Lysosomal Storage Disorders Flashcards
> 70 Lysosomal storage disorders
- Genetics
- incidence
GENETICS
- Most are AR
- 3 are X-linked
INCIDENCE
- as a group, 1:5,000
- individual, >1:50,000
How are LSDs different from other IEMs?
- slowly progressive (degenerative)
- not usually associated with acute metabolic derangements or with “metabolic crisis”
- common laboratory tests are often normal
Common LSD Clinical Manifestations
Failure to Thrive Abdominal distension with poor appetite Fatigue Bleeding diathesis Amennorrhea, menorrhagia Bone/joint pain sleep apnea Neural regression, loss of milestones, seizures, tremors, ayaxia
What are Mucopolysaccharidoses?
- 11 known lysosomal enzyme deficiences, 7 diff clinical types
- rare
- affect tissue storage of glycosaminoglycans
- progressive disorders with multisystemic involvement
Includes:
- Hurler
- Scheie
- Hunter
- Sanfilippo
- Morquio
Hurler syndrome (MPS I)
Deficiency of: enzyme alpha-L-iduronidase
Onset: > 6 mo
Rare
AR
3 forms: Hurler, Hurler-Scheie, Scheie
all patients have <1% of normal enzyme levels
Hurler MPS I-H symptoms
- *Valvular heart disease
- *Corneal clouding
- *Joint stiffness/contractures
- Obstructive airway disease
- Hearing loss
Death at age 3-10
SEVERE cognitive impairement
Progressive
Hurler-Scheie MPS I-H/S symptoms
- *Valvular heart disease
- *Corneal clouding
- *Joint stiffness/contractures
- Hearing loss
- Obstructive airway disease
Little to no intellectual defect
Death in late teens and 20s
Scheie MPS 1-S symptoms
- *Valvular heart disease
- *Corneal clouding
- *Joint stiffness
Normal intelligence
Less progressive physical problems
Death in later decades
Hurler syndrome clinical characteristics
Skeletal deformities
Short stature
Hepatosplenomegaly
Carpal tunnel syndrome and other nerve entrapments and compressions
Umbilical/inguinal hernia - often first clinical signs noted
Corneal clouding, may lead to blindness
- also common: retinal degradation
Coarse facial features
-
INVOLVES CNS*
remember: it’s progressive. more clinical signs appear as child ages
Hunter syndrome (MPS II)
- deficiency
- onset
- genetics
Deficiency of: iduronate-2-sulfatase
Onset: 1-3 yrs (severe form)
X-linked recessive
- carrier females do not show symptoms
- Rare
similar to MPS I, no corneal clouding
MPS II severe form
Onset: 1-3 yrs
Impaired intelligence
Life expectancy: 10-15 yrs
MPS II attenuated form
Gradual onset
Normal intelligence
Variable life expectancy
Hunter syndrome (MPSII) common features
PROGRESSIVE cognitive impairment Behavior problems - hyperactivity - obstinance - aggression - autistic-like Seizures Communicating hydrocephalus Hearing loss Decreased night and peripheral vision
UNIQUE: nodular skin lesions
Sanfilippo syndrome (MPS III)
- clinical manifestations
- genetics
4 disorders, all with the same clinical phenotype
CLINICAL MANIFESTATIONS:
- neurologic deterioration by 6-10 yrs old
- hyperactivity
- relatively mild somatic features
- death in teenage years
some mild forms, usually not detected
AR
Morquio syndrome (MPS IV
- genetics
- incidence
2 disorders with same clinical phenotype
- MPS IV-A
- MPS IV-B
both types have wide spectrum of clinical involvement
AR
Morquio syndrome (MPS IV) clinical characteristics
Normal intelligence Platyspondyly, beaking A spondyloepiphyseal dysplasia Short trunk dwarfism ligamentous laxity Atlanto-axial instability Genu valgum
Some bones may be affected more than others
Maroteaux-Lamy syndrome (MPS VI)
- deficiency
- symptoms
- prognosis
- genetics
Deficiency of: arylsulfatase B
Multi-systemic involvement
Normal intelligence
Early mortality (1st-2nd decade) in severe form - cardiac, airway disease
Very rare
AR
Sly syndrome (MPS VII)
Deficiency of: beta-glucuronidase
Common presentation : hydrops fetalis (swelling of newborn)
Somatic and CNS involvement similar to MPS I
Very rare
AR
Dysostosis multiplex
Constellation of radiographic findings classically seen in MPS, result from abnormal bone growth
seen in many disorders, including MPS II/III
Clavicles thickened and shortened
Ribs narrow posteriorly,, widen anteriorly
Thick, proximal pointing metacarpals
Anterior beaking/wedging
How is MPS diagnosed?
Clinical suspicion
X-ray to evaluate for dysostosis multiplex
Quantitative urine total GAG analysis, component analysis by LC-MS/MS
If all these indicate MPS, conduct lysosomal enzyme testing on serum, WBC’s, or fibroblasts
Glycoproteinoses/glycoprotein storage disorders
Group of LSDs resulting from defects in glycoprotein degradation
Each disorder has a wide spectrum of severity. Some phenotypes resemble as MPS
Oligosaccharidosis clinical features
Developmental delay/regression Hepatosplenomegaly Coarse-appearing facies Dysostosis multiplex Eye findings (cherry-red spots, cataracts) Hearing Loss Angiokeratomas
Mucolipidoses
All enzymes are present, but outside the lysosome
Lysosomal enzymes elevated in serum but decreased in WBC
Tay Sachs and Sandhoff disease
- Cause
GM2 Gangliosidoses
Both result from hexosaminidase deficiency (cannot store GM2 ganglioside in neurons)
Tay-Sachs: Hex A def
Sandhoff: Hex A & B def
GM2 gangliosides must be activated in order for Hex to act upon it
Pseudodeficiency common
Tay Sachs/Sandhoff different onsets
INFANTILE
- death before 4 yrs
- loss of motor milestones and vision
- seizures
- exaggerated startle
- weakness and jerks
- CHERRY RED SPOT
JUVENILE
- onset 2-10 yrs
- regression of milestones
- dementia
- optic atrophy/RP
ADULT
- dystonia
- spinocerebellar degradation
- ataxia
- psychosis
Tay Sachs and Sandhoff disease
- diagnosis
- incidence
- genetics
DIAGNOSIS:
- enzyme assay or DNA
CARRIER FREQUENCY
- 1/30 AJ
- 1/300 non-AJ
- increased freq in Moroccan Jews, French Canadian, Cajuns
3 muts account for 98% of AJ muts
90% reduction in incidence in AJ because of carrier screening
Niemann-Pick type A
neurodegenerative disorder of infancy neonatal hyperbilirubinemia Hepatosplenomegaly Lose milestones Blind, deaf, spastic Lung infiltrates Cherry red spots Death ~ 2 yrs old
AJ, high carrier freq
Niemann-Pick type C symptoms
Liver-brain involvement
Due to defect in cholesterol esterification
Degenerative neurologic disease
Liver disease in infancy in some
Hepatosplenomegaly
Ataxia, neurologic regression, dystonia, seizures
Supranuclear gaze palsy
Adults - psychiatric presentation, dementia
Niemann-Pick type C diagnosis
Cultured fibroblasts
- abnormal intracellular cholesterol homeostasis
- Filipin staining - accumulated unesterified cholesterol
DNA analysis
- NPC1 and NPC2
Measure oxysterols
Pompe Disease
- infantile
- late onset
Doesn’t resemble other LSD’s
INFANTILE
- hypotonia
- cardiomyopathy
LATE-ONSET
- childhood onset:
- muscle weakness
- may mimic DMD
- adult onset
- mimics limb-girdle muscular dystrophy
Krabbe disease
- early onset
- late-onset
EARLY ONSET
- very irritable
- elevated protein
- leukodystrophy
- neurological deterioration
presents in adults
- weakness
- vision loss
- neuropsychiatric disease
Metachromatic leukodystrophy infantile form
Arylsulfatase A deficiency INFANTILE FORM - 1-2 yrs - motor --> cognitive regression - hypotonia --> hypertonia - arm and leg pain - seizures - vision and hearing loss
Metachromatic leukodystrophy juvenile form
Onset 4-12 years
- problems with learning and behavior
- motor regression
- slurred speech
- seizures
Metachromatic leukodystrophy adult form
onset later Problem with performance at work personality changes substance abuse mood lability some have neurologic abnormalities, seizures, and/or peripheral neuropathy
