Tay-Sachs Disease

From Iusmgenetics

Revision as of 19:32, 18 October 2011

Tay-Sachs Disease

General background information

• Tay-Sachs disease is a lysosomal storage disease secondary to HexA deficiency and GM2 accumulation.
• Tay-Sachs primarily affects the brain.

Mode of inheritance

• Autosomal recessive
• Demonstrates allelic heterogeneity: > 90 mutations identified
  • Note that there are 3 particular mutations frequent in the Ashkenazi population
  • This is also responsible for the variability of symptoms.
• Caucasians:
  • Carrier frequency: 1/250
  • Disease frequency: 1/250K
• Ashkenazi Jews:
  • Carrier frequency: 1/30
  • Disease frequency: 1/3600
  • Only 16 babies born in 2003 with Tay Sachs
  • Significant decrease in occurrence in the last 40 years due to screening programs and education for potential parents.
• Homozygous patients don't live to reproduction.
• Haplosufficiency: you can test carriers by enzymatic activity because they have decreased enzymatic activity.

Single important gene

• HEXA: codes for the enzyme hexosaminidase A which degrades the GM2 sphingolipid found in neurons.
  • Note that HEXA codes for only one of the two subunits of the enzyme hexosaminidase.
  • HEXB codes for the other subunit of hexosaminidase.
  • An activator gene codes for an activator protein that must also be present for hexosaminidase to function.

• There are two forms of hexosaminidase: thermolabile (HexA-HexB) and thermostable (HexB-HexB).
  • Mutation of either HexA or HexB can cause disease: HexA mutants are called Tay-Sachs disease and HexB mutatns are called Sandhoff disease.

Etiology

• Tay-Sachs disease is a deficiency of hexosaminidase A which normally serves to break down sphingolipid GM2 ganglioside in neurons.
  • Hexosaminidase A is a two-subunit enzyme.
• GM2 gangliosidosis
  • There are two other diseases of this type, also.

• Heterodimer of α and β subunits
  • The HexA gene codes for the α subunit
• GM2 gangliosides are a specialized group of glycosphingolipids that function in cell signaling and are part of the plasma membrane
• Remove the terminal, non-reducing N-acetlygalactosamine from the GMA ganglioside
• HexA α is specifically responsible for hydrolysis
  • Beta is just as important, however.
• beta hex a has an alpha and beta subunit.
• beta hex b has two beta subunits.
• In infantile Tay Sachs disease, most mutations are in the alpha chain, but this is different for other TSDs.
• HexA should be breaking down GM2 in the lysosomes.
• Gangliosides are quickly made and then broken down in the brain
• Without HexA GM2 gangliosides cannot be broken down so they are retained in the lysosome
• This eventually causes neural impairment GM2 accumulation
• GM2 accumulation -> Neuron Cell body distension -> Neuronal cell death -> Eventual brain atrophy

• Over 100 mutations have been found
• Most common in Ashkenazi Jews
  • 4 bp insert in exon 11 of HEXA, yields a reading frame shift
    • Results in a premature stop codon
    • 80% of Ashkenazi Jewish carriers have this mutation
    • May be more complex than simple founder effect because even in the non-carrier population there is a higher mutation rate (or something like that).
• Most common in French Canadians
  • 7.5 Kb deletion including all of exon1 and some upstream DNA
• Most other mutations are restricted to a single pedigree

Pathogenesis

• Tay-Sachs disease is a deficiency of hexosaminidase A and generally manifests symptoms at 3-6 months and results in death before the age of 5.

• Later-onset forms include: late infantile-, juvenile-, and adult-onset.
  • Late infantile-onset and Juvenile-onset:
    • onset between 2-10 years;
    • ataxia, incoordination, dysarthria, spasticity, seizures;
    • progressive deterioration;
    • death in second decade
  • Adult-onset:
    • clinical variability
    • movement disorders, psychosis

• Juvenile
  • Essentially the same as infantile, just earlier
  • Presents at age 2 – 10
  • Same symptoms as infantile
  • Usually die between ages 10 and 15
  • All patients die, just like with infantile.
• Late Onset
  • Usually develops between 20 and 30
  • Speech and swallowing difficulties, motor control decline, cognitive decline, psychiatric illness
  • Usually live to normal ages, and can live relatively normal lives
  • Looks like other neural degenerative diseases
  • Usually wheelchair bound.
• The typical AJ mutation completely destroys function of protein, so it yields infantile. Other mutations retain some function and therefore generate the juvenile and late onset.
  • And you only need 10% removal of GM2 for pretty normal function.

Phenotypic information

• Normal at birth.
• Cherry red spot in the retina of the eye
  • Results from accumulation of sphingolipids in the surrounding nerves, thus causing a lighter area and accentuating the red spot of the fovea.
• Exaggerated response to loud noises by 3-6 months
• Motor weakness and hypotonia
• Loss of acquired milestones
• Loss of visual attentiveness, progression to blindness
• Macrocephalus by 18 months
• Spacticity
• Swallowing disorder
• Seizures
• Dementia by age 3
• Abnormal posturing by age 3
  • Decerebrate, involuntary extension of extremities
• Vegetative state and dead before age 5

• Cherry Red macula on retina – diagnosis
• Lack of developmental progress
  • Wont sit up, roll over, play with toys, lethargy, etc.
• Startled by loud noises - hyperacusis
  • An early phenotype
• Difficulty coordinating mouth and tongue when swallowing
• Increasing lethargy
• Seizures
• Asymptomatic for first 6 months of life
• Slowly lose CNS function
• Go deaf, blind and have breathing difficulties
• Eventual paralysis
• Usually die from wasting away or complications or paralysis
  • Breathing troubles etc.
• Infantile Tays Sachs patients usually show symptoms around 6 months of age and usually die by age 5
  • Really sad!
• Cloudiness around the macula is the build up of GM2.
• Used to diagnose using Cherry Red spot on retina
• Now use DNA testing using restriction endonucleases or do an enzymatic activity assay
  • Many people with the mutation have the same mutation, so we can do a simple endonuclease test.
• Not tested for in standard newborn screens.

Diagnosis

• Dx is generally by HexA activity enzyme assay; disease-state levels are usually zero or near zero.

• Carrier testing:
  • Carriers are identified by their markedly reduced HexA enzymatic activity (though not reduced enough to cause disease).
  • Males and non-pregnant, non-oral contraceptive women can be tested with a serum HexA activity assay.
    • This assay is complicated by pseudodeficiency alleles that have a low efficacy against a synthetic substrate (used in the test) but a normal activity against endogenous GM2.
  • Pregnant women or women on oral contraceptives can be tested with leukocyte mutation analysis.
  • Mutation analysis of the HexA gene is used primarily for establishing if carrier parents have a pseudodeficiency allele or a true disease-causing allele.
    • Tests for 2 polymorphisms: R247W and R249W which identify the alleles (though may not be the cause of disease).
  • Carrier testing in the Ashkenazi population has reduced the incidence of Tay-Sachs by 90%.

• Prenatal testing:
  • Prenatal testing is done when both parents have had positive enzyme tests, negative pseudodeficiency allele tests, yet a disease mutation is not found.
  • Prenatal testing is done by enzyme assay from a chorionic villus samping at 10-12 weeks gestation or amniocentesis at 16-18 weeks gestation.

Carrier testing

• Dor Yeshorim testing:
  • Hebrew for "upright generation"
  • Started by Rabbi that was father of four children with Tay Sachs
• Provide anonymous testing and mate screening in Jewish populations
  • Test High school age population
    • They test for 15 diseases and then you call the hotline to see if you and your mate are a good match.
• Programs like this have decreased the incidence of Tay Sachs by 90% in both the U.S. and Israel
  • High education has led to high abortion rates (550ish out of 625 pregnancies).
• This is a good model for preventing genetic disorders.
  • Lots of prevention, not just abortion.
  • Can test in vitro fertilization embryos before letting them implant.

Treatment

• None available
• No Cure and no treatments
• Can give anti seizure drugs to help control seizures in the early stages of the disease
  • Only increases quality of life.
• Possible future treatments
  • Gene therapy
  • Stem cell transplantation
  • Enzyme replacement therapy
    • Tried it; didn't work because brain couldn't absorb enzyme.

Recent research

5 important facts

• Tay Sachs is caused by a mutation in HexA
• 3 types
  • Infantile
  • Juvenile
  • Late Onset
• Infantile patients usually die before age 5 and juvenile patients before age 15
• Higher incidence in Ashkenazi Jew and French Canadian populations
• Autosomal recessive inheritance

Not to be confused with

• Sandhoff disease:
  • Recall that there are alpha and beta subunits to HexA.
  • Same as Tay Sachs but mutations are in the beta chain.
  • Lack function of both HexA and HexB
  • Undistinguishable from Tay Sachs phenotype
• AB variant
  • Very rare, not well studied.
  • Lacks function in the GM2 activator
  • Very rare, but also has symptoms similar to Tay Sachs
  • Completely functional HexA and HexB
  • Mutation is in ...?

Questions and answers

• Describe how a mutation in Hex A can lead to the neurological problems in Tay Sachs
• If a child is diagnosed with infantile Tay Sachs, describe the progression of symptoms and the expected life span of the patient