Inborn Errors: Glycolipid Disorders Flashcards
Introduction Glycolipids
a. Glycolipids are molecules that contain both carbohydrate and lipid components.
b. Glycolipids have roles in cell signaling, cell membranes, and as an energy source. In higher organisms, most glycolipids are glycosphingolipids, but glycoglycerolipids and other types exist.
c. The synthesis, functions, and degradation of glycolipids involve complex pathways involving dozens of substrates, and enzymes, cofactors.
d. They are important in many cell types, especially nervous tissues.
Lysosomes:
Lysosomes: The garbage (or recycling) centers in cells that are acidic, contain ~50 hydrolase enzymes, that break down macromolecules into smaller components.
Lysosomal Storage Diseases (LSDs):
a. LSDs are a group of disorders where defects in lysosomal ‘function’ are present and one (or more) biomolecules cannot be properly degraded and/or processed.
b. In most cases, LSDs are due to the absence of one or more lysosomal enzymes.
i. As a result, undigested glyco-lipids and extracellular components that would normally be degraded by lysosomal enzymes accumulate in lysosomes as large inclusions.
c. In most of these conditions, substrate storage is manifested clinically as an increase in the mass of the affected tissues and organs.
i. When the brain is affected, however, as is often the case, the picture is one of neurodegeneration.
d. The different presentations of LSDs is driven in part by which enzyme(s) is defective and what material(s) accumulate in which organ(s).
Lysosomal Storage Diseases (LSDs):
Major Points
Lysosomal Storage Diseases (LSDs): Occur when a lysosomal enzyme (usually) is deficient/missing resulting in substrate(s) accumulation (storage) in various organs.
Lysosomal Storage Diseases
Inheritance
a. The majority of LSDs are inherited in an autosomal recessive fashion.
b. Three exceptions that are inherited in X-linked fashion are:
1) Fabry disease (alpha-galactosidase)
2) Hunter syndrome (iduronate-2-sulfatase)
Clinical Considerations:
a. How to recognize disease?
i. Look for storage in the patient (things getting bigger) and recognize the key presentations/complications
b. How to remember the defect?
i. Remember (memorize) which enzyme goes with which disease
c. How to treat?
i. Remember (memorize) which treatment goes with which disease
Clinical Presentation of Lysosomal Storage Diseases
Large List
• Brain: cognitive function, behavior, loss-of-skills
• Skin: coarseness, thickness, hirsutism, angiokeratoma (Fabry)
• Skull (Brain): macrocephaly, hydrocephalus, seizures, ataxia, cognitive delay and cognitive regression
• Eyes (‘window to the brain’): corneal clouding, retinal degeneration, cherry red spot (often Tay Sachs)
• Hearing: hearing loss due to otitis media and Eustachian tube dysfunction
• Ear/Nose/Throat: macroglossia, thickened vocal cords, nasal congestion (large adenoids), sleep apena (complication)
• Heart: cardiomyopathy, arrhythmia, thickened heart valves
• Lungs: airway narrowing, pulmonary fibrosis • Liver: hepatosplenomegaly with typically preserved hepatic function
• GI: constipation and diarrhea (sometimes alternating)
• Kidneys: progressive renal failure and proteinuria (Fabry disease)
[Proteinuria/renal failure ~= Fabry on an exam]
• Skeletal: dysostosis multiplex, joint stiffness, scoliosis, atlanto-occipital instability, short stature
• Muscle: hypotonia, myoclonic jerks, spasticity, weakness
What does storage disease look like?
a. Skull (Brain): macrocephaly and cognitive regression
b. Eyes (‘window to the brain’): corneal clouding, cherry red spot (often Tay Sachs)
c. Ear/Nose/Throat: macroglossia, sleep apena (complication)
d. Liver: hepatosplenomegaly with typically preserved hepatic function
e. Kidneys: progressive renal failure and proteinuria (Fabry disease)
f. Skeletal: dysostosis multiplex, joint stiffness, short stature
Some specific comments on Storage Disease:
a. Hepatosplenomegaly: Can be massive, protuberant belly; typically does not lead to liver function abnormalities
b. Dysostosis Multiplex: abnormal bony structure on X-rays; Vertebral ‘beaking’, broad bases of metacarpals and phalanges, scoliosis
c. Cherry Red Spot: Most commonly a retinal finding connected with Tay Sachs disease
d. Facial Coarseness: Facial thickening, looks a bit swollen
Therapy Options for Lysosomal Storage Disease
Therapy Options:
a. While one could try to ‘fix’ the genetic defect, some of the damage that has occurred may be irreversible.
b. Supportive Surgery: heart valves, hernias, splenectomy (not often)
c. Bone Marrow Transplantation: some limited benefit in some cases (mucopolysaccharidoses); must be done before irreversible neurological disease; high-risk (mortality may be 20-30%) with long-term complications
d. Enzyme Replacement: now available for 6 diseases to improve degradation of the offending substance (Fabry, Gaucher, Hurler (MPS I), Hunter (MPS II), Maroteaux–Lamy (MPS IV), Pompe) Substrate Inhibition: use compounds to prevent the production of the offending substance (less substance accumulates); less production ! less accumulation
e. Chaperone Therapy: use small molecules to stabilize the damaged enzyme and recover some enzymatic function
Gaucher Type 1 (Adult Onset)
a. Inheritance- Autosomal recessive; Higher in Ashkenazi Jews
b. Onset- Adult onset
c. Clinical Presentation- Fatigue, bony pain, enlarging abdomen (big spleen)
d. Labs/Imaging: Anemia, thrombocytopenia, hepatosplenomegaly, avascular necrosis in bones, Erlenmeyer flask deformity (X-ray of distal femur)
e. Organs involved- Liver, spleen, bone marrow (no CNS)
f. Key Features- Hepatosplenomegaly, anemia, thrombocytopenia, looks like ‘lymphoma’ (big spleen/anemia) but isn’t
g. Enzyme Deficient- Beta glucosidase (a.ka. Glucocerebrosidase)
h. Treatment- Enzyme Replacement: Imiglucerase, Velaglucerase, Taliglucerase,
Oral substrate inhibition: Eliglustat, Miglustat
Gaucher Type 1 (Adult Onset)
Most imporant points
a. Clinical Presentation- Fatigue, bony pain, enlarging abdomen (big spleen)
b. Key Features- Hepatosplenomegaly, anemia, thrombocytopenia, looks like ‘lymphoma’ (big spleen/anemia) but isn’t
c. Enzyme Deficient- Beta glucosidase (a.ka. Glucocerebrosidase)
Goals for the Medical Student
Do not memorize all the pathways
-Identify the few (very few) key pathways
Identify the general presentations* of: -Storage diseases (right now) -Other Lectures: Amino Acid disorders Organic Acid disorders Mitochondrial disorders Glycogen Storage disorders
*really means recognizing the ‘clinical scripts’
Glycolipids
Glycolipids
a. molecules that contain both carbohydrate and lipid components.
b. roles in cell signaling, cell membranes, and as an energy source.
c. most glycolipids are glycosphingolipids
d. important in many cell types, especially nervous tissues.
Storage Diseases
a. Collection of >50 rare conditions
i. Group prevalence ~ 1:5,000 (>60K in US)
b. Pathophysiology
i. ‘Substrates’ normally degraded accumulate
ii. Typically (but not always) due to a missing, malfunctioning enzyme
iii. Typically (but not always) the accumulating substrate is not acutely toxic
iv. Pathology, due to gradual accumulation—> cellular dysfunction and death
c. Lysosomal Storage Diseases (LSDs) represent important, treatable, examples of storage diseases
