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MedGen 2 > Lysosomal Storage Disorders > Flashcards

Lysosomal Storage Disorders Flashcards

1
Q

> 70 Lysosomal storage disorders

  • Genetics
  • incidence
A

GENETICS

  • Most are AR
  • 3 are X-linked

INCIDENCE

  • as a group, 1:5,000
  • individual, >1:50,000
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2
Q

How are LSDs different from other IEMs?

A
  • slowly progressive (degenerative)
  • not usually associated with acute metabolic derangements or with “metabolic crisis”
  • common laboratory tests are often normal
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3
Q

Common LSD Clinical Manifestations

A 
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
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4
Q

What are Mucopolysaccharidoses?

A
  • 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
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5
Q

Hurler syndrome (MPS I)

A

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

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6
Q

Hurler MPS I-H symptoms

A
  • *Valvular heart disease
  • *Corneal clouding
  • *Joint stiffness/contractures
  • Obstructive airway disease
  • Hearing loss

Death at age 3-10
SEVERE cognitive impairement
Progressive

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7
Q

Hurler-Scheie MPS I-H/S symptoms

A
  • *Valvular heart disease
  • *Corneal clouding
  • *Joint stiffness/contractures
  • Hearing loss
  • Obstructive airway disease

Little to no intellectual defect
Death in late teens and 20s

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8
Q

Scheie MPS 1-S symptoms

A
  • *Valvular heart disease
  • *Corneal clouding
  • *Joint stiffness

Normal intelligence
Less progressive physical problems
Death in later decades

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9
Q

Hurler syndrome clinical characteristics

A

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
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10
Q

Hunter syndrome (MPS II)

  • deficiency
  • onset
  • genetics
A

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

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11
Q

MPS II severe form

A

Onset: 1-3 yrs
Impaired intelligence
Life expectancy: 10-15 yrs

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12
Q

MPS II attenuated form

A

Gradual onset
Normal intelligence
Variable life expectancy

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13
Q

Hunter syndrome (MPSII) common features

A 
PROGRESSIVE cognitive impairment
Behavior problems
- hyperactivity
- obstinance
- aggression
- autistic-like
Seizures
Communicating hydrocephalus
Hearing loss
Decreased night and peripheral vision

UNIQUE: nodular skin lesions

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14
Q

Sanfilippo syndrome (MPS III)

  • clinical manifestations
  • genetics
A

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

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15
Q

Morquio syndrome (MPS IV

  • genetics
  • incidence
A

2 disorders with same clinical phenotype
- MPS IV-A
- MPS IV-B
both types have wide spectrum of clinical involvement

AR

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16
Q

Morquio syndrome (MPS IV) clinical characteristics

A 
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

17
Q

Maroteaux-Lamy syndrome (MPS VI)

  • deficiency
  • symptoms
  • prognosis
  • genetics
A

Deficiency of: arylsulfatase B

Multi-systemic involvement
Normal intelligence

Early mortality (1st-2nd decade) in severe form
- cardiac, airway disease

Very rare

AR

18
Q

Sly syndrome (MPS VII)

A

Deficiency of: beta-glucuronidase

Common presentation : hydrops fetalis (swelling of newborn)

Somatic and CNS involvement similar to MPS I

Very rare

AR

19
Q

Dysostosis multiplex

A

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

20
Q

How is MPS diagnosed?

A

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

21
Q

Glycoproteinoses/glycoprotein storage disorders

A

Group of LSDs resulting from defects in glycoprotein degradation
Each disorder has a wide spectrum of severity. Some phenotypes resemble as MPS

22
Q

Oligosaccharidosis clinical features

A 
Developmental delay/regression
Hepatosplenomegaly
Coarse-appearing facies
Dysostosis multiplex
Eye findings (cherry-red spots, cataracts)
Hearing Loss
Angiokeratomas
23
Q

Mucolipidoses

A

All enzymes are present, but outside the lysosome

Lysosomal enzymes elevated in serum but decreased in WBC

24
Q

Tay Sachs and Sandhoff disease

- Cause

A

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

25
Q

Tay Sachs/Sandhoff different onsets

A

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
26
Q

Tay Sachs and Sandhoff disease

  • diagnosis
  • incidence
  • genetics
A

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

27
Q

Niemann-Pick type A

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

28
Q

Niemann-Pick type C symptoms

A

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

29
Q

Niemann-Pick type C diagnosis

A

Cultured fibroblasts

  • abnormal intracellular cholesterol homeostasis
  • Filipin staining - accumulated unesterified cholesterol

DNA analysis
- NPC1 and NPC2

Measure oxysterols

30
Q

Pompe Disease

  • infantile
  • late onset
A

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
31
Q

Krabbe disease

  • early onset
  • late-onset
A

EARLY ONSET

  • very irritable
  • elevated protein
  • leukodystrophy
  • neurological deterioration

presents in adults

  • weakness
  • vision loss
  • neuropsychiatric disease
32
Q

Metachromatic leukodystrophy infantile form

A 
Arylsulfatase A deficiency
INFANTILE FORM
- 1-2 yrs 
- motor --> cognitive regression
- hypotonia --> hypertonia
- arm and leg pain
- seizures
- vision and hearing loss
33
Q

Metachromatic leukodystrophy juvenile form

A

Onset 4-12 years

  • problems with learning and behavior
  • motor regression
  • slurred speech
  • seizures
34
Q

Metachromatic leukodystrophy adult form

A 
onset later
Problem with performance at work
personality changes
substance abuse
mood lability
some have neurologic abnormalities, seizures, and/or peripheral neuropathy

MedGen 2 (13 decks)

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