Tay-Sachs Disease

From Iusmgenetics

Contents 1 Tay-Sachs Disease 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.7.1 Carrier testing 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

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