Genetics

Mendelian Disorders

DR I.F. EZEJIOFOR
MBBS, FWACP, FMCPath
CONSULTANT HISTOPATHOLOGIST NAUTH, NNEWI
MENDELIAN DISORDERS
• All Mendelian disorders are the result of mutations in single genes
that have large effects.
• Every person carries 5-8 deleterious genes, but most of these genes
are recessive & therefore do not have serious phenotypic effects.
• About 80% to 85% of these mutations are familial while the rest are
new mutation.
IMPORTANT WORDS IN MENDELIAN’S
DXs
Mendelian traits are usually described as
ALLeles: Different forms of the same gene. Humans have 2 alleles, or 2
forms of every gene b/c we are known as diploid organisms with one
allele inherited from each parent. Different forms of the same gene
may also occurs due to imprinting of one allele (AA, aa, or Aa alleles in
the same locus of gene in different individuals)
ALLELS
IMPORTANT WORDS IN MENDELIAN’S
DXs
• Dominant; When a pair of the gene alleles is expressed.
• Recessive gene; is a gene whose effects are masked or hidden in a presence of a
dominant gene. It is only expressed when an organism has 2 recessive alleles for that
gene.
• Codominance; when both alleles are expressed equally, both alleles may be
dominant (Blood grp AB) or recessive(blood grp O) Examples are blood group
antigens & Histocompatibility.
• Pleiotropism; A single mutant gene leading to many end effects/many numbers of
phenotypic effect e.g SSDx, down syndrome.
• Genetic heterogeneity; this occurs when there are mutations at several genetic loci
but it produces the same trait/or the same phenotype e.g childhood deafness &
diabetes mellitus.
Transmission Patterns of Single-Gene
Disorders in Mendelian
They have three patterns of inheritance:
• Autosomal dominant,
• Autosomal recessive= largest category of Mendelian disorders.
• X-linked.
QUESTIONS?
• Can Autosomal Recessive gene manifest as heterozygote OR homozygote?
• NO; Because SSDx although (HbAS heterozygote: HbSS homozygote) can
only manifest in homozygote form.
• How will they present? Heterozygote here is asymptomatic

• Can Autosomal Dominant gene be heterozygote OR homozygote ?

• YES e.g familial hypercholesterinaemia
• How will they present? Both heterozygote & homozygote are
symptomatic with worsening symptoms in homozygote form
Mendelian disorders
• Autosomal mutations can be; heterozygote/homozygote
• In Homozygous mutant gene of SSDx,(HbSS) all the haemoglobin is of
the abnormal type (HbS) & even with normal oxygen tension the
disorder is fully expressed (i.e., sickling deformity of all red cells & full-
blown sickle cell anaemia).
• In heterozygote(HbAS), only a proportion of the haemoglobin is
abnormal (HbS) others are normal (HbA), & therefore red cell sickling
occurs only under lowered oxygen tension. This is referred to as the
sickle cell trait
(1) Features of Autosomal Dominant
Disorders
• Autosomal dominant disorders manifest in the *heterozygous* state,
showing that one of the parent of an index case is usually affected; &
that their offspring (both males & females are affected) can transmit
the condition to their generation.

• But if the affected offspring marries an unaffected one, every child

has one chance in two (50% chance)of having the disease and the
other 50% will not even be a carrier. This is true for each pregnancy
Other Features of autosomal dominant
conditions
• (1) Some proportion of patients with autosomal dominant disorder do
not have affected parents their disorder is from new mutations of
either the egg or the sperm of their parents from which they were
derived from. Their siblings are not affected in anyway. Majority of
times this new mutations occurs in germ cells of relatively older
fathers.
Other Features of autosomal dominant
conditions
• (2) Clinical features can be modified by incomplete penetrance & variable expressivity.
• Incomplete penetrance: Some pts may have mutant gene but physically look
normal. Penetrance is expressed in mathematical terms. Thus, 50% penetrance
indicates that 50% of those with mutant gene will express the trait.
• Variable expressivity: when all the individuals carrying mutant genes
express different phenotypic traits from one another. = this variability occur due to
environment/effect of other genes

• E;g familial hypercholesterolemia its expression in the form of atherosclerosis is majorly

due to dietary intake of lipids
Other Features of autosomal dominant
conditions
• (3) In many conditions of autosomal dominant disorders the age at
onset of symptoms is delayed (e.g Huntington dx the symptoms
appear at adulthood)
• (4) The biochemical mechanisms of autosomal dominant disorders
depend upon the nature of the mutation and the type of protein
involved. (i) Membrane receptors; e.g LDL-receptor, (ii) Key Structural
proteins (Collagen and cytoskeletal elements).
Other Features of autosomal dominant
conditions
• Collagen is normally a trimeric molecule, mutation in any of the three
collagen chains will prevent its formation ie ones one chain is mutated
it has a negative effect on the others (dominant negative/loss of
function mutation) e.g osteogenesis imperfecta
List of Autosomal Dominant Disorders

• Nervous; Huntington disease, Neurofibromatosis, Myotonic dystrophy

& Tuberous sclerosis
• Urinary; Adult Polycystic kidney disease
• Gastrointestinal; Familial polyposis coli
• Hematopoietic; Hereditary spherocytosis, Von Willebrand disease
• Skeletal; Marfan syndrome* Ehlers-Danlos syndrome (some
variants)* Osteogenesis imperfect, Achondroplasia
• Metabolic; Familial hypercholesterolemia* Acute intermittent
porphyria
(2) Autosomal Recessive Disorders
• They manifest only when both alleles at a given gene locus are
mutated (ie homozygote autosomal recessive individual).
• To have an autosomal recessive disorder, the individual must inherit 2
mutant genes from each parent.
• These disorder are usually passed on by 2 carriers = mother & father
who are asymptomatic heterozygote autosomal recessive individual
Features of autosomal Recessive Disorders
• (1) the parents with the heterogeneous mutant genes do not show phenotypic
trait but their siblings may show the disease.
• (2) siblings have one chance in four of having the trait (i.e. is 25% chance for
each birth)
• (3) if the mutant gene occurs with a low frequency in the population, there is a
strong likelihood that the affected individual (proband) is the product of a
consanguineous marriage.
• (4)The expression of the defect tends to be more uniform not variable
expressivity seen in autosomal dominant disorders. Example Albinism
• (5) Complete penetrance is common. Example Albinism
• (6) Onset is frequently early in life.
Features of autosomal Recessive Disorders
• (7) New mutations can also occur with autosomal recessive disorders
but it rarely detected clinically Since the individual with a new
mutation is an asymptomatic heterozygote, several generations may
pass before the descendants of such a person mate with other
heterozygotes and produce affected offspring.

• (8) Majority of recessive disorder mutant genes encode enzymes

(almost all inborn errors of metabolism), not membrane receptor or
key structural proteins as seen in Autosomal dominant disorders.
List of some Autosomal Recessive Disorders

• Metabolic; Cystic fibrosis, Phenylketonuria, Galactosemia, Wilson

disease, Homocystinuria, Lysosomal storage diseases*,α1-Antitrypsin
deficiency, Hemochromatosis, Glycogen storage diseases*
• Hematopoietic; Sickle cell anemia, Thalassemias.
• Endocrine; Congenital adrenal hyperplasia
• Skeletal; Ehlers-Danlos syndrome (some variants)*Alkaptonuria*
• Nervous; Neurogenic muscular atrophies, Friedreich ataxia,Spinal
muscular atrophy
(3) X-Linked Disorders
• All sex-linked disorders are X-linked recessive except only a few X-
linked dominant conditions example is (Vitamin D–resistant rickets).
• There is no Y-linked inheritance, once Y-gene is mutated, the males
are infertile.
• Female sex chromosomes are XX which are homologous to each other
but male sex chromosomes are XY which are not homologous but
hemizygous to each other.
• Hemizygous; is present of only one copy of a gene in a diploid cells e.g
XY
Features of X-Linked recessive Disorders
• (4) Sons of heterozygous women will have one chance in two (50%
chance)of receiving the mutant gene.
• (5) In X-linked dominant disorder, heterozygous female will
transmitted the disorder to half her sons and half her daughters but
affected male parent will transmit to all his daughters but none of his
sons, if the female parent is unaffected.
Features of X-Linked recessive Disorders
• (1) The heterozygous X-Linked recessive female should not express the
full phenotypic change due to paired normal allele but due to lyonization,
the presentation would be different When the inactivation affects the
mutant X gene the female will be protected but if the inactivation affects
the normal X gene the female will have full expression of the trait.
• (2) In affected male (XY=hemizygous) since the only X he has is MUTATED,
which does not have corresponding alleles on the Y gene, & there is no
Lyonization in his only X chromosome he will show full expression of the
disease.
• (3)An affected male does not transmit the disorder to his sons, but all his
daughters would be carriers
List of X-Linked Recessive Disorders
• Musculoskeletal; Duchenne muscular dystrophy
• Blood; Hemophilia A and B, Chronic granulomatous disease, Glucose-
6-phosphate dehydrogenase deficiency.
• Immune; Agammaglobulinemia, Wiskott-Aldrich syndrome.
• Metabolic; Diabetes insipidus, Lesch-Nyhan syndrome.
• Nervous; Fragile X syndrome
Pathogenesis/ Molecular Basis of Single-Gene in Mendelian
Disorders
• The genetic defect may lead to the formation of an
• abnormal protein
• or protein reduction
• or increase in the intermediate products.
• Mechanisms of single-gene disorders is classified into 4 categories
(1) Enzyme defects and their consequences
(2) Defects in membrane receptors & transport systems
(3) Alterations in the structure, function, or quantity of non-enzyme Proteins
(4) Mutations resulting in unusual reactions to drugs
(1)Mutations in Enzyme

This can lead to Enzyme defects and their consequences

=Accumulation of the intermediate products within the cell organelles LYSOSOMAL
STORAGE DISEASES.
= Reduced amount of end product (melanin) due to Lack of tyrosinase with ↑
injurious intermediate product= ALBINISM
= Loss of end product which has negative feedback to the enzyme initiating the
rxn results in accumulation of intermediate product which is injurious = Lesch-
Nyhan syndrome
= Lack of enzyme will also result in accumulation of a tissue-damaging
substrate e.g in patient with deficiency of α1-antitrypsin will lead to
accumulation of neutrophil elastase in the lungs resulting in emphysema.
(2) Mutation/Defects in Receptors and Transport Systems

Mutations in the receptors

=LDL receptors= familial hypercholesterolemia
= Vitamin-D-receptor= Vitamin-D–resistant rickets
Mutation in transport system
=Ion-channels (for chloride ions in exocrine glands)= cystic fibrosis
= Transport-Oxygen (Hemoglobins)= α-Thalassemia, β-Thalassemia
Sickle cell anemia
3) Mutations/Alterations in Structure, Function, or
(
Quantity of Non-enzyme Proteins

=defects in the structure of the globin molecule = sickle cell disease

= defect in amount of globin chains synthesized = Thalassemias
= defective structural proteins of collagen= osteogenesis imperfect,
EDSs, Alport syndrome & epidermolysis bullosa
= defective structural proteins of spectrin= hereditary spherocytosis
= defective structural proteins of dystrophin= muscular dystrophies
(4) Genetically Determined Adverse Reactions to
Drugs
Certain genetically determined enzyme deficiencies are unmasked
only after exposure of the affected individual to certain drugs=this is
called PHARMACOGENETICS e.g glucose-6 phosphate-dehydrogenase
(G6PD) deficiency= it occurs on administration of antimalarial drugs and
other drugs

In X-Linked Recessive Disorders

There is Full expression in male
Full expression only occur in females homozygote or heterozygous
with random inactivation of normal X chromosome.
Disorders Associated with
Defects in Structural Proteins
(extracellular structures)
•Marfan syndrome
•Ehlers-Danlos syndromes
(EDSs)
Marfan Syndrome
• Marfan syndrome is an autosomal dominant disorder of connective
tissues, manifested principally by changes in the skeleton, eyes, and
cardiovascular system.
• Its prevalence is estimated to be 1 in 5000.
• Approximately 70% to 85% of cases are familial the rest are sporadic
mainly from new mutations
• MS occur due to defect in an extracellular glycoprotein called
fibrillin. Fibrillin occurs in two forms, fibrillin-1 (encoded by FBN1
gene on chromosomes 15q21.1) while fibrillin-2 (encoded by FBN2
gene on chromosome 5q23.31).
Marfan Syndrome
• Mutations of FBN1 underlie Marfan syndrome; while mutations of the
FBN2 gene are less common but rather give rise to congenital
contractural arachnodactyly, an autosomal dominant disorder
characterized by skeletal abnormalities.
Congenital contractural arachnodactyly
Congenital contractural arachnodactyly
Pathogenesis of Marfan syndrome
• Fibrillin is the major component of microfibrils found in the
extracellular matrix widely distributed in the body, but more
abundant in the aorta, ligaments, and the ciliary zonules of the lens.
• These microfibrils provide a scaffolding on which tropoelastin is
deposited to form elastic fibres.
• (1) Mutations (missense mutation) on FBN1 gene will give rise to
abnormal fibrillin-1 which cannot polymerize into microfibrils
(dominant negative effect)/or reduction of fibrillin content weakens
the C.T (haploinsufficiency)
Pathogenesis of Marfan syndrome
• (2) Normal microfibrils sequester TGF-β and thus control the
bioavailability of this cytokine. Loss of microfibrils gives rise to
abnormal and excessive activation of transforming growth factor-β
(TGF-β).
• Excessive TGF-β signaling has deleterious effects on vascular smooth
muscle development and it also increases the activity of
metalloproteases, causing loss of extracellular matrix
MORPHOLOGY OF MS
• Skeletal abnormalities are the most striking feature.
• The pt is unusually tall with exceptionally long extremities & long, tapering
fingers & toes.
• The joint ligaments in the hands & feet are lax, suggesting that the patient is
double-jointed; & the thumb can hyperextend back to the wrist.
• The head is commonly dolichocephalic (long-headed) with bossing of the frontal
eminences & prominent supraorbital ridges.
• A variety of spinal deformities such as kyphosis, scoliosis, or rotation or slipping
of the dorsal or lumbar vertebrae may appear.
• The chest is classically deformed, presenting either pectus excavatum (deeply
depressed sternum) or a pigeon-breast deformity.
MORPHOLOGY OF Marfan Syndrome
• The ocular changes take many forms.
• Most characteristic is bilateral subluxation or dislocation (usually
outward & upward) of the lens, referred to as ectopia lentis =This is
specific for pt with MS.
Ectopic lentis (dislocation of lens outward &
upward )
MORPHOLOGY OF Marfan Syndrome
• Cardiovascular lesions are the most life-threatening features of this
disorder.
• The two most common lesions are mitral valve prolapse and aortic
incompetence or aortic dissection or aortic aneurysm (due to cystic
medionecrosis of the ascending aorta)
Clinical features
MS show great variation in the clinical expression of the dx.
• Patients with prominent eye or cardiovascular changes may have few
skeletal abnormalities, while those with striking skeletal changes will
have no eye changes.
• This variations are due to multiple mutations on FBN1 gene (about
600 missense mutations)
Diagnosis
• Because of these variations, the clinical diagnosis of MS is based on
“revised Ghent criteria.”
• These take into account family history
• Cardinal clinical signs in the absence of family history
• Presence or absence of fibrillin mutation.
• In general, major involvement of two of the four organ systems
(skeletal, cardiovascular, ocular, and skin) and minor involvement of
another organ is required for diagnosis
Treatment
• The mainstay of the medical treatment is administration of β blockers
which reduce heart rate and aortic wall stress.
• In animal models not in human; inhibition of TGF-β action by use of
specific antibodies has been found useful.
• In human strategies to block TGF-β signaling are being tested by using
angiotensin type 2 receptors Blockers.
 Ehlers-Danlos Syndromes (EDS)
• EDSs comprise; clinically & genetically heterogeneous group of disorders that result from
some defect in the synthesis or structure of FIBRILLAR collagen.

• Most contortionists have one of the EDSs which predispose them to joint dislocation

Collages are divided into 2

(1)Fibrillar collagens= collagens types I, II, III & V
(2)Non-fibrillary collagen= collagens types IV & VII

• Fibrillar collagens form a major proportion of the C.T in structures such as

• bone,
• tendon,
• cartilage,
• blood vessels, & skin, as well as in healing wounds and particularly scars.
COLLAGEN SYNTHESIS
• Collagen synthesis occur mainly in the cells of fibroblast. The synthesis occurs within &
outside the cell.

Within the cell

• (1) During translation, 2 types of peptide chains are formed on the ribosomes along
the rER. These are called alpha-1 & alpha-2 chains known as preprocollagens
• The preprocollagens are released into the lumen of rER where they are cleaved into
pro-α-chains
• Hydroxylation of proline and lysine of the pro-α-chain which is dependent on Vit C as a
cofactor occur, & with further glycosylation of specific hydroxylysine residues, the
chain will align into triple helix structure called procollagen (two-α1 chains & one α-2
chain).
COLLAGEN SYNTHESIS
Outside the cell
• (2) The procollagens are secreted outside the cell by exocytosis
through golgi apparatus, where C-propeptendoproteinase activity
(procollagen peptidase) is completely removed resulting in
tropocollagen which polymerizes in a staggered fashion into fibrillar
arrays . (This is the same for all the fibrillar collagens)
• The tropocollagen achieves lateral stability through collagen cross-
linking involving lysyl oxidase which link hydroxylysine & lysine
residues.
Six Clinical & molecular variants of EDS
EDS Type* Clinical Findings Inheritance Gene Defects

Classic (I/II) Skin hyperextensible & joint hypermobility, Autosomal dominant COL5A1,
atrophic scars, easy bruising, diaphragmatic COL5A2
hernia

Hypermobility (III) Joint hypermobility, pain, dislocations Autosomal dominant Unknown

Vascular (IV) Thin skin, colon, arterial or uterine rupture, Autosomal dominant COL3A1
bruising, small joint hyperextensibility
Kyphoscoliosis (VI) Hypotonia, joint laxity, congenital scoliosis, Most common Lysyl
ocular fragility Autosomal recessive hydroxylase
type (ENZYME)
Arthrochalasia (VIIa,b) Severe joint hypermobility, skin changes Autosomal dominant COL1A1,
(mild), scoliosis, bruising COL1A2

Dermatosparaxis (VIIc) Severe skin fragility, cutis laxa, bruising Autosomal recessive Procollagen N-
peptidase
(ENZYME)
Molecular variants of EDS
• Blood vessels & intestines are known to be rich in collagen type III,
they are therefore affected in Vascular type(IV) EDS.
• Only 30% to 50% of classic type EDS, have collagen 5 gene mutations,
the rest of classic types are due to genetic defects that affect the
biosynthesis of other extracellular matrix molecules that influence
collagen synthesis indirectly e.g is mutation in tenascin-X, a large
multimeric protein, that affects the synthesis & fibril formation of
collagens 6 & 1.
CLINICAL FEATURES OF EDS
• Clinical features may include extremely fragile & hyperextensible skin
which is vulnerable to trauma.
• Minor injuries produce gaping defects, & surgical repair or
intervention is difficult b/c the skin lacks normal tensile strength.
• Hypermobile joints.
• Ruptures involving large arteries, colon, cornea/retinal detachment.
• Wound healing is poor.
EDS. Note if is MS the thumb extension will only
stop at the wrist but EDS extends to the forearm
Disorders Associated with
Defects in Receptor
Proteins.
Familial Hypercholesterolemia
Familial Hypercholesterolemia

• Familial hypercholesterolemia is a “receptor disease” which occur

due to mutation in the gene encoding the receptor for LDL, a receptor
needed for transport and metabolism of cholesterol.

• This will lead to elevated levels of cholesterol in the plasma which will
induce premature atherosclerosis, leading to a greatly increased risk
of myocardial infarction (MI).
• There are >900 LDL receptor gene mutations these include insertions,
deletions, missense & nonsense mutations.
Familial Hypercholesterolemia
• Is an autosomal dominant disorder with 1 in 500 individuals being
Heterozygotes (have only 50% of the normal number of LDL Receptor)&
therefore have from birth a 2-fold to 3-fold elevation of plasma
cholesterol level, leading to tendinous xanthomas & premature
atherosclerosis in adult life.
• Homozygotes (All LDL Receptors are mutated) individual are much more
severely affected & have 5 to 6-fold elevations in plasma cholesterol
levels. Skin xanthomas, coronary, cerebral, and peripheral vascular
atherosclerosis may develop at an early age. MI occur before age 20
years.
• Both cases will have problem with LDL clearance & also in its synthesis
Xanthoma palpebrarum deposition of
cholesterol along tendon sheaths
Normal Process of Cholesterol Metabolism &
Transport.
• Approximately 7% of the body’s cholesterol circulates in the plasma, majorly
in the form of LDL.
• Synthesis & catabolism of cholesterol occur in the liver.
• The liver secrets very-low density lipoproteins (VLDLs) into the
bloodstream(the 1st step). VLDL particles are rich in triglycerides (TG), &
contain Apo C, Apo E, B-100 but lesser amounts of cholesteryl esters.
• When VLDL particle reaches the capillaries of adipose tissue or muscle, it is
cleaved by lipoprotein lipase to extracts most of the TG, the remaining residue
is called intermediate-density lipoprotein (IDL)
• The IDL is reduced in triglyceride but enriched in cholesteryl esters & contains
only 2 apoproteins (B-100 and E)
Normal Process of Cholesterol Metabolism and Transport
• Once the IDL is released from the capillary endothelium, 50% of it is taken up by liver
through its receptor (LDL receptor) which recognizes both apoprotein B-100 and E.
• In the liver cells, IDL is recycled to generate VLDL.
• The remaining 50% of IDL not taken by the liver is further metabolise to remove the
remaining TG & Apo E resulting in plasma Cholesterol-rich LDL.
• These plasma LDL is removed via 2 pathways (1) via LDL receptor in 70% of cases (2)
via receptor for acetylated or oxidized LDL (scavenger receptor) = present in
Monocytes, Macrophages, Fibroblasts, Lymphocytes, Smooth muscle cells,
Hepatocytes, & Adrenocortical cells.
• These scavenger cells are reasons for the appearance of xanthomas & premature
atherosclerosis.
Clearance of the 70% LDL within the liver
Normal Process of Cholesterol Metabolism and Transport
• In the lysosomes the LDL molecule is enzymatically degraded; its
apoprotein part is hydrolyzed to amino acids, whereas its cholesteryl
esters are broken down to free cholesterol.
• Cholesterol exit from the lysosomes by the help of 2 proteins, called
NPC1 and NPC2 (“Niemann-Pick Disease Type C”).
• HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase= is the
rate-limiting enzyme in cholesterol synthesis.
• Esterification & storage of excess cholesterol is achieved by activation
of the enzyme acyl-coenzyme A: cholesterol acyltransferase.
Classes of Familial Hypercholesterolemia

• Class I mutations (null allele).= relatively uncommon; there is complete failure of

synthesis of the receptor protein.
• Class II mutations= fairly common; is due to folding defects within the endoplasmic
reticulum (ER) making it to accumulate in the ER & not transported to the Golgi
complex for packaging.
• Class III mutations ; mutation affect the binding domain of the receptors, so the LDL
receptors reach the cell surface but fail to bind LDL or do so poorly.
• Class IV mutations; the receptors are synthesized & transported to the cell surface
efficiently, bind LDL normally, but fail to localize in coated pits, & hence are not
internalized.
• Class V mutations; the internalized endosome fails to dissociate the receptor from
bound LDL & they are therefore not recycled.
Mutations of LDL Receptors are classified into five groups
Treatment of Familial
Hypercholesterolemia
• Statins is very important because it suppresses intracellular
cholesterol synthesis by inhibiting the enzyme HMG CoA reductase.
This, in turn, will allows greater synthesis of LDL receptors.
• Statin is therefore used in treatment of ischemic heart disease.
•Disorders Associated with
Defects in Enzymes
•Lysosomal Storage Diseases
• Glycogen Storage Diseases (Glycogenoses)
Lysosomal Storage Diseases
• Lysosomes are “intracellular digestive tract.”
• They contain numerous hydrolytic enzymes (acid hydrolases), which
have two special properties (1)they provide acidic milieu of the
lysosomes, (2) these enzymes are destined for intracellular secretory
proteins organelles.
• LEs help in degrading intracellular organelles (autophagy), or substrates
acquired from outside the cells by phagocytosis (heterophagy).
• Failure to degrade these substances will result in secondary
accumulations (if is autophagy) and primary accumulations (if is
heterophagy) within the lysosome.
Subgroups of lysosomal storage dxs

• These subgroups are based on the biochemical nature of the

accumulated metabolite.
• Glycogenoses
• Sphingolipidoses (lipidoses)
• Mucopolysaccharidoses (MPSs)
• Mucolipidoses
• Sulfatidoses
• Other diseases of complex carbohydrates
Disease
Glycogenosis
Sphingolipidoses
GM1 gangliosidosis
Type 1—infantile, generalized
Type 2—juvenile
GM2 gangliosidosis
*Tay-Sachs disease*
Sandhoff disease
GM2 gangliosidosis variant AB
Mucopolysaccharidoses (MPSs)
*MPS I H (Hurler)*
*MPS II (Hunter)*
Enzyme Deficiency
Type 2—Pompe disease
α-1,4-Glucosidase (lysosomal
glucosidase)
GM1 ganglioside β-galactosidase
Hexosaminidase, α subunit
Hexosaminidase, β subunit
Ganglioside activator protein
α-L-Iduronidase
L-Iduronosulfate sulfatase
Major Accumulating Metabolites
Glycogen
GM1 ganglioside, galactose-
containing oligosaccharides
GM2 ganglioside
GM2 ganglioside, globoside
GM2 ganglioside
Dermatan sulfate, heparan sulfate
Disease
Disease Enzyme Deficiency Major Accumulating Metabolites

Mucolipidoses (MLs) Deficiency of phosphorylating Mucopolysaccharide, glycolipid

I-cell disease (ML II) and pseudo-
Hurler polydystrophy
enzymes essential for the
formation of mannose-6-phosphate
recognition marker; acid hydrolases
lacking the recognition marker
cannot be targeted to the
lysosomes but are secreted
extracellularly

Sulfatidoses Arylsulfatase A Sulfatide

Metachromatic leukodystrophy Arylsulfatase A, B, C; steroid Sulfatide, steroid sulfate, heparan
Multiple sulfatase deficiency sulfatase; iduronate sulfatase; sulfate, dermatan sulfate
heparan N-sulfatase.

Krabbe disease Galactosylceramidase Galactocerebroside

Fabry disease α-Galactosidase A Ceramide trihexoside
*Gaucher disease* Glucocerebrosidase Glucocerebroside
*Niemann-Pick dx: types A & B* Sphingomyelinase Sphingomyelin
Three (3) general treatment approaches of lysosomal
storage diseases.
• Enzyme replacement therapy.
• Substrate reduction therapy
• Molecular chaperone therapy= is under active investigation.= here
the involved enzyme are prone to misfolding and therefore degraded
in rER, to avoid this a folding template (chaperone) is introduced.
Clinical presentation
•Clinical presentation; depend on the site of distribution of under-
graded material ie

•(1)Where the degraded material is normally found.

•(2) The location where most of the degradation normally occurs.

=Degradation of variety of substrates occur in Mononuclear phagocyte
system which are rich in lysosomes.
=Organs rich in phagocytic cells such as spleen and liver, are
frequently enlarged in many forms lysosomal storage disorders.
Examples

• Gangliosides are found in the Brain, heart, retina, liver and spleen
therefore accumulation of gangliosides occur within these organs and
also in the neurons causing neurologic symptoms.
• Mucopolysaccharides are found in virtually every organ, therefore it
defective degradation will result in wide organ distribution.
GM2 Gangliosidosis
• Degradation of GM2 Gangliosides involve 3 enzymes (Hexosaminidase A,
Hexosaminidase β & GM2 activator) which are encoded by 3 distinct genes on
chromosome 15.
• When there is a gene mutation of any of these 3 enzymes causing abnormal folding of
enzyme protein (misfolded p) GM2 Gangliosidosis occur resulting in 3 variants.

(1) α-Subunit mutation = Hexosaminidase A def= Tay-Sachs Dx (MOST COMMON)

(2) β-subunit mutation = Hexosaminidase B def= Sandhoff disease
(3) GM2 activator = GM2 activator deficiency=GM2 gangliosidosis variant AB

All these variants have similar clinical signs and symptoms

(1) Tay-Sachs Dx=morphology
• Is common among Jews, esp Ashkenazic origin= 1 in 30
• The hexosaminidase A is absent from virtually all the tissues.
• GM2 ganglioside accumulates in many tissues = heart, liver, spleen,
nervous system), but the involvement of neurons in the central
(cerebellum, the basal ganglia, brain stem, spinal cord, and dorsal root
ganglia) and autonomic nervous systems and retina dominates the
clinical picture.
• Ganglioside is composed of glycosphingolipid (complex lipid)
• Stains the tissue for fat using oil red O and Sudan black B are positive
Histologic=the neurons are ballooned with distended
lysosome (vacuoles) filled with gangliosides
Electron microscope; show many cytoplasmic
inclusions like-whorled configurations within
lysosomes composed of onion-skin layers of
membranes
Clinical symptoms
• A cherry-red spot in the macula is xteristic of Tay-Sachs dx & other
storage disorders affecting the neurons.
• There is accentuation of the normal colour of the macular choroid
contrasted with the pallor swollen ganglion cells in the remainder of
the Retina
Clinical symptoms
• Infant are normal at birth but at 6 months they start manifesting signs
and symptoms such as motor incoordination, mental obtundation
leading to muscular flaccidity, blindness, and increasing dementia.
• By 1 or 2 years a complete vegetative state is reached, followed by
death at age 2 to 3 years.

• Diagnosis; enzyme assays, DNA-based analysis

• Treatment; chaperone therapy
Glycogen Storage Diseases (Glycogenoses)
• The glycogen storage diseases result from a hereditary deficiency of
one of the enzymes involved in the synthesis or in the sequential
degradation of glycogen

• In synthesis, glycogen synthetases & branching enzymes linked

together as many as 10,000 glucose molecules by α-1,4-glucoside
bonds which is highly branched with a molecular weight as high as
100 million
Glycogen degradation occur in 2 pathways
• (1) Major pathway of glycogen degradation, distinct phosphorylases
in the liver & muscle which split glucose-1- phosphate from the
glycogen until about four glucose residues called limit dextrin is left
which is degraded only by the debranching enzyme.
• (2) Glycogen is also degraded in the lysosomes by acid maltase (α-1,4-
Glucosidase) =This will give rise to lysosomal storage dx=Pompe dx
Classification of glycogenoses
• On the basis of specific enzyme deficiencies & clinical pictures,
glycogenoses are divided into 8 by roman numerals, & the list
continues to grow (see the diagram above)
• On the basis of pathophysiology glycogenoses are divided into 3
major subgroups.
Clinicopathologic Specific Type Enzyme Morphologic Changes Clinical Features
Category Deficiency

Hepatic type Hepatorenal Glucose-6- Hepatomegaly — In untreated patients: failure to

Von Gierke phosphatase intracytoplasmic thrive, stunted growth,
dx accumulations of glycogen & hepatomegaly, and renomegaly
(type I) small amounts of lipid; Hypoglycemia due to failure of
intranuclear glycogen glucose mobilization, often leading
to convulsions

Renomegaly — Hyperlipidemia and hyperuricemia

intracytoplasmic
accumulations of glycogen
in cortical tubular epithelial
cells
resulting from deranged glucose
metabolism; many patients
develop gout and skin xanthomas
Bleeding tendency due to platelet
dysfunction
With treatment: Most survive and
develop late
complications (e.g., hepatic
adenomas
Clinicopathologi Specific Type Enzyme Morphologic Changes Clinical Features
c Deficiency
Category

Myopathic type McArdle Muscle Skeletal muscle only— Painful cramps associated with
disease phosphorylase accumulations of strenuous exercise; myoglobinuria
(type V) glycogen predominant in occurs in 50% of cases;
subsarcolemmal onset in adulthood (>20 years);
location muscular exercise fails to raise lactate
level in venous blood; serum creatine
kinase always elevated; compatible
with normal longevity

Miscellaneous Generalized Lysosomal Mild hepatomegaly — Massive cardiomegaly, muscle

types glycogenosis glucosidase ballooning of lysosomes hypotonia, and
— (acid maltase) with glycogen, creating cardiorespiratory failure within 2
Pompe lacy cytoplasmic pattern years; a
disease Cardiomegaly —glycogen milder adult form with only skeletal
(type II) within sarcoplasm muscle
as well as membrane- involvement, presenting with chronic
bound myopathy; enzyme replacement
Skeletal muscle —similar therapy
to changes in heart available
 Pompe disease (glycogen storage disease type
II).
• Normal myocardium; cytoplasm is eosinophilic /myocardial fibres are
full of glycogen (clear spaces)

• Normal myocardium Pompe dx (clear spaces=glycogen)

Thank you