Inborn Errors : Glycolipid Disorders

Question 1

‘_______’refer to enzymes that can function in the

acid environment of the lysosome

Answer 1

Hydrolases

Question 2

hydrolases are targeted to the lysosomes by _____ on the hydrolases that are recognized by receptors.

Answer 2

Mannose-6-Phosphate (M6P)

Question 3

what are Lysosomes?

Answer 3

The garbage (or recycling) centers in cells that are acidic, contain ~50 hydrolase enzymes, that break down macromolecules into smaller components.

Question 4

what is Lysosomal Storage Diseases (LSDs):

Answer 4

Occurs when a lysosomal enzyme (usually) is deficient/missing resulting in substrate(s)
accumulation (storage) in various organs.

Question 5

The majority of LSDs are inherited in an autosomal recessive fashion.
Three exceptions that are inherited in X-linked
fashion are:

Answer 5

1) Fabry disease (alpha-galactosidase)
2) Hunter syndrome (iduronate-2-sulfatase)
3) Danon disease (Lysosome associated Membrane Protein 2).

Question 6

In general LSDs are _____diseases that present less _______ than many other metabolic conditions.

Answer 6

progressive,

acutely

Question 7

what enzyme is affected in gaucher’s disease?

Answer 7

Beta-glucosidase deficiency (glucocerebrosidase

Question 8

what is the presentation of gaucher’s disease

Answer 8

: fatigue, bone pain, cytopenias, hepatomegaly, splenomegaly, poor growth

Question 9

what is the treatment of gaucher?

Answer 9

Enzyme Replacement: Imiglucerase, Velaglucerase, Taliglucerase,
Oral substrate inhibition: Eliglustat, Miglustat

Question 10

what is the age of onset for gaucher?

Answer 10

adult

Question 11

what is the age of onset for hurler syndrome (MPS 1)

Answer 11

Childhood

Question 12

what is the age of onset for tay sachs ?

Answer 12

Infantile or early, early childhood

Question 13

what is the clinical presentation of tay sachs

Answer 13

Blindness, seizures, mental/motor deterioration, likely will die

Question 14

what is the clinical presentation of tay sachs

Answer 14

hypotonia,increased startle, Blindness, seizures, mental/motor deterioration, likely will die

Question 15

Cherry red spot on funduscopic exam is the classic physical exam finding for this disease

Answer 15

Tay sachs

Question 16

what enzyme is affected in Fabry disease

Answer 16

Alpha galactosidase deficiency

Question 17

describe the inheritance pattern of fabry disease

Answer 17

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

Question 18

Describe the symptoms of fabry seen in boys

Answer 18

acroparesthesias, temperature intolerance

Question 19

Describe the symptoms of fabry seen in boys

Answer 19

acroparesthesias (a condition of burning, tingling, or pricking sensations or numbness in the extremities).
temperature intolerance

Question 20

what is seen in adults with fabry disease?

Answer 20

renal failure, cardiomyopathy, strokes, heart attacks, angiokeratomas

Question 21

what enzyme is affected in Hurler syndrome

aka. Mucopolysaccharidosis type I (MPS I)

Answer 21

Alpha iduronidase deficiency results in Mucopolysaccharide storage and excretion in urine

Question 22

What is the clinical presentation of hurler syndrome (MPS 1)

Answer 22

Short stature, macrocephaly, characteristic facial appearance (coarse facies)
Joint contractures, particularly the fingers
Cardiac valvular disease
Dysostosis multiplex
corneal clouding
Hepatosplenomegaly,
hearing loss

Question 23

what is the treatment of hurler syndrome?

Answer 23

Treated with bone marrow transplantation or enzyme replacement therapy (laronidase)

Question 24

what is hunter syndrome MPS II

Answer 24

Iduronate sulfatase deficiency

Question 25

Hunter is clinically indistinguishable from hurler except for :

Answer 25

Hunter has no corneal clouding and is fully

X-linked no manifestations in females

Question 26

Descibe coarse facies as seen in hunter and hurler syndromes

Answer 26

Thick hair, widely spaced teeth, macroglossia, wide nose, depressed nasal bridge

Question 27

what is the age of onset and clinical presentation of pompe disease

Answer 27

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);

Question 28

what is Dysostosis multiplex as seen in hurler and hunter syndrome

Answer 28

Vertebral breaking (compare to normal), broad phalanges and metacarpals
Atlanto-axial subluxation

Question 29

What enzyme is deficient in pompe disease?

Answer 29

Alpha-glucosidase -> Deficiency results in glycogen accumulation in lysosomes

Question 30

what are the diagnostic tests for pompe disease?

Answer 30

Diagnostic testing: abnormal EKG (high voltage), elevated CK (muscle breakdown

Question 31

what is the treatment for pompe disease?

Answer 31

enzyme replacement therapy (Alglucosidase alfa)

Question 32

what is the treatment of fabry disease

Answer 32

Enzyme replacement therapy (agalsidase beta)

Question 33

what is the treatment for tay sachs

Answer 33

Supportive

Question 34

which storage disease can be treated with bone marrow transplant

Answer 34

hurler MPS 1

Question 35

what is Niemann Pick A and what is a key feature

Answer 35

sphingomyelinase deficiency, cherry red sport

Question 36

what are 2 key features of Niemann Pick C

Answer 36

supranuclear gaze palsy (can't look up) 
gelastic cataplexy (loss of muscle tone when laughing)

Question 37

what is Sanfilippo (MPS-III)

Answer 37

a mucopolysaccharidosis that largely affects the brain

Question 38

what is Morquio (MPS-IV)

Answer 38

a mucopolysaccharidosis that largely affects the skeleton

Question 39

which storage disease has no cognitive symptoms

Answer 39

pompe