Biochem Flashcards
(44 cards)
Cystinosis
AR, CTNS
Unlike all other LSD’s
FTT, Cornea cystals & photophobia, renal failure, ID, CNS calcifications
tx: cysteine reducer
Mut spectrum: 50% SNV, 50% CNV
Fabry disease
XL, GLA
Neuropathic pain, cardio arryhythmia, white matter hyperintensities, angiokeratomas (male genetalia), cornea verticillata
dysautonomia w/ anhirdrosis; end stage=renal failure
Biomarker=GL3 in urine (enzyme activity is unreliable)
tx=ERT (algalsidase A or B) or chaperone therapy (migalastat)
dx: in females, enzyme is unreliable, can only be done molecularly
Metachromatic leukodystrophy
; AR ASA
late infantile: hypotonia, clumsiness, Dev. regression, neuropathy, seizures, HL; sparing of U shaped fibers buzzword
Juvenile: intellectual decline, clumsiness, incontinence, seizures
adult: psychiatric, neuro regresion
common pseudodef. allele
tx: HSCT + ERT approved in 2024
Krabbe disease:
AR, GALC
on RUSP!
Infantile: peripheral neuropathy, extreme irritability, hypertonia (opisthonic posture), spasticity
Juvenile: gait disturbance, peripheral neuropathy, dev. regression
Adult: gait disturbance, peripheral neuropathy, dev. regression
pathology: globoid macrophage cells
dx: screen is elevated psychosine, but diagnosis is leukocyte enzyme activity
tx: stem cell transplant, poor prognosis
common 30kb deletion
Farber disease;
AR ASAH1
triad of joint nodules, joint stiffness, hoarse voice
severe form: NDD, similar to krabbe
Tx: HSCT
Gaucher disease:
AR, GBA
High in AJ pop, carriers high risk for parkinson’s (most common risk factor for parkinson)
most common LSD
Type 1: hepatosplenomegaly, bone crises, erlenmeyer flask deformity, cytopenias
type 2 (most severe): early onset neuro involvement (eye movt, swallowing issues), neurodegeneration, lifespan <2y
type 3: type 1 findings + subacute & progressive neuro (DD, epilepsy, horizontal saccades)
dx: enzyme activity in leukocytes; monitor w/ glucosylsphingosine
tx: ERT (imiglucerase) for type 1 or Miglustat/Eliglustat (substrate reduction); (none effective for neuro symptoms)
Niemann-Pick A/B;
AR, SMPD1
Progressive
A: hepatosplenomegaly by 3mo, cherry red macula, neuro deterioratioin, deathy by 3y
B: later onset, bruising, variable NDD, survival into adulthood
tx: ERT (olipidase alfa), boardable now since there is adrug
Niemann-Pick type C:
AR, NPC1/2
non-enzyme LSD, this affects a transporter
hepatosplenomegaly, cholestasis, FTT, liver failure, supranuclear gaze palsy
late onset form includes movement dx and psychosis too
tx: miglustat
dx: best is genetics, positive filipin staining
GM1 gangliosidosis:
AR, GLB1
beta-galactosidase enzyme def. (same gene as Morquoio, but different part of gene is mutatedjnhhhhm
pheno is similar to GM2 (tay-sachs/sandhoff), but more variable bone changes
infantile: skeletal dysplasia, hepatosplenomegaly, dev. arrest, hypotonia, cherry red macula, death <2y
juvenile: loss of walking, hip dysplasia, vision loss (no cherry red macula), seizures, death mid teens
adult: gait disturbance, dysarthria, intellectual regression, death age is variable
Tx: none
Tay Sachs:
AR, HEXA
High in AJ
Neurodegeneration & cerebellar atrophy,
Infantile: startle response, macular cherry-red spot, blindness, hypotonia, seizures, spasticity
Late-infantile: ataxia, spasticity, seizures
Adult: movement dx
Dx: enzyme activity (beware of pseudodeficiency alleles), do not test women’s serum for tay-sachs
tx: none
Pompe disease,
AR, GAA
on RUSP
Progressive muscle damage (heart, skeletal, respiratory), can mimic muscular dystrophy
Early onset: profound hypotonia + hypertrophic cardiomyopathy (shortening of PR interval)
Late onset: limb-girdle myopathy, no cardiac involvement
late onset SNHL in treated survivors
tx: ERT (alglucosidase A), earlier is best, CRIM status is important here
dx: enzyme activity
Neuronal ceroid lipofuscinoses (NCL),
CLN2
most common neurometabolic dx
seizures, vision loss, cognitive regression, ataxia, spasticity
dx: mostly genetics
tx: ERT (injected into brain)
MPS I (Hurler):
AR, IDUA
on RUSP!
elevated HS & DS- so bone and brain invlovement
normal dev. for first few months
coarse facial features, ID, corneal clouding, dysostosis multiplex, hepatosplenomegaly
Severe: death by 10-12y
Attenuated: normal intellect, HL, hepatosplenomegaly, death by 20-30 w/o intervention
Diagnosis: screen w/ urine GAGs, diagnosis w/ enzyme testing
tx: stem cell transplant (HSCT), ERT prior to HSCT. but ERT never makes it to brain
MSP II (hunter):
XL, IDS
on RUSP!
only XL MPS, so think hunters are male. like MPS1, but only for males
elevated HS & DS- so bone and brain invlovement
coarse facial features, ID, no corneal clouding, dysostosis multiplex, hepatosplenomegaly
thickened skin lesions and slate grey macules (mongolian spots) are unique
attenuated form: little/no NDD; lifespan can be normal
Diagnosis: screen w/ urine GAGs, diagnosis w/ enzyme testing; molecular tests miss 20% of variants d/t deletions/rearrangments
tx: ERT (not effective for CNS). HSCT not effective
MPS III (Sanfillipo);
AR 4 genes
purely NDD, (only HS is elevated), fewer dysmorphic features
childhood alzheimers, aggressive behaviors, seizures, DD, regression
Tx: none
MPS IV (Morquoio):
AR, GALNS, GLB1
only KS elevated (no NDD)
extreme dwarfism, contractures, corneal clouding, poor dentition
tx: ERT (Vimizim)
dx: enzyme analysis
MPS VI (Maroteaux-lamy):
AR, ARSB
elevated DS, normal intellect
coarse features, corneal clouding, short stature, hepatomegalcy
tx: ERT (naglazyme)
MPS VII (Sly):
AR, GUSB
HS+DS
short, coarse facies, NDD, hepatosplenomegaly (looks like mps1/2)
hyrops fetalis is most common presentaiton
tx: ERT (vestronidase alfa)
Mucolipidoses
like all LSDs in one since this is caused by a phosphotransferase that activates all LSD enzymes
enzyme levels will be high in blood, but can’t get into cells
I cell disase (GNPTAB): like a severe MPS, onset at birth
dx: massive GAG increase in urine
Pseudo-hurler: like MPS I
Zellweger spectrum:
AR, PEX genes
NDD, hepatomegaly, bone stippling, dysmorphic features, vision/hearing loss
dysmorphic features: large fontanelle, high forehead
dx: VLCFA elevated (NBS), pristanic/phytanic acid elevated
XL-ALD:
XL, ABCD1
Most common peroxisome dx, on RUSP, childhood onset & progressive
Adrenal insufficiency (bronze skin), Severe cerebral anomalies, posterior white matter changes on MRI (T2 hyperintensity)
impaired cognition, vision/hearing loss, ataxia, spasticity
psychiatric changes, irritability, progressive demetnia
Dx: elevated VLCFA (NBS C26:0)
tx: corticosteroid replacement for adrenal insuff., HSCT, or gene therapy autotransplantation (elivaldogene autotemcel)
treatment guidelines- positive NBS isn’t enough to start treatment, need to see MRI lesions and declining neuro function
but treatment only works if presymptomatic
Refsum disease:
AR, PEX7
late childhood RP, anosmia, motor neuropathy, ichthyosis, short metacarpals, cardiac arrhythmia
dx: elevated phytanic acid
Rhizomelic chondrodysplasia
AR, PEX7
proximal shortening of the humeri, punctate calcifications in cartilage, coronal clefting of the several vertebrae and congenital cataracts
dx: low plasmalogen, normal VLCFA
Glycogen storage dx
themes: looks like MPS1/2 hepatomegaly +/- hypoglycemia, FTT, dysostosis multiplex, cherry red spots, angiokeratomas
type 1: hepatomegaly, hypoglycemia, doll like facies, short stature
tx: contunous feeding, cornstarch
Type 3: like type 1, but milder
Type 0: glycogen syntahse def. looks like type 1, but excellent prognosis
Type V (Mcardle’s disease)
muscle weakness & cramping, second wind phenomenon (fatigue at first, but ok once warmed up)
onset in adulthood
tx: glucose w/ exercise
