Large, Sphingolipidoses

Question 1

[Met/SLs]

Examples of sphingolipidose diseases? (6)

Answer 1

Gaucher disease
Fabry disease
Niemann-Pick disease
Tay-Sachs disease
Krabbe’s disease
Sandhoff’s disease

Question 2

[Met/SLs/Gaucher]

Major types of Gaucher disease? (3)

Answer 2

Type 1 Gaucher: non-CNS
Type 2 Gaucher: CNS-involved, rapidly progressive
Type 3 Gaucher: CNS-involved, slowly progressive

Question 3

[Met/SLs/Gaucher]

Two other subtypes of Gaucher disease?

Answer 3

Perinatal-lethal Gaucher
Cardiovascular Gaucher

Question 4

[Met/SLs/Gaucher]

Clinical characteristics of Type 1 Gaucher? (3)

Answer 4

(No CNS involvement)
Hepatosplenomegaly in presentation
Bone pains (growing pain): osteopenia, focal lytic lesions
Bone marrow infiltration: anemia, thrombocytopenia

Question 5

[Met/SLs/Gaucher]

Clinical characteristics of Type 2 and 3 Gaucher? (3)

Answer 5

CNS involvement: limited psychomotor development
Hepatosplenomegaly
Type 2: rapidly progressive, death by 2-4 years
Type 3: slowly progressive, death by 20-30s

Question 6

[Met/SLs/Gaucher]

Clinical characteristics of perinatal-leathal Gaucher? (2)

Answer 6

Ichthyosiform or collodion skin abnormalities
Nonimmune hydrops fetalis

Question 7

[Met/SLs/Gaucher]

Clinical characteristics of cardiovascular Gaucher? (4)

Answer 7

Calcification of the aortic and mitral valves
Mild splenomegaly
Corneal opacities
Supranuclear ophthalmoplegia

Question 8

[Met/SLs/Gaucher]

Enzyme defect, causal gene and accumulating substance in Gaucher disease?

Answer 8

Enzyme: Glucocerebrosidase defect
Gene: GBA
Substance: glucocerebroside

Question 9

[Met/SLs/Gaucher]

Treatment for Gaucher disease type 1?

Answer 9

Enzyme replacement therapy (ERT): Cerezyme, VPRIV, Elelyso
Substance reducing therapy (SRT)

Question 10

[Met/SLs/Gaucher]

Response to enzyme replacement therapy for type 2 and 3 Gaucher disease?

Answer 10

Type 2 (neurologic rapidly progressing): non-responding
Type 3 (neurologic slowly progressing): variable

Question 11

[Met/SLs/Gaucher]

Population with High carrier frequency of Gaucher disease?

Answer 11

Ashkenazi Jewish

Question 12

[Met/SLs/Gaucher]

Disease with hepatosplenomegaly and bone pain
Cells with ‘wrinkled tissue pattern’

Answer 12

Gaucher disease

Question 13

[Met/SLs/ASMD-NPD]

Current classification of Niemann-Pick disease?

Answer 13

Acid Sphingomyelinase Deficiency (Niemann-Pick A and B)
Niemann-Pick type C

Question 14

[Met/SLs/ASMD]

Types of Acid Sphingomyelinase Deficiency (Niemann-Pick A&B)?

Answer 14

Severe, early onset, Infantile neurovisceral ASMD: Niemann-Pick type A
Late-onset, Chronic visceral form ASMD: Niemann-Pick type B

Question 15

[Met/SLs/ASMD]

Clinical presentation of Acid Sphingomyelinase Deficiency (Niemann-Pick A&B)? (3 by age)

Answer 15

For Infantile neurovisceral ASMD: Niemann-Pick type A
Hepatosplenomegaly by three months
Psychomotor deterioration and failure to thrive by 2 years
Interstitial lung disease and cherry-red spot in macula by 3 years
(Chronic visceral form ASMD: Niemann-Pick type B, similar, but slow presentation)

Question 16

[Met/SLs/ASMD]

Causal gene of Acid Sphingomyelinase Deficiency (Niemann-Pick A&B)?

Answer 16

SMPD1

Question 17

[Met/SLs/ASMD]

Treatment of of Acid Sphingomyelinase Deficiency (Niemann-Pick A&B)? (2)

Answer 17

Supportive
Hematopoietic stem cell transplantation (HSCT) (but doesn’t stabilize neurologic)

Question 18

[Met/SLs/NPC]

[Large, SLs - NPC]
Disease mechanism of Niemann-Pick type C?

Answer 18

Genetic defect of NPC1 or NPC2
Involved in routing of cholesterol esters within the lysosome

Question 19

[Met/SLs/NPC]

Clinical presentation of Niemann-Pick type C?

Answer 19

Hepatosplenomegaly, jaundice at birth
Neurologic impairment in late infancy: cataplex, narcolepsy, supra-nuclear vertical gaze palsy

Question 20

[Met/SLs/NPC]

Diagnostic test of Niemann-Pick type C?

Answer 20

NPC1 or NPC2 gene defect
(Not an enzyme defect, Genetic defect of cholesterol ester routing protein)

Question 21

[Met/SLs/NPC]

Screening test for of Niemann-Pick type C?

Answer 21

Assay of oxysterols

Question 22

[Met/SLs/TSD]

[Large, SLs - TSD]
Three subtypes of Tay-Sachs disease?

Answer 22

Classic Tay-Sachs: Infantile onset
Subacute juvenile TSD: onset in toddlers
Late-onset TSD: onset in teens and young adults

Question 23

[Met/SLs/TSD]

Clinical characteristics of classic Tay-Sachs disease? (5)

Answer 23

Onset in 3-6 months
Exaggerated startle response
Progressive weakness, loss of motor skills, seizures
Cherry red spot in retinas
Death by 4-5 years old

Question 24

[Met/SLs/TSD]

Clinical characteristics of subacute/late-onset Tay-Sachs disease?

Answer 24

Clumsy and awkward child
Intention tremor, dysarthria, proximal muscle weakness
Psychiatric: anxiety and depression

Question 25

[Met/SLs/Fabry]

Enzyme defect, gene and accumulating substance in Fabry disease?

Answer 25

Enzyme: Alpha-galactosidase A (α-Gal A)
Gene: GLA
Substance: Globotriaosylceramide

Question 26

[Met/SLs/TSD]

Enzyme defect and accumulating substance in Tay-Sachs disease?

Answer 26

Enzyme: hexosaminidase A
Substance: glycolipid GM2 ganglioside

Question 27

[Met/SLs/Fabry]

Clinical characteristics of classic Fabry disease? (7)

Answer 27

Onset: childhood or adolescence
Neuropathic pain: periodic crises of severe pain in the extremities (acroparesthesia)
Skin: angiokeratomas
Autonomic: anhidrosis, hypohidrosis, and rarely hyperhidrosis
Eye: corneal and lenticular opacities
Kidney: proteinuria, ESRD
Heme: cerebrovascular stroke, myocardial infarction

Question 28

[Met/SLs/Fabry]

Clinical characteristics of late-onset male Fabry disease?

Answer 28

Left ventricular hypertrophy, cardiomyopathy, arrhythmia
Proteinuria; renal failure
Cerebrovascular disease
(Without skin or pain crisis)

Question 29

[Met/SLs/Krabbe]

Two subtypes of Krabbe disease?

Answer 29

Infantile onset: <12 months
Later-onset: >12 months, varied symptoms

Question 30

[Met/SLs/Krabbe]

Symptoms of infantile onset Krabbe disease? (2)

Answer 30

Progressive neurologic deterioration in infancy
Death before age two years

Question 31

[Met/SLs/Krabbe]

Symptoms of later onset Krabbe disease? (2)

Answer 31

Slow development of motor milestones or loss of milestones
Seizure, spasticity, peripheral neuropathy