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
Lysosomal Storage Diseases (LSDs)
a. Rare diseases
i. ~50 recognized distinct LSDs
ii. Each due to a deficiency of a lyososomal protein/activity or (in few cases) from problems with lysosomal biogenesis
b. Most inherited in autosomal recessive manner
i. Fabry (~XLD), Hunter (XLR), and Danon disease (XLD) are exceptions
c. Common theme is gradual, progressive, accumulation of lysosomal substrates (usually in lysosomes)
LSD Incidence
a. Rare*
i. Gaucher: ~1:57,000
ii. Sialidosis: ~1:42,000,000
iii. ~All: ~1:7,700 (1:9,000 if prenatal cases excluded)
iv. ~~All: 1:5,000
b. Populations:
i. Gaucher: 1:855 (Ashkenazi Jews) (also high risk of Tay Sachs)
ii. Aspartylglucosaminuria: 1:18,500 (Finnish)
* Australian Data
What does storage disease look like?
Brain: cognitive function, behavior, loss-of-skills
Skin: coarseness*, thickness, hirsutism, angiokeratoma
Skull (Brain): macrocephaly*, hydrocephalus, seizures, ataxia, cognitive delay and cognitive regression
Eyes (‘window to brain’): corneal clouding, cherry red spot
Hearing: hearing loss
Ear/Nose/Throat*: macroglossia, sleep apena
Heart: cardiomyopathy, arrhythmia, thickened heart valves
Lungs: airway narrowing, pulmonary fibrosis
Liver: hepatosplenomegaly (preserved hepatic function)
GI: constipation and diarrhea (sometimes alternating)
Kidneys: progressive renal failure and proteinuria (Fabry disease)
Skeletal*: dysostosis multiplex, joint stiffness, short stature
Muscle: hypotonia, myoclonic jerks, spasticity, weakness
Tay Sachs Type I
a. Inheritance- Autosomal recessive; Higher in Ashkenazi Jews
b. Onset- Infantile or early, early childhood
c. Clinical Presentation- Blindness, seizures, mental/motor deterioration, likely will die
d. Lab/Imaging- No key Features
e. Organs involved- Eye (Cherry Red spot)
f. Key Features- Increased startle reflex, blindness, seizures
g. Enzyme Deficient- Beta-hexosaminidase A
h. Treatment- Supportive
Fabry Disease
a. Inheritance- X-linked (men generally affected more severely than women; but probably a male on boards)
b. Onset- Pre-Teen/Teen with neurological findings or
Adult with renal failure of
Older adult with LVH or stroke
c. Clinical Presentation:
- Acroparesthesias (pain in palms/soles, esp. with fevers)
- Proteinuria and renal failure
- Left ventricular hypertrophy/stroke
- Dark red, angiokeratomas (bathing suit distribution)
d. Lab/Imaging- Proteinuria, LVH
e. Organs involved - Nervous system, Renal, Cardiac, endothelial
f. Key Features- Above + family history of early renal failure in male relatives
g. Enzyme Deficient- Alpha-galactosidase
h. Treatment- agalsidase beta
Pompe Disease
a. Inheritance- Autosomal recessive
b. Onset- Infantile: present at 3-6 months; dead at 1 year (w/o Rx)
i. Childhood: not likely tested on
ii. Adult: slowly progressive muscle weakness
c. Clinical Presentation:
i. Infant with progressive muscle weakness and severe LVH; normal intelligence
ii. Adult with proximal muscle weakness and respiratory weakness (sleep apnea); normal intelligence
d. Lab/Imaging- Elevated CK; no cherry red spot; normal liver/spleen; glycogen on muscle biopsy
e. Organs involved- Skeletal muscles (all); heart (infant)
f. Key Features-Infant with muscle weakness, high CK, and LVH on ECG
Adult with sleep apnea and trouble climbing stairs
g. Enzyme Deficient- Alpha-glucosidase
h. Treatment- Alglucosidase alfa
Hunter Disease
a. Inheritance- X-linked recessive
b. Onset- Childhood
c. Clinical Presentation:
i. Coarse facies, airway disease, ear infections, hoarse voice, NO corneal clouding
d. Lab/Imaging- Hepatosplenomegaly, short stature
e. Organs involved- Brain, airway, liver, heart valves, skeleton
f. Key Features- Male only with above features and no corneal clouding
g. Enzyme Deficient- Iduronate sulfatase
h. Treatment- Idursulfase
Hurler Disease
a. Inheritance-Autosomal recessive
b. Onset- Childhood
c. Clinical Presentation
i. Coarse facies, airway disease, ear infections, hoarse voice, + corneal clouding, hearing loss
d. Lab/Imaging- Hepatosplenomegaly, short stature
e. Organs involved- Brain, airway, liver, heart valves, skeleton
f. Key Features- Probably a girl with this (so you know it’s not Hunter)
g. Enzyme Deficient- Alpha iduronidase
h. Treatment- laronidase
McArdle Disease
a. Inheritance- Autosomal recessive
b. Onset- Adulthood
c. Clinical Presentation:
i. Muscle weakness and cramping; often exercise related cramping
d. Lab/Imaging- High CK
e. Organs involved- Muscles
f. Key Features- Exercise related cramping and ‘second wind’ phenomenon (weak upon initial exercise; then gets ‘second wind’)
g. Enzyme Deficient- Glycogen phosphorylase
h. Treatment-Supportive
If you only remember 3 things!
- Cherry red spot in baby with increased startle reflex = Tay Sachs
- Adolescent/young male with acroparesthesias (pain in hands/feet) with fevers and bathing trunk rash = Fabry
- Floppy infant with LVH (probably seen with an ECG) = Pompe
Tay Sachs Type I
Must knows
- Inheritance- Autosomal recessive
i. * Higher in Ashkenazi Jews - Organs involved- Eye (Cherry Red spot)
- Key Features- Increased startle reflex, blindness, seizures
i. look for the increased startle reflex - Enzyme Deficient-
Beta-hexosaminidase A
Fabry Disease
Must know
- Inheritance- X-linked (men generally affected more severely than women; but probably a male on boards)
- Clinical Presentation:
i. Acroparesthesias (pain in palms/soles, esp. with fevers)
ii. renal failure
iii. Dark red, angiokeratomas (bathing suit distribution) - Key Features- Above + family history of early renal failure in male relatives
- Enzyme Deficient- Alpha-galactosidase
Pompe Disease
Must Knows
- Onset- Infantile: present at 3-6 months; dead at 1 year (w/o Rx)
i. Childhood: not likely tested on
ii. Adult: slowly progressive muscle weakness - Clinical Presentation:
i. Infant with progressive muscle weakness and severe LVH; normal intelligence
ii. Adult with proximal muscle weakness and respiratory weakness (sleep apnea); normal intelligence - Lab/Imaging- Elevated CK; NO cherry red spot; normal liver/spleen; glycogen on muscle biopsy
- Key Features-Infant with muscle weakness, high CK, and LVH on ECG
i. Adult with sleep apnea and trouble climbing stairs - Enzyme Deficient- Alpha-glucosidase
Hunter Disease
Must know points
- Inheritance- X-linked recessive
- Clinical Presentation:
i. Coarse facies, airway disease, ear infections, hoarse voice, NO corneal clouding - Key Features- Male only with above features and no corneal clouding
- Enzyme Deficient- Iduronate sulfatase
Hurler Disease
Must know points
- Inheritance-Autosomal recessive
i. Different than Hunter (is X) - Clinical Presentation
i. Coarse facies, airway disease, ear infections, hoarse voice, + corneal clouding, hearing loss
ii. Notice there is Corneal Clouding - Key Features- Probably a girl with this (so you know it’s not Hunter)
- Enzyme Deficient- Alpha iduronidase
Hurler and Hunter Disease
Hunter Disease:
1. Inheritance- X-linked recessive
- Clinical Presentation:
i. Coarse facies, airway disease, ear infections, hoarse voice, NO corneal clouding - Key Features- Male only with above features and NO corneal clouding
- Enzyme Deficient- Iduronate sulfatase
Hurler Disease:
- Inheritance- Autosomal recessive
i. Different than Hunter (is X) - Clinical Presentation
i. Coarse facies, airway disease, ear infections, hoarse voice, + corneal clouding, hearing loss
ii. Notice there is Corneal Clouding - Key Features- Probably a girl with this (so you know it’s not Hunter)
- Enzyme Deficient- Alpha iduronidase
McArdle
Must know
- Clinical Presentation:
i. Muscle weakness and cramping; often exercise related cramping
ii. Organs involved- Muscles - Key Features- Exercise related cramping and ‘second wind’ phenomenon (weak upon initial exercise; then gets ‘second wind’)
- Enzyme Deficient- Glycogen phosphorylase
A 25 year-old woman with a history of hepatosplenomegaly with eventual splenectomy, bone and joint pain, and a liver biopsy that showed wrinkled-looking cells (‘or foamy macrophages’) with accumulations of glucosylceramides. The most likely diagnosis is?
Fabry disease Farber disease Gaucher disease Krabbe Disease Niemann-Pick disease
Gaucher disease
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)
Mucopolysaccharidoses are inherited storage diseases caused by?
a. an increased rate of synthesis of proteoglycans
b. the synthesis of polysaccharides with an altered structure
c. defects in the degradation of proteoglycans
d. the synthesis of abnormally small amounts of protein cores
e. an insufficient amount of proteolytic enzymes
c. defects in the degradation of proteoglycans
A 13 month-old child who died at home had been suffering from cardiomegaly and progressive muscle weakness for the past five months. Prior to death his electrocardiogram showed rapid conduction time and wide amplitude QRS complex. A skeletal muscle biopsy showed elevated glycogen. Of the following, the most likely diagnosis is:
Fabry Disease Hurler disease Pompe disease Tay-Sachs disease Von Gierke’s disease
Pompe disease
- Onset- Infantile: present at 3-6 months; dead at 1 year (w/o Rx)
i. Childhood: not likely tested on
ii. Adult: slowly progressive muscle weakness - Clinical Presentation:
i. Infant with progressive muscle weakness and severe LVH; normal intelligence
ii. Adult with proximal muscle weakness and respiratory weakness (sleep apnea); normal intelligence - Lab/Imaging- Elevated CK; NO cherry red spot; normal liver/spleen; glycogen on muscle biopsy
- Key Features-Infant with muscle weakness, high CK, and LVH on ECG
i. Adult with sleep apnea and trouble climbing stairs - Enzyme Deficient- Alpha-glucosidase
A 13 month-old child who died at home had been suffering from cardiomegaly and progressive muscle weakness for the past five months. Prior to death his electrocardiogram showed rapid conduction time and wide amplitude QRS complex. A skeletal muscle biopsy showed elevated glycogen. Which of the following enzymes is most likely to be deficient?
a. Alpha-galactosidase
b. Alpha-glucosidase
c. Alpha-iduronidase
d. Glucocerebrosidase
e. Sphingomyelinase
Pompe disease
Enzyme Deficient- Alpha-glucosidase
Clinical Presentation:
i. Infant with progressive muscle weakness and severe LVH; normal intelligence
ii. Adult with proximal muscle weakness and respiratory weakness (sleep apnea); normal intelligence
Lab/Imaging- Elevated CK; NO cherry red spot; normal liver/spleen; glycogen on muscle biopsy
Key Features-Infant with muscle weakness, high CK, and LVH on ECG
i. Adult with sleep apnea and trouble climbing stairs
An 18 year-old man complains of a multi-year history of recurrent painful episodes involving his palms and the soles of his feet. He also has a history of irritable bowel syndrome and has been hospitalized twice for heat-intolerance this past summer. His past medical history is remarkable for two clavicular fractures, myopia, and one hospitalization for pneumonia.
Which of the following tests is most likely to reveal his diagnosis?
a. 24-hour urine collection and urinary creatinine measurement
b. Alpha-galactosidase activity in leukocytes
c. Bone survey X-rays
d. Echocardiogram
e. Serum ionized calcium
b. Alpha-galactosidase activity in leukocytes
Fabry Disease
1. Inheritance- X-linked (men generally affected more severely than women; but probably a male on boards)
- Clinical Presentation:
i. Acroparesthesias (pain in palms/soles, esp. with fevers)
ii. renal failure
iii. Dark red, angiokeratomas (bathing suit distribution) - Key Features- Above + family history of early renal failure in male relatives
- Enzyme Deficient- Alpha-galactosidase
