J a v a d J a m s h i d i

F a s a 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 4

S e s s i o n 7Medical Genetics

Hemoglobinopathies and Biochemical Genetics

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

Some 200 of these electrophoretic variants are single amino acid substitutions resulting from a point 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 ThalassemiaResults from underproduction of the α-globin chains and occurs most commonly in Southeast Asia

Two main types of α-thalassemia:

The severe formNo α chains are produced, fetal deathHydrops fetalisTetramer of γ chains, called Hb Barts

The milder formSome α chains but still a relative excess of β chainsβ -globin tetramer Hb H-known as Hb H disease

Normal and Deleted α-globin Structural Genes

β ThalassemiaCaused by underproduction of the β-globin chain of Hb.

Two main types of β-thalassemia:

The major formHomozygotes for β chains defect, Cooley's anemiaSevere transfusion-dependent anemiaAn unusually shaped face and skullAffected individuals used to die in their teens or early adulthood

The minor formHeterozygotes for β chains defectUsually have no symptoms or signs

Mild hypochromic, microcytic anemia, may be confused with iron deficiency anemia.

β Thalassemia Major Bone Changes

Biochemical DisordersAmino 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

PhenylketonuriaDeficiency of the enzyme required for the conversion of phenylalanine to tyrosine, phenylalanine hydroxylase (PAH)

Children with phenylketonuria (PKU), if untreatedSeverely intellectually impaired Often develop seizuresOften have blond hair and blue eyes

Treatment by controlling phenylalanine diet intake

Deficiency of dihydropteridine reductase or dihydrobiopterin synthase

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 tyrosin

Lack of pigment in the skin, hair, iris, and ocular fundusPoor visual acuity and uncontrolled pendular eye movements-nystagmus

OCA is genetically and biochemically heterogeneous.

OCA1, defective tyrosinase gene, tyrosinase-negative and positive forms, 11qOCA2, mutation in the P gene locates on 15qThere are some other locouses

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

Because of the metabolic block, glycogen is unavailable, result in hypoglycemia, impairment of liver function and neurological abnormalities.

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 in 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 Syndrome

The most severe MPS

Infants present in the first year with corneal clouding, and subsequent poor growth.

Develop hearing loss, coarse facial features, an enlarged liver and spleen in the second year.

These features progress with mental deterioration and eventually death by mid-adolescence from a combination of cardiac failure and respiratory infections.

Reduced activity of the lysosomal hydrolase, α-L-iduronidase

Hurler and Hunter Syndromes

Tay-Sachs DiseaseInfants 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 DiseaseXLR , 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

Zellweger Syndrome

Newborn infants present with hypotonia and weakness and have mildly dysmorphic facial features

May also have cataracts and an enlarged liver

Generally go on to have fits with developmental regression and usually die by 1 year of age.

Peroxisome biogenesis defect, It is genetically heterogeneous

Zellweger Syndrome

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