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Inborn Errors of Metabolism

Assoc
...
Savina Hadjidekova

Department of Medical Genetics
Medical University – Sofia

What this seminar will cover
• Overview of principles in IEM (Inborn errors of
metabolism)

• Approach to diagnosis
• Examples from disorders of intermediary
metabolism
• Neonatal screening

It won’t and can’t be a comprehensive review of all IEM

„It is an old experience that through her errors,
Nature often grants us insights into her secrets
which are otherwise a closed domain
...
Loewy and C
...
Hoppe-Seyler’s Physiol Chem, 43:338-354, 1904)

Four congenital metabolic diseases:
•Albinism
•Alkaptonuria
•Cystinuria
•pentosuria
Autosomal recessive inheritance
He called these inborn errors of metabolism
...


Metabolic block
z
a

b

c

c’ase
active

d

cofactor
c’ase
inactive
A loss of function of one of the steps in the pathway will lead to the accumulation
of metabolites prior to the block and a depletion of the metabolites after the block
...
B
...


• Vitamins
thiamine supplementation benefits several types of disorders
that cause lactic acidosis
...
)
Acute intermittent porphyria
Lesch-Nyhan syndrome
Lipoid congenital adrenal hyperplasia, congenital adrenal
hyperplasia
Kearns-Sayre syndrome, Pearson syndrome
Zellweger syndrome, adrenoleukodystrophy
Wilson disease
Hypophosphatasia
Crigler-Najjar syndrome

I
...

• Inheritance:
Autosomal recessive

Incidence
Population
Turks
Irish
Northern European
origin, East Asian
Japanese
Finnish, Ashkenazi
Jewish
African

PAH Deficiency in Live Births Carrier Rate
1:2,600
1/26
1:4,500
1/33
1:10,000

1/50

1:143,000

1/200

1:200,000

1/225

~1:100,000

?

History

1934 discovered
by Ivar Følling
as oligophrenia
phenylpyruvica

1937 Dr
...
Horst
Bickel
develops first
diet treatment

1958 Dr
...
Savio
Woo identified
the PAH gene,
located
at
12
...
1

Classification of
hyperphenylalaninemias
• Phenylketonuria

• Hyperphenylalaninemia (HPA)
o BH4deficiency

• Variant PKU

Classical PKU - characteristics
• Most severe of the three types;
• Plasma Phe concentrations greater than 1000
µmol/L;

• Complete or near-complete deficiency of PAH
activity

• Dietary Phe tolerance is of less than 500 mg/day;
• High risk of severely
development if not treated
...
2
Gene product: phenylalanine hydroxylase
Mutations: more than
500 mutations → the
most common mutation
Arg408Trp (R408W)

Enzyme function
Conversion of phenylalanine to tyrosine in
cooperation with tetrahydrobiopterin
(BH4)
...


Clinical description of classical
PKU
•Blond hair, light skin and

eyes;
•Eczematous rashes
•Microcephaly

Severe HPA identified and
treated from birth
Children with persistent severe hyperphenylalaninemia identified and
treated from birth may still have some underlying consequences:

• Neuropsychological issues
–
–
–
–

suboptimal cognitive outcome
slow motor reaction time
tremor
anxiety and depression, phobias and panic attacks

• Osteopenia
• Vitamin B12 deficiency

Malignant HPA
(Tetrahydrobiopterin deficiency )
• Definition:
Rare
autosomal
recessive
disorder
characterized by hyperphenylalaninemia and
severe neurologic symptoms including axial
hypotonia and truncal hypertonia, abnormal
thermogenesis, and microcephaly
...


Malignant HPA – diagnosis and
treatment
• Analysis of pterins in the urine;
• Loading test with BH4
• Treatment requires the normalization of
BH4 availability
• Without treatment is lethal

Maternal PKU embryopathy
Women with PAH deficiency who have been properly treated throughout
childhood and adolescence have normal physical and intellectual
development
...


• Genetic diagnosis
–
–
–
–

Targeted mutation analysis - sequence analysis of select exons
Sequence analysis /mutation scanning
Duplication/deletion analysis
Linkage analysis

Newborn screening for PKU
PAH deficiency is most frequently diagnosed through newborn screening
programs using dried blood spots
...
Then a small disc is punched from the
center of the spot of blood
...

Circle must be filled and evenly saturated
...
One
affected individual with PKU is
identified at the center of this gel
...
Both Phe and Tyr are quantified and
Phe/Tyr ratio is determined
...

Heterozygotes are asymptomatic and do not have PAH
deficiency
...


Once an at-risk sib is known to be unaffected, the risk of
his/her being a carrier is 2/3
...
Carbohydrate metabolism
Galactosemia
• Definition:
Galactosemia is a rare genetic metabolic disorder
that affects an individual's ability to metabolize the
sugar galactose properly
...
coli sepsis
Late complications despite adequate

treatment from an early age:
• developmental delays
• speech problems (apraxia and dysarthria)
• abnormalities of motor function
• premature ovarian insufficiency (POI)
...
Gln188Arg
...


Diagnosis of classical
galactosemia
• detection of elevated erythrocyte galactose-1phosphate concentration
• reduced erythrocyte galactose-1-phosphate
uridyltransferase (GALT) enzyme activity
• biallelic mutations in GALT, the gene encoding
galactose-1-phosphate uridyltransferase
...

Note:
Clinicians need to be alert to early signs and remove lactose from the
diet and initiate soy-based dietary therapy while awaiting results of
newborn screening and/or diagnostic tests
...


Type II galactosemia
(Galactokinase deficiency)
• Gene: GALK 1 gene
• Location: 17q24
• Gene product: galactokinase 1
• Function:
• Clinical symptoms: early cataracts
• Treatment: low galactose diet

Type III galactosemia
(UDP galactose epimerase)
• Gene: GALE1 gene
• Location: 1p36-p35
• Gene product:
UDP-galactose-4-epimerase
• Function: conversion of UDP-glucose to
UDP-galactose

Clinical forms
Type III galactosemia
• Generalized (the enzyme activity is profoundly
decreased in all tissues tested)

• Peripheral (enzyme activity deficient in red
blood cells and circulating white blood cells, but
normal or near normal in all other tissues)

• Intermediate (enzyme activity is deficient in
red blood cells and circulating white blood cells
and less than 50% of normal levels in other cells
tested)

Clinical characteristics
•
•
•
•
•
•
•
•
•

Hypotonia
Poor feeding
Vomiting
Weight loss
Jaundice
Hepatomegaly
Liver dysfunction
Aminoaciduria
Cataracts
...

Heterozygotes are asymptomatic and do not have PAH
deficiency
...


Once an at-risk sib is known to be unaffected, the risk of
his/her being a carrier is 2/3
...
Urea cycle defects
OTC deficiency
• Definition:
Ornithine transcarbamylase deficiency is an inherited
disorder that causes ammonia to accumulate in the
blood
...
The nervous system is especially sensitive to the
effects of excess ammonia
...
4
Gene product: Ornithine transcarbamylase

Mutations:

More
pathogenic OTC variants

than

400

Diagnosis of OTC deficiency
• Blood gases
• Plasma ammonia concentration
...
Disorders of organic acid
metabolism (organic acidurias)
Organic aciduria, is a term used to classify a group of metabolic
disorders which disrupt normal amino acid metabolism,
particularly branched-chain amino acids, causing a buildup of
acids

•
•
•
•

Alkaptonuria
Propionic acidaemia
Methyl malonic aciduria
Isovaleric acidaemia

What is alkaptonuria?
• Definition:
Alkaptonuria is caused by deficiency of homogentisate
1,2-dioxygenase, an enzyme that converts homogentisic
acid (HGA) to maleylacetoacetic acid in the tyrosine
degradation pathway
...


Diagnosis and treatment of
alkaptonuria
• Diagnosis
– gas chromatography-mass spectrometry
analysis (detection of a significant amount of HGA in the
urine by gas chromatography-mass spectrometry analysis)

– molecular genetic testing
o Targeted mutation analysis
o Sequence analysis

• Treatment
symptomatic

V
...

• Lysosomes are sacs of enzymes within cells that digest
large molecules and pass the fragments on to other
parts of the cell for recycling
...
If one of
these enzymes is defective, because of a mutation, the
large molecules accumulate within the cell, eventually
killing it
...

The disorder is characterized by bruising, fatigue,
anemia, low blood platelets, and enlargement of the liver
and spleen, bone disease
...
v
...
Peroxisomal disorders
Peroxisomal disorders represent a class of medical
conditions caused by defects in peroxisome functions
...


• Adrenoleukodystrophy
• Zellweger syndrome,

Adrenoleukodystrophy
• Definition:
Genetic disease of peroxisomal fatty acid beta
oxidation which results in the accumulation of very-long
chain fatty acids in tissues throughout the body
...

Lorenzo's Oil is an American drama film directed
by George Miller
...


•demyelination

Diagnosis and treatment of
adrenoleukodystrophy
• Diagnosis
– Clinical
– Plasma very long chain fatty acid (VLCFA) determination
by gas chromatography-mass spectrometry
– Molecular genetic analysis
– Newborn screening

• Treatment
–
–
–
–

Dietary therapy
Transplant
Gene therapy
Treatment of the adrenal insufficiency

Thank you for your attention!



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