This document discusses lysosomal storage disorders, which are a group of rare inherited disorders caused by deficiencies in lysosomal enzymes. Specific disorders discussed include Gaucher disease, the most common lysosomal storage disease caused by glucocerebrosidase deficiency; Tay-Sachs disease caused by hexosaminidase A deficiency; Niemann-Pick disease types A and B caused by sphingomyelinase deficiency; and Fabry disease caused by alpha-galactosidase A deficiency. Signs and symptoms as well as characteristics of each disease are described.

1. LYSOSOMAL STORAGE
DISORDERS
By-Davud
Ahmadzada
220I-1a

2. OVERVIEW
▶ Lysosomes are sub cellular organelles responsible for the physiologic turnover
of cell constituents.
▶ The lysosomes is commonly referred to as the cell’s recycling centers.
▶ They contain catabolic enzymes which require a low pH environment in order
to function optimally.
▶ If one of these catabolic enzymes is defective, because of a mutation, large
molecules accumulate within the cell, eventually killing it.

3. ▶ Lysosomal storage diseases describe a heterogeneous group of rare inherited
disorders characterized by the accumulation of undigested or partially
digested macromolecules, which results in cellular dysfunction and clinical
abnormalities.
▶ Lysosomal storage disorders are caused by lysosomal dysfunction usually as a
consequence of deficiency of a single enzyme required for the metabolism of
lipids, glycoproteins (sugar containing proteins) or so called
mucopolysaccharides.

4. ▶ Classically, lysosomal storage diseases encompassed only enzyme deficiencies of the lysosomal
hydrolases.
▶ 40 types of LSD like Tay Sach Disease, Fabry Disease, Gaucher disease, Niemann Pick disease,
Pompe’s disease etc.
▶ All are autosomal recessive disease except Hunter, Danon and Fabry disease which are X linked.

6. GAUCHER DISEASE
▶ This disease is a multisystem lipidosis characterized by hematological
changes, organomegaly and skeletal involvement, manifested in the form of
bone pains and multiple fractures.
▶ It is the most common genetic disorder among Ashkenazi Jews.
▶ It is the commonest Lysosomal storage disease.
▶ It results from deficient activity of Lysosomal Hydrolase,
β- Glucocerebrosidase which results in accumulation of undegraded
glycolipid in the form of Glucosyl ceramide in the cells of reticuloendothelial
system.

7. There are three clinical subtypes
Type-1- (from early childhood- adulthood)
• easy bruising due to thrombocytopenia, chronic fatigue due to anemia
• hepatomegaly Progressive enlargement of spleen
• Clinical bone involvement in the form of bone pains, or pathological fractures.

8. Type 2-
• less common,
• characterized by neurodegeneration, extreme visceral involvement
• death within 2 years of life.
Type 3-
• is intermediate in presentation to type 1 and 2.
•Neurological involvement is there but occurs later in life with decreased
severity as compared to Type 2.

9. Tay Sach Disease
▶ This is an inborn error of metabolism due to failure of degradation of
gangliosides.
•The enzyme hexosaminidase A is deficient which is composed of an α and β
subunits
-Mutation in α subunit.
▶ It is inherited as an autosomal recessive traits, with a predilection in the
Ashkenazi Jewish population, where the carrier frequency is about 1/25.

10. ▶ Tay-Sachs disease is classified in variant forms, based on the time of onset of
neurological symptoms.
 Infantile TSD
Birth: normal but develop
▶ Loss of motor skills
▶ Increased startle reaction
▶ Macullar pallor and retinal cherry red spot
▶ Decreased eye contact
▶ Hyperacusis
▶ Progressive development of idiocy and blindness are diagnostic of this disease and
they are due to wide spread injury to ganglion cells, in brain and retina.

11.  Juvenile TSD
▶ extremely rare
▶ presents in children between 2 - 10 years who develop
 cognitive, motor, speech difficulties (dysarthria)
 swallowing difficulties (dysphagia)
 unsteadiness of gait (ataxia) and spasticity.
▶ Patients with Juvenile TSD usually die between 5–15 years.

12.  Adult/Late Onset TSD.
 rare form of the disorder
 occurs in patients in their 20s and early 30s.
▶ It is characterized by
 unsteadiness of gait and progressive neurological deterioration.
speech and swallowing difficulties
 unsteadiness of gait.
 spasticity, cognitive decline and psychiatric illness.

13. Niemann Pick Disease
▶ Autosomal Recessive disorder
▶ Defect in sphingomyelinase enzyme.
There are 2 types: A and B

14.  Type A:
▶ Present within first 6 months.
▶ There is progressive mental retardation, spasticity.
▶ Massive hepatosplenomegaly.
▶ Failure to thrive.
▶ Children die within 2 years of life
 Type B:
▶ Late onset
▶ There is no involvement of brain but sphingomyelin is present in excessive amount
in liver, spleen, and bone marrow.

15. ▶ Cirrhosis, hepatic replacement by foam cells.
▶ Progressive pulmonary disease.
▶ Death occurs within 20 years of life.

16. Fabry Disease
▶ Fabry disease is caused by mutations in the GLA gene that result in an
absence of alpha-galactosidase A activity.
▶ Sign and Symptoms
 Pain:
▶ One of the first symptoms which often begins in childhood is a painful burning
sensation in the hands and feet called acroparesthesia.
▶ The pain can be severe and worsen with exercise, stress, illness, and
variations in temperature.

17.  Stomach and Intestines
▶ Early gastrointestinal symptoms of Fabry disease include abdominal cramps,
frequent bowel movements shortly after eating, diarrhea, and nausea.
 Eye
▶ Corneal and lenticular opacities.

18.  Skin Condition
▶ A common skin condition associated with Fabry disease is a red, non-painful rash known as
angiokeratoma.
▶ It usually appears in the area between the belly and the knees, but may also appear on other
parts of the body such as the lips, tongue, hands, and toes.