Tay Sachs Flashcards
(28 cards)
What is a lysosome?
Organelle that degrades complex molecules within cells
True or false: most LSD are asymptomatic at birth
TRUE
What is the gene and mode of inheritance of Tay Sachs?
HEXA (AR)
What is the biological mechanism in Tay Sachs?
GM2 ganglioside accumulation primarily in CNS leads to neurodegeneration
What is the carrier freq of AJ for Tay Sachs?
~1/30
Besides AJ what other groups are affected by Tay Sachs?
French Quebec, Amish, Cajun
What is the genotype/phenotype correlation in Tay Sachs?
Two null = infantile
One null + one missense = subacute juvenile-onset
Two missense = milder late-onset
(lower level of enzyme the more severe the phenotype)
When does ganglioside accretion occur?
As early as the 10th week of gestation
Continues through year 5 of life
What is the Hex A activity in the infantile form of Tay Sachs (untreated)?
0-5%
What is the phenotype of the infantile form of Tay Sachs (untreated)?
Onset by 6 mos
Death 2-4 years
Neurodegeneration 3-6 months
No organomegaly
Cherry red spot in almost all patients
What is the neurodegeneration in the infantile form of Tay Sachs (untreated)?
Loss of motor skills with progressive weakness
Decreased attentiveness with increased startle response
Progressive spasticity, seizures, loss of vision, swallowing, awareness, followed by death
What is a cherry red spot?
Small circular red spot in the center of the macula
Produced when ganglion cells are filled with lipid degenerate
What is the Hex A activity in the juvenile and adult form of Tay Sachs (untreated)?
5-15%
What is the phenotype of the juvenile and adult form of Tay Sachs (untreated)?
Progressive dystonia, spasticity, incoordination, ataxia
Speech and cog decline
Optic atrophy +/- cherry red spot
Psychosis, agitation, hallucinations, dementia
Death after 10-15 years (juvenile)
What are possible cardio findings in Tay Sachs?
prolonged QT interval
nonspecific T wave changes
How many mutations account for 94% allele carrier detection rate in AJ?
~6 mutations:
3 null
G269S
2 pseudo-deficiency alleles
What should you suspect if both Hex A and Hex B levels are low?
Sandhoff Disease
What does Pseudodeficiency mean in Tay Sachs?
Pseudodeficiency refers to an in vitro phenomenon caused by specific HEXA variants that renders the enzyme unable to process the synthetic (but not the natural) GM2 substrates, and leads to false positive enzyme testing results.
What do we know about non-Jewish individuals, HEX A enzyme-based testing, and pseudodeficiency allele?
About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele.
What is an important note when ordering biochemical carrier testing in a pregnant person?
Leukocyte testing (rather than serum testing) should be ordered for TSD carrier detection in women who are pregnant or using oral contraceptive medication.
What are the brain MRI findings in Tay Sachs?
Atrophy of white matter demyelination
How do you treat Tay Sachs?
No preventative therapy (BMT, ERT, SRT not effective)
AEs for seizures
Respiratory support
Supplemental nutrition
What is a differential diagnosis of Tay Sachs?
Activator-deficient TSD 1 (GM2 gangliosidosis, AB variant) caused by variants in GM2A
Normal Hex A and Hex B levels
What are the clinical features of Sandhoff Disease?
Progressive neurodegeneration
Starts at 6 months
Hyperacusis
Cherry red spot
Blindness
Hepatosplenomegaly
Skeletal abnormalities
Deficiency of both HEX A & HEX B enzyme activity
