate synthetase (CPS) deficiency

2. Ornithine transcarbamylase (OTC) deficiency

3. Arginininosuccinate synthetase (ASS) deficiency

4. Argininosuccinate lyase (AL) deficiency

5. Arginase deficiency

Front 16

Hyperammonemia causes

Back 16

- Liver disease

- Transient hyperammonemia of the newborn

- Reye syndrome (clinical diagnosis)

- Poisonings

- Primary errors (Urea cycle defects, transport - disorders)

- Secondary errors (Organic acidurias, FAO, respiratory chain defects)

Front 17

What disorder is the exception of inheritance to urea cycle disorders?

Back 17

OTC deficiency which is X-linked

(severe nenonatal ammnoia intoxication in males)

Front 18

Clinical manifestations of hyperammonemia

Back 18

Poor feeding

Respiratory alkalosis

Vomiting

Lethargy

Coma

Death

Front 19

Biochemical features of CPSI Deficiency

Back 19

High glutamine

Low citrulline

No Orotic acid

Front 20

Biochemical features of OTC deficiency

Back 20

High Orotic acid and glutamine

Low Citrulline and arginine

Front 21

Biochemical features of Citrullinemia (AS deficiency)

Back 21

Very high citrullline

+/- orotic acid

Front 22

Biochemical features of Argininosuccinic aciduria (AL deficiency)

Back 22

Very high argininosuccinic acid and citrulline

Front 23

Acute treatment for Urea Cycle

Back 23

1. All intake of protein should be stop (anabolism should be promoted by administration of glucose)

2. Increasing nitrogen excretion through alternative pathway (sodium benzoate, phenylacetate, phenylbutryate)

3. Arginine supplementation

Front 24

What are sodium benzoate, phenylacetate, phenylbutryate?

Back 24

Ammonia-Savenging medications

Front 25

Chronic treatment of urea cycle?

Back 25

Diet (protein restriction)

Pharmacologic

Liver transplant

Front 26

Survival rates of urea cycle

Back 26

28-94%

Front 27

What does tyrosine become?

Back 27

Pigment, Neurotransmitter, Tyroxine

Front 28

Classical PKU Clinical features

Back 28

- Progressive intellectual disability

- "Mousy odor"

- Hypopigmentation

- Abnormal gait, stance, sitting posture

- Eczema

- Seizures

Front 29

What is PKU deficiency?

Back 29

Phenylalanine hydroxlase deficiency (liver enzyme)

Front 30

What laboratory findings diagnose PKU?

Back 30

1. Plasma phenylalanine level above 20 mg/dl

2. Phenylalanine/tyrosine ratio >3

3. Increased urinary metabolites of phenylalanine

4. Normal concentration of cofactor tetrahydrobiopterin

Front 31

Treatment for PKU

Back 31

1. Low Phenylalanin diet

2. Biopterin (Saproperin, Kuvan) - cofactor for phenylalanin hydroxylase

Front 32

What is important of tyrosine hydroxylase?

Back 32

Synthesis of norepinephrine

Front 33

What is important of tyrptophan hydroxylase?

Back 33

Synthesis of serotonin

Front 34

What are the variants of PKU?

Back 34

1. Classical PKU

2. Persistent hyperphenylalaninemia

3. Transient hyperphenylalaninemia

4. Cofactor defect: tetrahydrobiopterin

5. Maternal PKU

Front 35

What is different in treatment of classical PKU and tetrahydrobiopterin?

Back 35

In addition to strict diet, you have to replenish the neurotransmitter of norepinephrine and serotonin in deficiency in tetrahydrobiopterin.

Front 36

Maternal PKU

Back 36

Phe is a teratogen

Untreated mothers have higher incidence of miscarriageand infants with IUGR, microcephaly, MR, congenital heart disease, subtle dysmorphism

Goal is have Phe level <6 mg at least 3 months prior to conception

Front 37

Causes of Hypertyrosinemia (inborn errors of tyrosine catbolism)

Back 37

Hepatorenal tyrosinemia (HT1)

Oculocutaneous tyrosinemia (type II)

pHPPD deficiency (type III)

Front 38

Hepatorenal tyrosinemia (HT1)

Back 38

Autosomal recessive1/100,000;

fumarylacetoacetate hydrolase deficiency

Founder effect in Quebec and Finland

Front 39

What accumulates in Hepatorenal tyrosinemia (HT1)?

Back 39

Accumulation of fmarylacetoacetate (FAA) in hepatocytes. Diverted to form succinylacetoacetate and succinyl acetonin

Can present with prophyria like symptoms

Front 40

How is Hepatorenal tyrosinemia (HT1) diagnosed?

Back 40

Elevated succinylacetone in blood and urine

*marker*

Elevated plasma methionine, tyorsine, and phenylalanine

Front 41

How is Hepatorenal tyrosinemia (HT1) treated?

Back 41

Nitisinone (Orfadin) or NTBC

- blocks 4-hydroxyphenylpyruvic acid dioxygenase enzyme (2nd step in tyrosine degradation)

Liver transplant if non-responsive

Front 42

Nonketotic Hyperglycinemia - Deficient enzyme

Back 42

Primary disorder of glycine metabolism

deficient activity of glycine cleavage enzyme system usually T or P protein

Mutation in gene encoding P-protein component accounts for 75%

Front 43

Nonketotic Hyperglycinemia clinical presentation

Back 43

Neonatal period (85% severe form, 15% attenuated form

Progressive lethargy, seizures, hypotonia, apnea

Front 44

How is Nonketotic hyperglycinemia diagnosed?

Back 44

Abnormal elevation of glycine in blood, urine and cerebrospinal fluid (CSF)

Normal pH, ammonia, organic acids, no ketones

Front 45

How is Nonketotic hyperglycenmia treated?

Back 45

No effective treatment

Diet will not work because you need glycine for nucleotide formation

Front 46

Homocystinuria's enzyme

Back 46

Cystathionine-b-synthase deficiency

1/250,000

Front 47

Clinical presentation of Homocystinuria

Back 47

Abnormal long bone formation (Marfan like)

Ectopia lentis(dislocated lenses)

Myopia

Increased risk for thromboembolytic events

Variable mental retardation (50% of patients)

Front 48

How is Homocystinuria diagnosed?

Back 48

Elevated plasma methionine and homocysteine

Front 49

How is Homocystinuria treated?

Back 49

Betaine and pyridoxine (B6)-50% of cases responders

low methionine diet