Lysosomal Storage Diseases

Lysosomes

- An organelle containing digestive enzymes that breakdown numerous biological structures

What can lysosomes breakdown?

- Proteins

- Nucleic Acids

- Carbohydrates

- Lipids

How do Lysosomal Storage diseases occur in general?

- Someone is born with the absence of one of the lysosomal enzymes → inability to breakdown complex molecules → accumulation → diseases

What is the inheritance of most lysosomal storage diseases?

- Autosomal recessive

Is there a known treatment/cure for Lysosomal Storage Diseases?

- Most have no treatment or cure

Sphingosine

- Long chain amino alcohol

What happens when a fatty acid is added to the amino (NH2) of Sphingospine?

- Becomes ceramide

Sphingolipids

- Lipids (FAs) with a sphingosine backbone: ceramide, sphingomyelins, glycosphingolipids, gangliosides

Most of the accumulation that occurs in lysosomal storage disorders are what?

- Ceramide derivatives (all of them sphingolipids)

Ceramide Derivatives

- Occur when a "head group" is added to the OH on ceramide

- Important structures for nerve tissue

Key Ceramide Derivatives

- Glycosphingolipids

- Sulfatides

- Ganglioside

What happens when Ceramide derivatives are unable to be broken down?

- They accumulate in the liver/spleen → disease

Fabry's Disease: Deficiency and Accumulation

- D: α-Galactosidase A

- A: Ceramide Trihexoside

Fabry's Disease: Inheritance

- X-linked recessive

Unique bc/ most diseases are AR

Fabry's Disease: Symptoms

- Slowly progressive symptoms, beginning early childhood

- Neuropathy: Pain in hands/feet

- Angiokeratomas: Small dark, red/purple raised spots from dilated Surface Capillaries on skin

- Decreased sweat

Fabry's Disease: What organs does it effect?

- Renal: Proteinuria, Renal failure

- Cardiovascular: L Ventricular Hypertrophy, Heart Failure

- CNS: TIA/Stroke at early age

Fabry's Disease: Dx and Treatment

- Dx: Often misdiagnosed initially d/t subtly of symptoms

- Tx: Enzyme replacement → recombinant galactosidase

Fabry's Disease: Classic Case

- Child w/ pain in hands/feet

- Lack of sweat

- Skin findings

What is the most common lysosomal storage disease?

- Gaucher's Disease

Gaucher's Disease: Deficiency and Accumulation

- D: Glucocerebrosidase

- A: Glucocerebroside

Gaucher's Disease: Inheritance

- Inheritance: AR

Where do the lipids in Gaucher's disease accumulate?

- Spleen

- Liver

- Bones

Gaucher's Disease: Presentation

- Hepatosplenomegaly

- Easy bruising form low platelets

- Avascular necrosis of joints (joint collapse)

- Rarely: Gaze plasy, dementia, ataxia

Gaucher Cell

- Macrophage filled with sphingolipids (looks like crinkled tissue paper)

Gaucher's disease: What occurs in bones

- Severe bone pain due to bone infarction → d/t gaucher cells in intramedullary space

Gaucher's Disease Type I: Presentation

- Presents from childhood → adult

- Minimal CNS dysfunction

- Hepatosplenomegaly, bruising, anemia, joint problems

Gaucher's Disease Type I: Treatment

- Enzyme replacement therapy: Synthetic Glucocerebrosidase → relief from many symptoms → normal lifespan possible

Gaucher's Disease Type II: Presentation

- Presents in infancy with marked CNS symptoms

- Death < 2 years

Gaucher's Disease Type III: Presentation

- Childhood onset

- Progressive dementia

- Shortened lifespan

Gaucher's disease: Classic Case

- Child of Ashkenazi Jewish Descent

- Splenomegaly on exam

- Anemia, Bruising

- Joint pain/fractures

Sphingomyelin

A sphingophospholipid containing a sphingosine backbone and a phosphate head group.

Neimann-Pick Disease: Deficiency and Accumulation

- D: Acid Sphingomyelinase

- A: Sphingomyelin

Neimann-Pick Disease: Presentation

- CHERRY RED SPOT IN BACK OF EYE

- Hepatosplenomegaly WITH neurologic defects (Differs from Gaucher's)

- Progressive neuro impairment → loss of motor skills (as sphingolipids accumulate)

Neimann-Pick Disease: Pathology

- Foam Cells: Large macrophages with lipids; found in spleen/bone marrow

Severe Neimann-Pick Disease: Prognosis

- Death

Neimann-Pick Disease: Classic Case

- Previously healthy child presenting with weakness/loss of motor skills

- Enlarged liver/spleen

- Cherry red spot in macula

Krabbe's Disease: Deficiency and Accumulation

- D: Galactocerebrosidase

- A: Galactocerebroside

Galactocerebroside is a major component of what?

- Myelin → if unable to breakdown Galactocerebroside and it accumulates → neuro impairment

Krabbe's Disease: Presentation

- Developmental delay, floppy limbs, loss of head control

- Absent reflexes

- Optic Atrophy: Vision loss

- Fever w/out infection

Krabbe's Disease: Prognosis

- Death < 2 yrs

What is unique about Krabbe's Disease?

- There is no liver/spleen/bone marrow involvement which is common in other lysosomal diseases

Krabbe's Disease: Histology

- Globoid cells: Globe shaped cells, often more than one nucleus

- Found w/in neuronal tissue

Tay-Sachs Disease: Deficiency and Accumulation

- D: Hexoamidase A

- A: GM2 Ganglioside

Gangliosides

- Glycolipids with a head group composed of oligosaccharides with a terminal sialic acid (NANA) molecule.

Which Lysosomal Storage Diseases are more common in the Ashkenazi Jewish Population?

- Gaucher's

- Neimann-Pick

- Tay-Sachs

Tay-Sachs Disease: Classic Presentation

- 3-6 months in age (Jewish)

- Developmental delay

- Exaggerated startle response

- CHERRY RED SPOT

Tay-Sachs Disease: Prognosis

- Death in childhood

Tay-Sachs Disease: Pathology

- Lysosomes with onion skinning: circles inside lysosomes that look like the skin of an onion

Metrachromatic Leukodystrophy: Deficiency and Accumulation

- D: Arylsulfatase A

- A: Sulfatides

Sulfatides are a major component of what?

- Myelin

Metrachromatic Leukodystrophy: Presentation

- ~2 yrs of age (most common)

- Ataxia: Gait problems, falls

- Hypotonia: Speech problems

- Dementia can develop

Metrachromatic Leukodystrophy: Prognosis

- Most children do not survive childhood

Fabry's: Buzzwords

- Hand/feet pain

- ↓ Sweat

- Rash

Gaucher's: Buzzwords

- Spleen

- Anemia

- Bone fractures

Metrachromatic Leukodystrophy: Buzzwords

- 2 yrs old

- Ataxia

Neimann Pick: Buzzwords

- Older child

- Liver/spleen

- Cherry red spot

Tay-Sachs: Buzzwords

- Baby

- Cherry spot

- Ashkenazi

- No spleen involvement

Glycoaminoglycans

- An unusual dissacharide found in ground substance that attracts sodium and holds water

What are Glycoaminoglycans important for?

- Important structure in cartilage/ligaments/tendons

- Regulates water and electrolyte balance in connective tissues

Hurler's and Hunter's Syndrome: MOA and Dx

- MOA: Inability to breakdown heparan and derma tan (GAGs)

- Dx: Mucopolysaccarides in Urine

Hurler's Syndrome: Deficiency, Accumulation, and Inheritance

- D: α-L-iduronidase

- A: Heparin and dermatan sulfate

- I: Autosomal Recessive

Hurler's Syndrome: Presentation

- Face abnormalities, short stature

- Intellectual disability

- Hepatosplenomegaly

- Corneal clouding

- Ear/sinus infections

Hunter's Syndrome: Deficiency, Accumulation, and Inheritance

- D: Iduronate 2-Sulfatase

- A: Heparin and dermatan sulfate

- I: X-Linked Recessive

Hunter's Syndrome: Presentation

- No corneal clouding

- Behavioral problems/learning difficulty

- Aggressive

I-Cell Disease

- Absent enzyme marker in Golgi apparatus (mannose 6-phosphate); empty lysosomes

- Similar to hurler's in symptoms

Pompe's Disease: Deficiency and Accumulation

- D: α-Glucosidase

- A: Glycogen in lysosomes

Pompe's Disease: Symptoms and Prognosis

- Muscle weakness and cardiac failure

- Often death in infancy/childhood