Lysosomal Diseases

Question 1

What are clinical manifestations of lysosomal storage diseases in general?

Answer 1

belly distension, poor appetite, hepatosplenomegally, other organ enlargement
bleeding diathesis, pan cytopenia, amennorrhea/menorrhagia,
bone/joint pain or contractures, poor growth, failure to thrive, fatigue, sleep apnea
cardiac dysfunction
neural regression/loss of milestones/seizures/tremors/ataxia
cherry red spots, abnormal eye movements

Question 2

What distinguishes lysosomal storage diseases from other inborn errors of metabolism?

Answer 2

not usually associated with acute crisis
slowly progressive (degenerative)
normal labs

Question 3

How are lysosomal storage diseases inherited?

Answer 3

all are autosomal recessive except for Fabry and Hunter syndrome (X linked)

Question 4

What is MPSI?

Answer 4

Hurler, Hurler/Scheie, Scheie syndrome
results in build-up of GAG in muscles due to alpha-L-iduronidase deficiency
symptoms include macrocephally, chronic rhinitis/otitis media, carpal tunnel/contractures, hearing loss, developmental delay, Gibbus skeletal deformaty, short stature

Question 5

What is the prognosis for MPSI?

Answer 5

severe form (S)- presents first 6 months of life with lifespan of less than 10 years old
attenuated (H/HS)- presents at 3-8 years with normal lifespan
BMT is curative for severe form
ERT used for attenuated

Question 6

What is MPSII?

Answer 6

Hunter Syndrome
X-linked
resembles MPSI with no corneal clouding
hearing loss may be prominent
ERT is standard of care

Question 7

What is MPSVI?

Answer 7

Maroteaux Lamy Syndrome
mostly skeletal presentation with abnormal dentition, extreme short stature
HSCT improves quality of life and prevents ID

Question 8

What conditions should be included on a DDx for a patient with a cherry red spot?

Answer 8

Tay Sachs/Sandhoff
Gaugher Type 2
GM
Niemann-Pick A
Sialidosis
Galactosialidosis
Farber
Metachromatic leukodystrophy
Krabbe

Question 9

What is ISL mucolipidosis?

Answer 9

all lysosomal enzymes are present by not imported into the lysosome, so enzyme levels will be elevated in serum but low in WBCs

Question 10

What is oligosaccharidoses?

Answer 10

defects in enzymes that tag/package lysosomal enzymes with post translational modifications leading to defects in degradation
clinical features include hearing loss, hepatosplenomegally, developmental delay/regression, non-immune fetal hydrops, coarse appearing facies, dyostosis multiplex, and eye findings (corneal opacities, cherry red spot, cataracts)

Question 11

What is Tay Scahs?

Answer 11

G2 Gangliosidoses (storage of G2 ganglioside in neurons)
deficiency of hexosaminidase A (alpha beta)- alpha subunit deficiency
only neuronal presentation

Question 12

What is Sandhoff?

Answer 12

G2 gangliosidoses (storage of G2 ganglioside in neurons)
deficiency of hexosaminidase B (beta beta)- beta subunit deficiency
neuronal presentation with hepatosplenomegally

Question 13

Describe Infantile Onset G2 gangliosidoses.

Answer 13

death before age 4
loss of motor milestones and vision
seizures, exaggerated startle, weakness, and jerks
cherry red spots

Question 14

Describe Juvenile Onset G2 gangliosidoses.

Answer 14

presents at 2-10 years old

regression of milestones, dementia, optic atrophy/retinitis pigmentosa

Question 15

Describe Adult Onset G2 gangliosidoses.

Answer 15

dystonia
spinocerebellar degradation and ataxia
psychosis

Question 16

What is Niemann Pick Disease A/B in general?

Answer 16

sphingomyelinase deficiency
SMPD1 gene (11p15)

Question 17

Describe Niemann Pick Disease A.

Answer 17

life expectancy 2 years
frequent in AJ populations
presents with hepatosplenomegally w/ neonatal hyperbilirubinemia (3-4 months), severe neurodegenerative disorder, developmental progression until about 6 months then slow loss of milestones, blind, deaf, spastic, feeding issues –> wasting, cherry red spots, and lung infiltrates

Question 18

Describe Niemann Pick Disease B.

Answer 18

adolescent onset (less severe)
cognitively normal
more mild phenotype than A but similar symptom profile

Question 19

Describe Niemann Pick Disease C.

Answer 19

adolescent onset
due to defect in cholesterol esterification
NPC1 and NPC2 genes
liver and brain involvement (hepatosplenomegally, ataxia, neurological regression, dystonia, seizures, and supranuclear gaze palsy)
adults with psychiatric presentation with dementia

Question 20

What is Krabbe disease?

Answer 20

galactocerebroside beta-galactosidase deficiency
GALC gene
spectrum of severity
affects white matter of central and peripheral nervous system
late onset forms show weakness, vision loss, and neurophychiatric disease

Question 21

What is Metachromatic leukodystrophy?

Answer 21

arylsulfatase A deficiency
late infantile, juvenile, and adult neuropsychiatric forms
treated with ERT
BMT is curative and can prevent symptoms if done pre-symptomatically

Question 22

Describe the late infantile form of Metachromatic leukodystrophy.

Answer 22

presents 1-2 years old
motor regression --> cognitive regression
hypotonia --> hypertonia
pain in arms and legs
seizures
vision and hearing loss

Question 23

What is Lysosomal Acid Lipase Deficiency?

Answer 23

enzyme responsible for triglyceride and cholesterol ester hydrolysis
LIPA gene on 10q23 (AR)
infantile and later oneset forms

Question 24

Describe infantile onset Lysosomal Acid Lipase Deficiency.

Answer 24

Wolman disease
fatal before 1 year old
complete absence of LAL
failure to thrive, hepatosplenomegally, severe liver disease, anemia, progressive delays, adrenal enlargement, and calcifications

Question 25

Describe later onset Lysosomal Acid Lipase Deficiency.

Answer 25

cholesterol ester storage disease with variable onset
mild LAL deficiency
hypercholesterolemia and hypertriglyceridemia

Question 26

False positives on enzyme testing can be due to pseudodeficiencies in which lysosomal storage diseases?

Answer 26

Tay Sachs
MLD
Fabry
Pompe
Sly
MPSI

Question 27

What options are present for treatment of lysosomal storage diseases?

Answer 27

ERT
BMT/HSCT (good for neurological)
chaperone protein targeted therapy (small molecule)
preventative therapy
gene therapy (in vivo/ ex vivio)
substrate reduction therapy (small molecule)
symptomatic therapy