Genetic disorders

Dr.K.V.Bharathi

Normal karyotype

• Study of chromosomeskaryotyping

• A karyotype is the standard arrangement of a photographed, stained chromosomes pairs which are arranged in order of decreasing length

When chromosomes are preparing to divide, the DNA When chromosomes are preparing to divide, the DNA replicates itself into two strands called chromatidsreplicates itself into two strands called chromatids

Replicating chromosome The same chromosome under normal conditions

Centromere

Telomere

Telomere

The two chromatids

Chromosome nomenclature

• Two arms– p (petite) small and q (follows p in alphabet)

• 1-22 = autosome numbers

• X, Y = sex chromosomes

Cytogenetic terminology• Short arm p and long arm q

• Each Chromosome is divided into 2 or more regions

• Each region is subdivided into bands and sub-bands

• Total no of chromosomes is given first followed by sex chromosome and finally description of abnormality in ascending order.eg:47,XY,+21 ,and Xp 21.2

• 46,XY,del(16)(p11.2 p13.1)

The normal human karyotype

• Somatic cells: 22 pairs of autososmes & 1 pair of sex chromosomes (46,XX or 46,XY).

• The normal karyotype is diploid (2 copies of each chromosome).

• Sperm & eggs carry 23 chromosomes & are haploid (one copy of each chromosome).

What is the difference between an What is the difference between an Autosome and a Sex-chromosome?Autosome and a Sex-chromosome?

AutosomesAutosomes are the first 22 are the first 22 homologous pairs of human homologous pairs of human chromosomes that do not chromosomes that do not influence the sex of an influence the sex of an individual.individual.

Sex ChromosomesSex Chromosomes are the 23 are the 23rdrd pair of chromosomes that pair of chromosomes that determine the sex of an determine the sex of an individual.individual.

• Sperm determines genotypic sex by contributing either an X or a Y chromosome during fertilization.

46,XX = female46,XX = female 46,XY = male46,XY = male

Giemsa banding (G-banding)

Three classes of chromosome

• Metacentric - centromere in middle

• Submetacentric - centromere distant from middle

• Acrocentric - centromere at end

Uses of karyotype analysis:

1. Genotypic sex ( identification of X & Y chromosomes).

2. Ploidy ( euploid, aneuploid or polyploid).

3. Chromosomal structural defects (translocation, isochromosome, deletion etc..).

Some definitions

• Haploid (n)- refers to a single set of chromosomes (23 in humans).Sperm & eggs are haploid.

• Diploid (2n)- refers to a double set of chromosomes (46 in humans). Somatic cells are diploid.

• Euploid- refers to any multiple of the haploid set of chromosomes (from n-8n)

• Polyploid- refers to any multiple of the haploid set of chromosomes> diploid (2n).

• Aneuploid- refers to karyotypes that do not have multiples of the haploid set of chromosomes.

• Monosomy- refers to an aneuploid karyotype with one missing chromosome (XO in Turner’s syndrome).

• Trisomy- refers to an aneuploid karyotype with one extra chromosome (trisomy 21 in Down’s syndrome))

Aneuploidy results from the failure of chromosomes to separate normally during cell division:

Meiotic Nondisjunction

NORMAL SEPARATION

NORMAL ZYGOTE

First meiotic division

Second meiotic division

Gametes

Fertilization

Zygotes

4N

2N

N

2N

NONDISJUNCTION

TRISOMIC ZYGOTE MONOSOMIC ZYGOTE

First meiotic division

Second meiotic division

Gametes

Fertilization

Zygotes

• Aneuploidy usually results from non-disjunction

• Chromosomes or chromatids fails to separate

• An error of mitotic or meiotic spindle attachment to centromere

• May occur in either the maternal or the paternal germ cells

• More commonly arises in the mother• Frequency of non-disjunction increases

with maternal age

Structural abnormalities of chromosomes

Six main types

• Deletion• Ring chromosome• Duplication• Isochromosome• Inversion

– paracentric & pericentric

• Translocation– Robertsonian & reciprocal

• Involves loss of part of a chromosome

• Results in monosomy of that chromosomal segment

• Clinical effects due to– Insufficient gene products– Unmasking of mutant

alleles on normal chromosome

Deletion

Beforedeletion

Afterdeletion

Two types of deletion

Interstitial Terminal

Ring chromosomeBreaks occur in both arms of a chromosome.

The two broken ends anneal; the two acentric fragments are lost.

Results in double deletion (in p and in q).

Epilepsy, mental retardation and craniofacial abnormalities

IsochromosomeIsochromosomeMirror image chromosome

Loss of one arm with duplication of other

Loss of p-arm Duplication of q-arm

InversionTwo breaks in one chromosome

The fragment generated rotates 180o and reinserts into the chromosome

Pericentric - involves p and q armPericentric - involves p and q arm Paracentric - involves only one armParacentric - involves only one arm

Translocation - exchange of chromosomal material between two or more

chromosomes

• Reciprocal

• Robertsonian

• If no essential chromosome material lost or genes damaged then the individual is clinically normal

• However, there is an increased chance of chromosomally unbalanced offspring

Reciprocal Translocation• Involves two chromosomes • One break in each chromosome• The two chromosomes exchange broken segments

Before translocation After translocation

Robertsonian translocation• Named after W. R. B. Robertson who first identified them

in grasshoppers in 1916

• Most common structural chromosome abnormality in humans– Frequency = 1/1000 livebirths

• Involves two acrocentric chromosomes

• Two types– Homologous acrocentrics involved– Non-Homologous acrocentrics involved

Homologous acrocentric, i.e. chromosome 14

+ =

lost

Non-homologous acrocentric, i.e. chromosomes 14 & 21

+ =

lost

A balanced chromosome 14 & 21 A balanced chromosome 14 & 21 Robertsonian translocationRobertsonian translocation

Mutations

What is mutation?

• A mutation may be defined as a permanent change in the DNA.

• These structural DNA changes affect protein expression & function.

Mutations affect protein synthesis

Transcription: Mutated DNA will produce faulty mRNA leading to the production of a faulty protein.

Somatic & Germ cell mutations

Mutations that occur in somatic cells such as skin cells or hair are termed Somatic. Germline mutations occur only in the gametes. These mutations are more threatening because they can be passed to offspring .

• Germline mutations can be transmitted to future generations.

• Those that occur in somatic cells may contribute to the pathogenesis of neoplasia.

• Drugs, chemical & physical agents that increase the rate of mutation act as carcinogens.

Mutagens are agents that cause mutations. They include:1. High Temperatures 2. Toxic Chemicals (pesticides, etc)3. Radiation (nuclear and solar)

Types of mutationsChromosomal mutation: affecting whole or a part of a chromosome

Gene mutation: changes to the bases in the DNA of one gene

Major types of genetic mutations

1. Point mutations: Single base substitutions .

2. Frameshift mutations: base pair insertions or deletions that change the codon reading frame.

3. Large deletions: can result in loss of gene or juxtapose genes to create a hybrid that encodes a new “fusion” protein.

4. Expansion of trinucleotide repeats: can arise in genes that have repeated sequences. Affected patients can have 100s or 1000s of repeats (normal:10-30).

Gene Mutations: DNA base alterations

Point mutation- eg:sickle cell anemiaInsertionDeletionInversionFrame Shifts

Point mutation - when a base is replaced with a different base.

CGG CCC AAT to CGG CGC AAT Guanine for Cytosine

Insertion - when a base is added

CGG CCC AAT to CGG CGC CAA T Guanine is added

Deletion - the loss of a base

CGG CCC AAT to CGG CCA A T loss of Cytosine

Frame Shift mutations• A frame shift mutation results from a base

deletion or insertion. Each of these changes the triplets that follow the mutation.

CGG CCC AAT to CGG CGC CAA T

• Frame shift mutations have greater effects than a point mutation because they involve more triplets.

• This in turn changes the amino acids of the protein!

Classification of genetic disorders

1.Gross chromosomal abnormalities 2.Diseases with multifactorial inheritance

3.Disorders related to mutant genes of large effect

Cytogenetic disorders involving autosomes

Common types of trisomy

• Trisomy 21 - Down's Syndrome- karyotype 47, XX +21 or 47, XY+21- frequency about 1 in 600 births

• Trisomy 18 - Edward's Syndrome- karyotype 47, XX +18 or 47, XY+18- frequency about 1 in 8,000births

• Trisomy 13 - Patau's Syndrome- karyotype 47, XX +13 or 47, XY+13- frequency about 1 in 10,000 births

• Sex chromosome trisomies- 47, XXY (Klinefelter Syndrome), 47,XXX,

47,XYY

• Triploidies of other chromosomes– Rare– usually incompatible with life

• - Polysomy X e.g. XXXX– - Frequency about 1 in 1000

Trisomy 21(Down’s syndrome)

The most common malformation Incidence: 1 per 660 live births, closely

related to maternal ageMother’s age<30 year risk:1 per 5000Mother’s age>35 year risk:1 per 250

Clinical findings

• Flattened face • Mental retardation• Congenital heart disease:50%endocardial

cushion,ASD,AV malformation,VSD• 10 to 20 fold increased risk of developing

leukemia• Infection are common• Premature agingall patints older than 40 will

have Alzheimer disease(degenerative disorder of brain)

• Musculoskeletal problems

Normal karyotypeTrisomy 21

Trisomy 18(Edwards syndrome)

Trisomy 18

• Incidence :1 in 8000 births

• Karyotypes:– 47,xx+18– 46,xx/47,xx+18

Micrognathia and prominent occiput

Trisomy 13(Patau syndrome)

Trisomy 13

• Incidence :1 in 15,0000• Karyotypes:

– Trisomy13 type:47xx+13

– Translocation type:46,xx,+13,der(13;14)(q10;q10)

– Mosaic type:46,xx/47,xx,+13

Cleft lip

Cleft palate

Rockerbottom feet

Cytogenetic diorders involving sex chromosomes

• They cause chronic problems relating to sexual development and fertility

• They are often difficult to diagnose at birth,and many are recognised at the time of puberty

• Higher the number of x chromosomes, greater the likelihood of mental retardation

Lyon hypothesis:• In somatic cells of a female

only one of the X chromosomes is active

• X-inactivation– Occurs early in embryonic life– Is random

• either paternal or maternal X– Is complete– Is permanent– Is clonally propagated through

mitosis

Mary Lyon

Y chromosome

• Regardless of the number of X chromosomes, the presence of single Y determines male sex

• The gene that indicates testicular development is sry gene (sex determining region Y gene)

• Located on distal arm of Y chromosome

Turner syndrome

• Partial monosomy of X chromosome• Hypogonadism in phenotypic females• Karyotype:45,X

Mosaic patients with 45,X /46,XX• Cystic hygromas, Congenital heart disease

(coarctation of aorta and bicuspid aortic valve), failure to develop secondary sexual characterstics

• Mental status is usually normal

Klinefelter syndrome

• 47,XXY

• Results from meiotic nondisjunction

• The discovery of the karyotype of Klinefelter was the first demonstration that sex in humans is determined by the presence of the Y rather than the number of X chromosomes

• Male hypogonadism

Klinefelter syndromeKlinefelter syndrome

• Lower IQ than sibsLower IQ than sibs

• Tall statureTall stature

• Poor muscle tonePoor muscle tone

• Reduced secondaryReduced secondarysexual characteristicssexual characteristics

• Gynaecomastia Gynaecomastia (male breasts)(male breasts)

• Small testes/infertilitySmall testes/infertility

• Plasma gonadotropin levels( FSH) and estrodiol is elevated

• Testosterone levels are decreased

• Testicular tubules are totally atrophied

• Some shows primitive tubules

Hermaphroditism

• Genetic sex is determined by the presence or absence of Y chromosome

• Gonadal sex is based on histological characteristics of gonads

• Phenotypic sex is based on the appearance of external genitalia

• True hermaphrodite implies the presence of both ovarian and testicular tissue

• Pseudohermaphrodite represents disagreement between the phenotypic and gonadal sex (eg:female pseudohermophrodite has ovaries but male external genitalia)

Transmisson patterns of single gene disorders

• Autosomal dominant

• Autosomal recessive

• X-linked

Autosomal TraitsAutosomal Traits Genes located on Autosomes control Genes located on Autosomes control

Autosomal traits and disorders.Autosomal traits and disorders.

2 Types of Traits:2 Types of Traits: Autosomal DominantAutosomal Dominant Autosomal RecessiveAutosomal Recessive

Autosomal Dominant TraitsAutosomal Dominant Traits

If dominant allele is present on the autosome, then the If dominant allele is present on the autosome, then the individual will express the trait.individual will express the trait.

A = dominant a = recessiveA = dominant a = recessive

What would be the genotype of an individual with an What would be the genotype of an individual with an autosomal dominant trait?autosomal dominant trait?– AA and Aa (Heterozygotes are affected)AA and Aa (Heterozygotes are affected)

Autosomal Dominant InheritanceAutosomal Dominant Inheritance Are manifested in heterozygous stateAre manifested in heterozygous state One parent of an index case is usually affectedOne parent of an index case is usually affected Both males and females are affected and both can transmit Both males and females are affected and both can transmit

the conditionthe condition 50% chance of affected heterozygote passing gene to 50% chance of affected heterozygote passing gene to

childrenchildren A new mutation in the gene resulting in the offspring being A new mutation in the gene resulting in the offspring being

first affected and then may be inherited in a dominant first affected and then may be inherited in a dominant fashion fashion

Dominant genes may exhibit lack of penetrance, which is Dominant genes may exhibit lack of penetrance, which is an all or none phenomenon; either the gene is expressed or an all or none phenomenon; either the gene is expressed or not expressednot expressed

May show variable expressivity with different family May show variable expressivity with different family members showing different manifestations of the traitmembers showing different manifestations of the trait

Autosomal Dominant InheritanceAutosomal Dominant Inheritance

System Disorder

Nervous •Huntington disease.•Neurofibromatosis.•Myotonic dystrophy.•Tuberous sclerosis.

Urinary •Polycystic

kidney disease

G.I.T •Familial polyposis coli

Hematopoietic •Hereditary spherocytosis•Von Willebrand disease

Skeletal •Marfan syndrome,

•Osteogenesis imperfecta,

•Achondroplasia

Metabolic •Familial hypercholesterolemia,

•Acute intermittent porphyria

Autosomal Recessive TraitsAutosomal Recessive Traits

If dominant allele is present on the autosome, then the If dominant allele is present on the autosome, then the individual will not express the trait. individual will not express the trait.

In order to express the trait, two recessive alleles In order to express the trait, two recessive alleles

must be present.must be present.

• A = dominant a = recessiveA = dominant a = recessive

• What would be the genotype of an individual What would be the genotype of an individual with an autosomal recessive trait?with an autosomal recessive trait?– aaaa

• What would be the genotype of an individual What would be the genotype of an individual without the autosomal recessive trait?without the autosomal recessive trait?– AA or Aa AA or Aa – Aa – called a Aa – called a CarrierCarrier because they carry the because they carry the

recessive allele and can pass it on to offspring, recessive allele and can pass it on to offspring, but they do not express the trait.but they do not express the trait.

Autosomal Recessive TraitsAutosomal Recessive Traits Heterozygotes are Carriers with a normal phenotype.Heterozygotes are Carriers with a normal phenotype. Most affected children have normal parents. (Aa x Aa)Most affected children have normal parents. (Aa x Aa) Two affected parents will always produce an affected child. Two affected parents will always produce an affected child.

(aa x aa)(aa x aa) Close relatives who reproduce are more likely to have affected Close relatives who reproduce are more likely to have affected

children.children. Both males and females are affected with equal frequency.Both males and females are affected with equal frequency. Pedigrees show Pedigrees show bothboth male and female carriers. male and female carriers. Complete penetrance is commonComplete penetrance is common Onset is early in lifeOnset is early in life

System Disorder Metabolic •Cystic fibrosis,

•Phenylketonurua,•Galactosemia, •Homocystinuria,•Lysosomal storage diseases,

•Α1-antitrypsion deficiency,

•Wilson disease,•Hemochromatosis,•Glycogen stroage diorders

Hematopoietic Sickle cell anaemia,Thalassemia.

Endocrine Congenital adrenal hyperplasia

Skeletal Alkaptonuria

Nervous Neurogenic muscular atrophies,Friedreich ataxia, Spinal muscular atrophy.

X-Linked InheritanceX-Linked Inheritance

Involves particular genes located on the X Involves particular genes located on the X chromosomechromosome

Disorders more commonly affect malesDisorders more commonly affect males Heterozygote female will pass the gene to 50% of Heterozygote female will pass the gene to 50% of

her sons who will express the trait, and to 50% of her sons who will express the trait, and to 50% of her daughters who will be carriers for the traither daughters who will be carriers for the trait

Affected males pass the gene to all of their Affected males pass the gene to all of their daughters and none of their sonsdaughters and none of their sons

Hallmark is absence of male to male transmissionHallmark is absence of male to male transmission

X-Linked InheritanceX-Linked Inheritance

System Disease

Musculoskeletal Duchenne muscular dystrophy

Blood Hemophilia A and B,Chronic granulomatous disease, glucose -6-phophate dehyderogenase deficiency

Immune Agammaglobulinemia,Wiskott-aldrich syndrome

Metabolic Diabetes insipidus, Lesch-Nyhan syndrome

Nervous Fragile-X syndrome

Single gene disorders

1.With classical (Mendelian) inheritance2.With non-classical inheritance •Mitochondrial genes •Trinucleotide repeats •Genetic imprinting

Single-Gene “Mendelian” Disorders

1. Structural proteins– –Osteogenesis imperfecta and Ehlers-Danlos(collagens); – Marfan syndrome (fibrillin); – Duchenne and Becker muscular dystrophies (dystrophin)

2. Enzymes and inhibitors– Lysosomalstorage diseases;– PKU (phenylalanine hydroxylase); – Alpha-1 antitrypsin deficiency

3. Receptors– Familial hypercholesterolemia (LDL receptor)

4. Cell growth regulation– Neurofibromatosis type I (neurofibromin); – Hereditary retinoblastoma (Rb)

5. Transporters– Cystic fibrosis (CFTR); – Sickle cell disease (Hb); – Thalassemias(Hb)

Marfan syndrome (defect in the structural proteins)

• Is a disorder of connective tissues, manifested by changes in skeleton,eyes and cardiovascular system

• Autosomal dominant

Pathogenesis

• Marfan syndrome results from inherited defect in extracellular glycoprotein –fibrillin-1

• Fibrillin is the major component microfibrils• These fibrils form a basement on which

tropoelastin is deposited to form elastic fibers• Microfibrils are abundant in aorta, ligaments,and

ciliary zonules of lens• Mutations of FBN1 are mapped on the

chromosome 15q21.

Morphology

• Cardiovascular System: Dilatation of ascending aorta due to cystic medial necrosis, mitral vale insufficiency,aortic dissection

• Eyes: Dislocation of lens (usually outward and upward) called as ectopia lentis, severe myopia

• Musculoskeletal: exceptionally tall with long extremities and tapering fingers and toes– The ratio of upper segment to the lower segment of

the body is lower than normal– Joint ligaments of hands and feet are lax;typically

thumb can be hyperextended back to the wrist– The head is dolicocephlic(long headed) with bossing

of frontal eminences– Pectus excavatum deformity, scoliosis

Marfan Syndrome

Subluxation of the lens

Ehlers-Danlos Syndrome

• A family of disorders with defect in synthesis and structure of fibrillar collagen characterized by hyperextensibility of skin, joint hypermobility, early bruisability

• Mode of inheritence show all three types of Mendelian patterns

• Orthopaedic problems: joint instability, joint laxity, arthralgia and scoliosis

Lysosomal storage disorders(defects in enzymes)

• Key component of intracellular “digestive” tract

• Composed of acid hydrolases that catalyse the breakdown of macromolecules

• Inherited deficiency-catabolism of macromolecules is incomplete accumulation of partially degraded macromoleculescell organelles become largelysosomal storage disease

Tay-Sachs disease (Gm2 gangliosidosis: Hexosaminidase α-subunit deficiency)

Cause of Tay-Sachs

Hex-A Accumulation of GM2 in neuronsAbsence of

Involvement of CNS, ANS and retina common

The absence of a vital enzyme called Hexosamindase A (Hex-A)

Gene Location

• Chromosome 15 showing location of the syndrome

Characteristics

• Birth: Appear normal

• 6 months: Development slows

• 2 years: Seizures and deteriorating mental functions

• 3 years: Blindness, mentally retardation, paralysis and non-responsiveness.

• Cherry red spot in the macula• Common in Jews

• Microscopy: neurons are ballooned with cytoplasmic vacuoles having lysosomes filled with gangliosides

• EM: Whorled configuration with lysosomes composed of “onion skin” layer of membranes

Ballooned out neuron

Detection Methods:

• Amniocentesis

• Chorionic villus sampling

• Blood samples to detect carriers

In Summary

• Tay-Sachs is a genetic disorder that causes Hex-A, an enzyme important to the function of nerve cells, not to be produced.

• Babies with Tay-Sachs often appear normal at birth, but develop severe symptoms in the first few years of life.

• There is genetic counseling as well as support groups available for carriers of Tay-Sachs or parents with an affected child.

Niemann –pick disease (type A and B)

• Deficiency of sphingomyelinase accumulation of sphingomyelin

Type A

• More severe infantile form with extensive neurological involvement

• Marked visceral accumulation of sphingomyelin

• Progressive wasting and early death within 3 years

• Cherry red spot in the macula

Type B

• Patients have organomegaly but no CNS involvement

• Survive to adulthood.

Morphology

• Accumulation of sphingomyelin in mononuclear phagocytes

• Affected cell become large

• Innumerable small vacuoles of uniform sizeimparting foaminess to the cytoplasm

• Vacuoles stain for fat

• Phagocytic foam cells widely distributed in spleen ,liver, lymph node, bone marrow, tonsils, g.i.t,lungs

• Brain: Gyri shrunkened,sulci widened with vacuolation and ballooning of neurons

• EM: zebra bodies

• Clinical Features: Evident by 6 monthsProtuberant abdomenFailure to thrive, vomiting,fever,Deterioration of psychomotor functionDeath by 2 yrs

Gaucher disease

• Autosomal recessive

• Mutation in the gene encoding glucocerebrosidase

• Most common

• Glucocerebroside accumulates in phagocytic cells

• 3 types

Type I: Chronic non-neuronopathic formStorage limited to mononuclear phagocytes throughout the

body

Splenic and skeletal involvement common

Type II: acute neuronopathic ,dominated by CNS involvement,death by 2 years

TypeIII: intermediate between I and II, progressive CNS involvement

Morphology

• Glucocerebrosides accumulates in phagocytic cells

• Distended phagocytic cells (Gaucher)cells found in spleen liver,BM,LN,TONSILS,thymus and peyer patches

• Cells have fibrillary pattern instead of vacuolated (crumpled tissue paper )and have eccentrically placed nucleus.

Gaucher cells (Phagocytic cells with a “crumpled tissue paper” appearance)

Phenylketonuria

• Autosomal recessive disorder• Deficiency of phenylalanine hydroxylase

hyperphenylalaninemia• Common in scandinavian people• Normal at birth• By 6 months severe mental retardation• Seizures,decreased pigmentation of hair and skin• Mental retardation can be avoided by restriction

of phenylalanine intake early in life

Galactosemia

• Autosomal recessive disorder

• Deficiency of galactose -1-phosphate uridyl transferase

• Galactose -1-phosphate accumulates in liver, spleen, kidneys, lens of eye, cerebral corex

• Alternative metabolic pathways activated, leading to the production of galacitol

Clinical features

• Failure to thrive

• Vomiting, diarrhea

• Hepatomegaly

• Opacification of lens (cataracts)

• Aminoaciduria

• Diagnosis can be suspected by demonstration in the urine of reducing sugars

• Many morphological changes can be prevented by early removal of galactose from diet

Oochronosis (alkaptonuria)

• First human inborn error of metabolism to be discovered

• Autosomal recessive• Lack of homogentisic oxidase blocks

metabolism of phenylalanine-tyrosine at the level of homogentisic acid

• Homogentisic acid accumulates in the body• Large amount is excreted,imparting a black

color to the urine if allowed to stand

Morphology

• The retained homogentisic acid selectively binds to collagen in connective tissues, tendons ,cartillage imparting blue black pigmentation

• Most evident in the ears, nose and cheeks.

• Wear and tear erosion of abnormal cartilage leads to denudation of subchondral bonedegenerative arthropathy

Mucopolysaccharidoses

• Result from genetic deficiency of enzymes involved in the degradation of mucopolysaccharides

• Progressive disorder chacterised by involvement of multiple organs like liver,spleen, heart and blood vessels

• Most are associated with coarse facial features,joint stiffness and mental retardation

• The accumulated mucopolysaccharides are grnerally found in mononuclear phagocytic cells,endothelial cells,smooth muscle cells and fibroblsts.

Glycogen storage diseases

• Hereditary deficiency of one of the enzymes involved in the synthesis and breakdown of glycogen.

• Hepatic form: an inherited deficiency of hepatic enzymes involved in glycogen metabolism leads to storage of glycogen in liver and also hypoglycemia.eg :deficiency of glucose-6-phosphatase

• Myopathic form:in muscles glycogen is mainly used as a source of energy

• If the enzymes that fuel glycolytic pathway are deficient, glycogen storage occurs in muscles.

• eg: deficiency of muscle phosphofructokinase, muscle phosphorylase

Emphasize on:

1. Down’s syndrome

2. Turner’s syndrome

3. Klinefelter syndrome

4. Marfan syndrome

5. Gaucher’s disease

Thank you