Transcript 1) Structural globin chain variants

Session
7
Medical Genetics
Hemoglobinopathies
and
Biochemical Genetics
J a v a d
F a s a
J a m s h i d i
U n i v e r s i t y
o f
M e d i c a l
S c i e n c e s ,
N o v e m b e r
2 0 1 5
Hemoglobinopathies
At least 250,000 people are each year with disorders of
hemoglobin (Hb), called Hemoglobinopathies
Hb is the protein present in red blood cells that is responsible
for oxygen transport
Hb being made up of a tetramer consisting of two pairs of
different polypeptides referred to as the α and β globin chains
Protein and Gene Structure
16p13
11p15
Disorders of Hemoglobin
1) Structural globin chain variants
such as sickle cell disease
2) Disorders of synthesis of the globin chains
such as the thalassemias
Structural Variants/Disorders
More than 300 Hb electrophoretic variants have been
described due to a variety of types of mutation
The majority are rare and not associated with clinical disease
A few are associated with disease and relatively prevalent in
certain populations.
Sickle Cell Disease Mutation
The amino acid valine, at the sixth position of the β-globin
chain, is substituted by glutamic acid.
Disorders of Hemoglobin Synthesis
The thalassemias are the commonest single group of inherited
disorders in humans
Persons from the Mediterranean region, Middle East, Indian
subcontinent, and Southeast Asia
The same pathophysiology, An imbalance of globin-chain
production results in the accumulation of free globin chains in the
red blood cell
α and β Thalassemia
α Thalassemia
Results from underproduction of the α-globin chains and occurs
most commonly in Southeast Asia
Two main types of α-thalassemia:
The severe form
No α chains are produced, fetal death
Hydrops fetalis
Tetramer of γ chains, called Hb Barts
The milder form
Some α chains but still a relative excess of β chains
β -globin tetramer Hb H-known as Hb H disease
Normal and Deleted α-globin Structural Genes
β Thalassemia
Caused by underproduction of the β-globin chain of Hb.
Two main types of β-thalassemia:
The major form
Homozygotes for β chains defect, Cooley's anemia
Severe transfusion-dependent anemia
An unusually shaped face and skull
Affected individuals used to die in their teens or early adulthood
The minor form
Heterozygotes for β chains defect
Usually have no symptoms or signs
Mild hypochromic, microcytic anemia, may be confused with iron
deficiency anemia.
β Thalassemia Major Bone Changes
Biochemical Disorders
Amino acid metabolism
Urea cycle
Carbohydrate metabolism
Steroid metabolism
Lipid metabolism
Lysosomal storage disorders
Disorders of purine/pyrimidine metabolism
Porphyrin metabolism
Copper metabolism
Peroxysomal disorders
Disorders of Amino Acid Metabolism
Phenylketonuria
Deficiency of the enzyme required for the conversion of
phenylalanine to tyrosine, phenylalanine hydroxylase (PAH)
Children with phenylketonuria (PKU), if untreated
Severely intellectually impaired
Often develop seizures
Often have blond hair and blue eyes
Treatment by controlling phenylalanine diet intake
Maternal PKU
Treated and untreated PKU
Alkaptonuria
Block in the breakdown of homogentisic acid, a metabolite of
tyrosine
Deficiency of the enzyme homogentisic acid oxidase
homogentisic acid accumulates and is excreted in the urine,
which then darkens on exposure to air
Dark pigment is also deposited in certain tissues, such as,
cartilage, and joints
Can lead to arthritis later in life.
Oculocutaneous Albinism (OCA)
Deficiency of the enzyme tyrosinase, which is necessary for
the formation of melanin from tyrosine
Lack of pigment in the skin, hair, iris, and ocular fundus
Poor visual acuity and uncontrolled pendular eye movementsnystagmus
OCA is genetically and biochemically heterogeneous.
OCA1, defective tyrosinase gene, tyrosinase-negative and positive
forms, 11q
OCA2, mutation in the P gene locates on 15q
There are some other loci
Oculocutaneous Albinism
Disorders of Monosaccharide Metabolism
Galactosemia
Hereditary Fructose Intolerance
Galactosemia
Deficiency of the enzyme galactose 1-phosphate uridyl
transferase, necessary for the metabolism of galactose.
Newborns present with vomiting, lethargy, failure to thrive, and
jaundice in the second week of life.
If untreated, they develop complications that include mental
retardation, cataracts, and liver cirrhosis
Can be prevented by early diagnosis and feeding infants with
milk substitutes that do not contain galactose or lactose
Hereditary Fructose Intolerance
Autosomal recessive, resulting from a deficiency of the
enzyme fructose 1-phosphate aldolase
Affected, present at different ages, depending on when
fructose is introduced into the diet
Symptoms include failure to thrive, vomiting, jaundice, and
seizures
Glycogen Storage Diseases (GSDs)
Glycogen in muscle and liver, acting as a reserve energy
source.
In GSDs glycogen accumulates in excessive amounts
because of a variety of inborn errors of the enzymes
Glycogen Storage Diseases (GSDs)
Primarily Affect Liver
Von Gierke Disease (GSD-I)
Cori Disease (GSD-II)
Anderson Disease (GSD-IV)
Hepatic Phosphorylase Deficiency (GSD- VI)
Primarily Affect Muscle
Pompe Disease (GSD-II)
McArdle Disease (GSD-V)
Glycogen Storage Diseases (GSDs)
Primarily Affect Liver
Von Gierke Disease (GSD-I)
Deficiency of the enzyme glucose-6-phosphatase
Enlarged liver (hepatomegaly) and a fast heart rate due to hypoglycemia
Treatment is frequent feeding and avoidance of fasting
Primarily Affect Muscle
Pompe Disease (GSD-II)
Deficiency of the lysosomal enzyme α-1,4-glucosidase
Usually present in the first few months of life with hypotonia
Delay in the gross motor milestones because of muscle weakness
Develop an enlarged heart and die from cardiac failure in the first or
second year
Familial Hypercholesterolemia
The most common autosomal dominant single-gene disorder in
Western society
Raised cholesterol levels with a significant risk of developing
early coronary artery disease
Dietary restriction of cholesterol intake and drug treatment with
'statins' that reduce the endogenous synthesis of cholesterol
High cholesterol levels are due to deficient or defective function
of the LDL receptors leading to increased levels of endogenous
cholesterol synthesis.
Lysosomal Storage Disorders
Deficiency of a lysosomal enzyme involved in the
degradation of complex macromolecules leads to their
accumulation.
Children are usually normal initially but with the
passage of time commence a downhill course
Mucopolysaccharidoses
Hurler Syndrome (MPS-I)
Hunter Syndrome (MPS-II)
Sanfilippo Syndrome (MPS-III)
Morquio Syndrome (MPS-IV)
Maroteaux-lamy Syndrome (MPS-VI)
Sly Syndrome (MPS-VII)
Hurler and Hunter Syndromes
Tay-Sachs Disease
Infants usually present by 6 months of age with poor feeding,
lethargy, and floppiness.
Developmental regression in late infancy
Feeding becomes increasingly difficult
Progressively deteriorates
Deafness, visual impairment, and spasticity
Death usually occurs by the age of 3 years from respiratory infection
Deficiency of the a subunit of the enzyme β-hexosaminidase that
leads to accumulation of the sphingolipid GM2 ganglioside
Lesch-Nyhan Syndrome
Disorder of purine metabolism, XLR inheritance
Deficiency of hypoxanthine guanine phosphoribosyl
transferase, increased levels of phosphoribosyl pyrophosphate.
An increased rate of purine synthesis and accumulation of
uric acid
The main effect is neurological, with uncontrolled
movements, spasticity, mental retardation and self-mutilation
Menkes Disease
XLR , Serum copper and ceruloplasmin levels are very low
The first few months of life with feeding difficulties, vomiting,
and poor weight gain.
Subsequently, hypotonia, seizures, and progressive
neurological and deterioration ensue,
death from recurrent respiratory infection usually occurring
by the age of 3 years
Caused by mutation in an ATPase cation transport protein for
copper
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Disorders Affecting Mitochondrial Function
Myoclonic Epilepsy and Ragged Red Fiber Disease (MERRF)
Mitochondrial Encephalomyopathy, Lactic Acidosis, and
Stroke-Like Episodes (MELAS)
Neurodegeneration, Ataxia, and Retinitis Pigmentosa (NARP)
Leigh Disease
Leber Hereditary Optic Neuropathy
Barth Syndrome