Inborn Errors : Glycolipid Disorders Flashcards
‘_______’refer to enzymes that can function in the
acid environment of the lysosome
Hydrolases
hydrolases are targeted to the lysosomes by _____ on the hydrolases that are recognized by receptors.
Mannose-6-Phosphate (M6P)
what are Lysosomes?
The garbage (or recycling) centers in cells that are acidic, contain ~50 hydrolase enzymes, that break down macromolecules into smaller components.
what is Lysosomal Storage Diseases (LSDs):
Occurs when a lysosomal enzyme (usually) is deficient/missing resulting in substrate(s)
accumulation (storage) in various organs.
The majority of LSDs are inherited in an autosomal recessive fashion.
Three exceptions that are inherited in X-linked
fashion are:
1) Fabry disease (alpha-galactosidase)
2) Hunter syndrome (iduronate-2-sulfatase)
3) Danon disease (Lysosome associated Membrane Protein 2).
In general LSDs are _____diseases that present less _______ than many other metabolic conditions.
progressive,
acutely
what enzyme is affected in gaucher’s disease?
Beta-glucosidase deficiency (glucocerebrosidase
what is the presentation of gaucher’s disease
: fatigue, bone pain, cytopenias, hepatomegaly, splenomegaly, poor growth
what is the treatment of gaucher?
Enzyme Replacement: Imiglucerase, Velaglucerase, Taliglucerase,
Oral substrate inhibition: Eliglustat, Miglustat
what is the age of onset for gaucher?
adult
what is the age of onset for hurler syndrome (MPS 1)
Childhood
what is the age of onset for tay sachs ?
Infantile or early, early childhood
what is the clinical presentation of tay sachs
Blindness, seizures, mental/motor deterioration, likely will die
what is the clinical presentation of tay sachs
hypotonia,increased startle, Blindness, seizures, mental/motor deterioration, likely will die
Cherry red spot on funduscopic exam is the classic physical exam finding for this disease
Tay sachs
what enzyme is affected in Fabry disease
Alpha galactosidase deficiency
describe the inheritance pattern of fabry disease
X-linked semi-dominant inheritance
Most women are symptomatic but at an older age than men. Often, patients will have an extensive family history of symptomatic individuals without a diagnosis
Describe the symptoms of fabry seen in boys
acroparesthesias, temperature intolerance
Describe the symptoms of fabry seen in boys
acroparesthesias (a condition of burning, tingling, or pricking sensations or numbness in the extremities).
temperature intolerance
what is seen in adults with fabry disease?
renal failure, cardiomyopathy, strokes, heart attacks, angiokeratomas
what enzyme is affected in Hurler syndrome
aka. Mucopolysaccharidosis type I (MPS I)
Alpha iduronidase deficiency results in Mucopolysaccharide storage and excretion in urine
What is the clinical presentation of hurler syndrome (MPS 1)
Short stature, macrocephaly, characteristic facial appearance (coarse facies)
Joint contractures, particularly the fingers
Cardiac valvular disease
Dysostosis multiplex
corneal clouding
Hepatosplenomegaly,
hearing loss
what is the treatment of hurler syndrome?
Treated with bone marrow transplantation or enzyme replacement therapy (laronidase)
what is hunter syndrome MPS II
Iduronate sulfatase deficiency
Hunter is clinically indistinguishable from hurler except for :
Hunter has no corneal clouding and is fully
X-linked no manifestations in females
Descibe coarse facies as seen in hunter and hurler syndromes
Thick hair, widely spaced teeth, macroglossia, wide nose, depressed nasal bridge
what is the age of onset and clinical presentation of pompe disease
Infantile: present at 3-6 months; hypotonia and severe cardiomyopathy, dead at 1 year (w/o Rx)
Adult: slowly progressive proximal muscle weakness and respiratory weakness (sleep apnea);
what is Dysostosis multiplex as seen in hurler and hunter syndrome
Vertebral breaking (compare to normal), broad phalanges and metacarpals Atlanto-axial subluxation
What enzyme is deficient in pompe disease?
Alpha-glucosidase -> Deficiency results in glycogen accumulation in lysosomes
what are the diagnostic tests for pompe disease?
Diagnostic testing: abnormal EKG (high voltage), elevated CK (muscle breakdown
what is the treatment for pompe disease?
enzyme replacement therapy (Alglucosidase alfa)
what is the treatment of fabry disease
Enzyme replacement therapy (agalsidase beta)
what is the treatment for tay sachs
Supportive
which storage disease can be treated with bone marrow transplant
hurler MPS 1
what is Niemann Pick A and what is a key feature
sphingomyelinase deficiency, cherry red sport
what are 2 key features of Niemann Pick C
supranuclear gaze palsy (can't look up) gelastic cataplexy (loss of muscle tone when laughing)
what is Sanfilippo (MPS-III)
a mucopolysaccharidosis that largely affects the brain
what is Morquio (MPS-IV)
a mucopolysaccharidosis that largely affects the skeleton
which storage disease has no cognitive symptoms
pompe
