Pathbio 2 Lysosomal Diseases

Front 1

Mucopolysaccharidoses
(General)

Back 1

- Mucopolysaccharides or glycosaminoglycans (GAG). Macromolecules- structural integrity of extracellular matrix w/ varied tissue involvement & cells (mast cells & neutrophils) & plateletes
- Enzyme defect results in tissue accumulation & urine excretion

Clinical features:
- Chronic & Progressive Course
- Multisystem involvement
- Organomegaly
- Dysostosis Multiplex
- Abnormal facies

Diagnosis:
- GAGS
Urinary
age dependent (present in normal infants up to 1 year)
Normal urine contains mostly chondroitin sulfate, with small amounts of heparan and dermatan sulfate
Screening tests
qualitative and quantitative analysis
- Amniotic fluid
- Enzyme assays
Prenatal
Cultured cells from amniotic fluid
Chorionic villous biopsy is less suitable because normal villi have low enzyme activity
Postnatal
measure enzyme activity in plasma or leukocytes
Enzyme activity from skin fibroblast

Front 2

Hurler
MPS I

Back 2

- α-1-iduronidase deficiency
- Lysosomal accumulation of GAGS (heparin & dermatan sulfate)
- Autosomal recessive

Onset in early infancy 6-8 months
Death usually before ten years of age

Clinical features:
- respiratory
- skeletal
- cardiovascular
- ocular
Corneal clouding
Retinal disease
Glaucoma
Results in blindness
- neurologic: storage in neurons, macrophages & meninges
Mental retardation
Hydrocephalus
Headaches
Spinal cord compression
Thicken leptomeninges
- course facial features
- alder-reilley anomaly
Accumulation of course material in neutrophils

Front 3

Hunter
MPS II

Back 3

- Deficiency in iduronate sulfatase
- Accumulation of heparin & dermatan sulfates
- X-linked

- Similar to Hurler syndrome but less severe
- appear in late infancy & early childhood
- lack corneal clouding
- slower progression of somatic & CAN involvement than Hurler disease

- Stacks of lipid profiles

Front 4

Spingolipidoses
(General)

Back 4

- Membrane lipids
Phospholipids, cholesterol
spingolipids

Front 5

Niemann-Pick Disease

Back 5

Types I (A and B) caused by deficiency of
sphingomyelinase -> progressive accumulation of spingomyalin (ubiquitous component of cellular and organellar membranes)
Type II (C & D)


- foamy bubble looking cells
- swirls lysosomes

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Type A (severe infantile)

Spingolipidoses

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- 70 -80%
- first weeks of life


Clinical features:
- hypotonia
- failure to thrive
- Severe neurodegenerative course
- 50 % will have macular cherry red spot
- marked visceral accumulation of sphingomyelin
- death within 3 years

Front 7

Type B (chronic visceral)
Spingolipidoses

Back 7

- No CNS involvement
- Present with splenomegaly and ultimately develop generalized visceral involvement

Front 8

Type C
Spingolipidoses

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- Defect involves NPC-1 (95%) and NPC 2 genes
which code for a protein involved in lipid transport (free cholesterol from the lysosomes  cytoplasm)
- More common than type I ( A and B combined)
- Cholesterol accumulates in affected cells of the spleen, liver, bone marrow and accumulation of cholesterol in neurons ultimately causes destruction

Clinical features:
- Variable
- Classic phenotype (neurovisceral)
Presents in childhood
Variable hepatosplenomegaly
Vertical supranuclear opthalmoplegia
(supranuclear palsy)
Progressive ataxia
Psychomotor regression
Hydrops fetalis and stillbirth
Fatal neonatal liver disease “giant cell hepatitis”
Adult presentation with psychosis and dementia

Front 9

Type D
Spingolipidoses

Back 9

variant of type C patients appear to be
less severely affected, Nova Scotia

Front 10

Gangliosidoses
(General)

Back 10

- Autosomal recessive
- Normal component of cell membranes particularly neurons

Front 11

GM1 Gangliosidoses

Back 11

- Β- Galactosidase deficiency
- Accumlation of ganglioside in neurons
- in other sites
- 3 isoenzymes A,B,C
Type I: virtual absence of all three isoezymes
Type II: Absence of A,B isoenzymes
- clinical variability depends on amount of residual enzyme activity
- Transcription of β- galactosidase requires an activator which may also be deficient & thus cause similar features

Type I (Generalized gangliosidosis): infantile, birth to 6 months

Type II (juvenile): later onset 1-2 years

Clinical features:
Type I:
- neurodegeneration
- accumulation of gangliosides in neurons, liver, spleen, and renal tubular epithelium, macular “cherry red spots”
- Skeletal deformities
Features of both neurolipidoses & mucopolysaccharidoses “pseudo-Hurler phenotype”

Type II:
- slower progressive psychomotor retardation
- less visceromegaly
- milder skeletal disease
- death occurs by age 3-10 years

Diagnosis:
Lab studies
 Measurement of β galactosidase activity in
peripheral blood leukocytes
 Type I: virtually no enzyme activity
 Type II: 5-10% activity
 Peripheral blood smear: vacuolization of lymphocytes (crude method as many lysosomal storage diseases may have this feature)

Front 12

GM2 Gangliosidoses
Tay-sachs α
Sandhoff diseases β
GM2activator deficiency

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- Inability to catabolize GM2 ganglioside which requires 3 poypeptides (αβ active enzyme complex + activator) encoded by 3 separate loci
- Phenotypic effects are similar bc they are all result in accumulation of GM2 ganglioside


GM2 ganglioside accumulates in many tissues (CNS & retinal represent the dominant features of the disease)

Clinical features:
- loss of motor skills at 3-6 months
- macular cherry red spot
- progressive neurodegeneration, seizures, blindness and death by 2-4 yrs of age
- Ashkenazi Jewish decent carrier rate 1/30

Front 13

Metachromatic Leukodystrophy
(Sulfatidoses)

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- Deficiency of Arylsulfatase A
- characterized by accumulation of non-degradable (cerebroside sulfate)
- white matter of brain
- peripheral nerves
- liver, kidney


- causes breakdown of myelin sheaths which leads to demyelination & gliosis
- Primarily a neurodenerative disorder

Clinical features:
Three types:
• late infantile (most common form): present with regression of motor skills,mental
deterioration, rigidity and convulsions, unusual loss of white matter on CNS imaging -> death before 5 years
• juvenile: change in gait, cognitive skills, and progressive regression of all skills death 6-8 years after diagnosis
• adult onset: psychiatric or cognitive symptoms, with motor symptoms occurring later

Diagnosis:
Urine
-spot screening test -> confirms the presence of sulfatides
-Quantitative measurement
Imaging studies: unusual loss of white matter due to demyelination
Biopsy (usually of a sural nerve): demyelination and metachromatic granules
-PAS +
-Alcian blue
-Acidified Crystal violet
Arylsulfatase A activity levels
Genetic testing (gene located on long arm of chromosome 22)

Front 14

Multiple sulfatase deficiency
(Sulfatidoses)

Back 14

Deficiency of arylsulfatase A,B,C as well as other sulfatases

Combined clinical features of metachromatic leukodystrophy & mucopolysaccaridosis

Front 15

Gaucher Disease
Type I

Back 15

Defect in glucocerebrosidase

Type I:
- chronic non-neuropathic form, most common (99%)
- reduced levels of glucocerebrosidase
- Children & adults
- Ashkenzai Jewish


Clinical features:
Type I:
Accumulation of glucocerebroside limited to mononuclear phagocytes throughout the body, without brain involvement
- splenomegaly/hepatomegaly
-cytopenias secondary to hypersplenism & bone involvement
- Bone involvement
• Avascular necrosis esp of hip
• Osteopenia w/ fractures
• Lytic lesion
• Bone crises: occur when collections of Gaucher cells interfere w/ vascularization causing severe pain
Erlenmeyer flask deformity: abnormality in new bone formation resulting in flattened ends of femurs

Front 16

Gaucher Disease
Type 2

Back 16

Defect in glucocerebrosidase

Type 2:
- Acute, neuropathic form
- no predilection for Ashkenazi Jewish (panethic)
- Absent glucocerebrosidase


 progressive CNS involvement with death at an early age (usually by 2 years of age)
 Hepatomegaly/splenomegaly
 cytopenias secondary to hypersplenism

Front 17

Gaucher Disease
Type 3

Back 17

Defect in glucocerebrosidase

Type 3:
- subacute, intermediate, juvenile form
- reduced glucocerebrosidase


 progressive CNS involvement beginning in teens and twenties
 Hepatomegaly / splenomegaly
 cytopenias secondary to hypersplenism
 bone involvement