Lysosomal Diseases Flashcards
What are clinical manifestations of lysosomal storage diseases in general?
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
What distinguishes lysosomal storage diseases from other inborn errors of metabolism?
not usually associated with acute crisis
slowly progressive (degenerative)
normal labs
How are lysosomal storage diseases inherited?
all are autosomal recessive except for Fabry and Hunter syndrome (X linked)
What is MPSI?
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
What is the prognosis for MPSI?
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
What is MPSII?
Hunter Syndrome X-linked resembles MPSI with no corneal clouding hearing loss may be prominent ERT is standard of care
What is MPSVI?
Maroteaux Lamy Syndrome
mostly skeletal presentation with abnormal dentition, extreme short stature
HSCT improves quality of life and prevents ID
What conditions should be included on a DDx for a patient with a cherry red spot?
Tay Sachs/Sandhoff Gaugher Type 2 GM Niemann-Pick A Sialidosis Galactosialidosis Farber Metachromatic leukodystrophy Krabbe
What is ISL mucolipidosis?
all lysosomal enzymes are present by not imported into the lysosome, so enzyme levels will be elevated in serum but low in WBCs
What is oligosaccharidoses?
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)
What is Tay Scahs?
G2 Gangliosidoses (storage of G2 ganglioside in neurons) deficiency of hexosaminidase A (alpha beta)- alpha subunit deficiency only neuronal presentation
What is Sandhoff?
G2 gangliosidoses (storage of G2 ganglioside in neurons) deficiency of hexosaminidase B (beta beta)- beta subunit deficiency neuronal presentation with hepatosplenomegally
Describe Infantile Onset G2 gangliosidoses.
death before age 4
loss of motor milestones and vision
seizures, exaggerated startle, weakness, and jerks
cherry red spots
Describe Juvenile Onset G2 gangliosidoses.
presents at 2-10 years old
regression of milestones, dementia, optic atrophy/retinitis pigmentosa
Describe Adult Onset G2 gangliosidoses.
dystonia
spinocerebellar degradation and ataxia
psychosis
What is Niemann Pick Disease A/B in general?
sphingomyelinase deficiency SMPD1 gene (11p15)
Describe Niemann Pick Disease A.
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
Describe Niemann Pick Disease B.
adolescent onset (less severe) cognitively normal more mild phenotype than A but similar symptom profile
Describe Niemann Pick Disease C.
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
What is Krabbe disease?
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
What is Metachromatic leukodystrophy?
arylsulfatase A deficiency
late infantile, juvenile, and adult neuropsychiatric forms
treated with ERT
BMT is curative and can prevent symptoms if done pre-symptomatically
Describe the late infantile form of Metachromatic leukodystrophy.
presents 1-2 years old motor regression --> cognitive regression hypotonia --> hypertonia pain in arms and legs seizures vision and hearing loss
What is Lysosomal Acid Lipase Deficiency?
enzyme responsible for triglyceride and cholesterol ester hydrolysis
LIPA gene on 10q23 (AR)
infantile and later oneset forms
Describe infantile onset Lysosomal Acid Lipase Deficiency.
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
Describe later onset Lysosomal Acid Lipase Deficiency.
cholesterol ester storage disease with variable onset
mild LAL deficiency
hypercholesterolemia and hypertriglyceridemia
False positives on enzyme testing can be due to pseudodeficiencies in which lysosomal storage diseases?
Tay Sachs MLD Fabry Pompe Sly MPSI
What options are present for treatment of lysosomal storage diseases?
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
