2. 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

3. Protein and Gene Structure
زنجیره آلفا 141 اسید آمینه و زنجیره بتا 146

5. 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

6. 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.

7. Sickle Cell Disease Mutation
The amino acid valine, at the sixth position of the β-globin chain, is substituted by glutamic acid.

8. 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
excessive α chains are more haemolytic than β chains

9. α Thalassemia Two main types of α-thalassemia: The severe form
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

10. Normal and Deleted α-globin Structural Genes

11. 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.

12. β Thalassemia Major Bone Changes

13. 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
اکثرا مغلوبند

14. Disorders of Amino Acid Metabolism

15. 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
tetrahydrobiopterin
So rare Why screen??

16. Treated and untreated PKU

17. 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.

18. 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 movements- nystagmus
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

19. Oculocutaneous Albinism

20. Disorders of Monosaccharide Metabolism
Galactosemia
Hereditary Fructose Intolerance

21. 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

22. 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

23. 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

24. 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)

25. 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

26. 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.
Disorders of Lipid Metabolism

27. 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

28. 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)

29. Hurler and Hunter Syndromes

30. 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
Sphingolipidoses (Lipid Storage Diseases)
اشکنازی

31. 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
Purine/Pyrimidine Metabolism
پیش ساز سنتز پورین ها

33. 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
Copper Metabolism ( menkes and Wilson)

34. 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