Lysosomal storage disorders

• Genetic defect leading to reduced synthesis of

lysosomal enzymes
• Recently proved – genetic defects affecting the
steps involved in the synthesis, post-translational
processing transport and activation.
• Leads to accumulation of substrate
– build up of unmetabolized or partially metabolized
material in the lysosomes
– Lysosomes become swollen--->Cells lose their
function--->organ dysfunction
– Several types based on the specific tissue involved
 Tay-Sachs Disease
• Hexosamindase A a-subunit deficiency
• More common among Ashkenazi Jews—
Eastern European origins
• Heterozygote carrier 1 in 30
• Normal appearing at birth, then develop
profound retardation
• Low blood levels of hexosaminidase A
• Blindness-Cherry Red spot in the macula
• Neurological defects
• DEATH 2 to 3 years of age
 Tay-Sachs Disease
• Deficiency of hexosaminidase A (15q)
– Responsible for GM2 ganglioside degradation
• GM2 normally present in plasma membranes
(especially neurons)
– Results in GM2 ganglioside accumulation
• in the lysosomes of all cells
• brain neurons and retinal cells most affected
Neuron with the accumulated GM2 ganglioside
Tay Sachs disease -“whorling pattern” or “onion
skinning” in lysosomes..
Cherry red spot
 Niemann-Pick Disease
• Accumulation of sphingolipid (Types A and B) and,
cholesterol (Type C)
• Types A (infantile) and B (adult) due to deficiency of
sphingomyelinase
• Products accumulate in neurons in brain, and in
phagocytic cells in spleen, liver, bone marrow, lungs
and lymph nodes
• Type A, 75-80% - extensive neuronal involvement,
visceromegaly, progressive wasting; Neurologic
deterioration with death about 5 years in type A.
• Type B: adults with organomegaly alone
Type A Niemann-Pick Disease
 Niemann-Pick Disease

Spleen with accumulated storage

Swollen, distended neurons with product in reticuloendothelial
accumulated sphingomyelin cells.
 Gaucher’s Disease
• Deficiency in glucocerebrosidase — cleaves
glucose from ceramide residue
• Type I due to accumulation of glucocerebroside in
RE cells — Gaucher cells predilection for Jews
• Source is usually degrading RBC and WBC
membranes
• 99% are Type I, chronic non- neuronopathic form
- splenomegaly and bone fracture
• Type II, infantile form, lethal in 6 months, no
predilection for Jews
 Gaucher Disease

Spleens in Gaucher’s disease may be up to 10

kg in size.The RE cells are stuffed full of Spleen with macrophages
glucocerebroside stuffing sinusoids. Macrophages
are loaded with the
glucocerebroside.( wrinkled-paper
appearance)
 Mucopolysaccharidoses
• Hurler Syndrome (MPS 1H) due to deficiency of a-
1-iduronidase
• MPS - failure to remove terminal sugar from
proteoglycans
• MPS disorders develop profound facial changes
(gargoylism), joint stiffness, clouding cornea and
mental retardation
• Death within 10 years
• Hunter syndrome (MPS 2) differ from MPS 1H by
X – linked inheritence, absence of corneal
clouding and mild clinical course
Child with Hurler’s syndrome EM of lysosome in Hurler syndrome.
Lamellated zebra bodies

Liver with hepatocytes filled with

swollen lysosomes
 Glycogen storage disorders
• Autosomal recessive - Hereditary deficiency of
one of the enzymes involved in the synthesis
or sequential degradation of glycogen
• Localized or systemic
• Broadly divided into three groups
– Hepatic
– Myopathic
– Miscellaneous types
category Enzyme defect Changes
Specific
type

Hepatic G-6-phosphatase Enlarged liver &

Von Gierke (type I) kidney.
(type I), III, VI Debrancher (III) hypoglycemia
Liver phosphorylase
(VI)

Myopathic Muscle Muscle cramps

McArdle (V) & phosphorylase (V), after exercise,
VII muscle phospho- failure of lactate
fructokinase (VII) level increase

Miscellaneous Acid maltase (II) Deposition in all

Pompe (II) & IV Brancher (IV) organs –
cardiomegaly (II)
 Alkaptonuria
• First human inborn error of metabolism
• Lack of Homogentisic oxidase - blocks the
metabolism of phenylalanine - tyrosine at the
level of Homogenitsic acid
• Homogentisic acid is excreted in urine – urine
turns black on standing
• HA binds to collagen leads to blue - black
pigmentation (Ochronosis)
• Severe form - Degenerative arthropathy and
severe crippling