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 1.13 Tay Sachs 1.14 Discovered by Warren Tay and Bernard Sachs 1.15 Incidence 1.16 Tay Sachs affects the CNS 1.17 Tay Sachs leads to a progressive loss of CNS function 1.18 Diagnosis 1.19 Caused by HexA mutation 1.20 Inheritance 1.21 Hexosaminidase A functions to remove and break down GM2 gangliosides from the neuron 1.22 Genotype to phenotype correlation: GM2 gangliosides are retained in the lysosome 1.23 Workflow 1.24 Common mutations that cause Tay Sachs 1.25 Other types of Tay Sachs 1.26 Sandhoff disease and AB variant Are related to Tay Sachs 1.27 Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay–Sachs disease 1.28 Followed progression of Tay Sachs disease in a Child from 15 months till 3 years 1.29 MRIs showed progressive white matter lesions 1.30 MRI 1.31 Cytokines levels were slightly elevatedPro-inflammatory cytokines were elevated 1.32 Conclusion: Inflammation is important in the pathophysiology of Tay Sachs 1.33 Treatments 1.34 Screening Programs 1.35 5 important facts 1.36 Test questions

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
• Caucasians:
  • Carrier frequency: 1/250
  • Disease frequency: 1/250K
• Ashkenazi Jews:
  • Carrier frequency: 1/30
  • Disease frequency: 1/3600

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.
• Tay-Sax

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

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

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.

• • However,

Carrier testing

• HexA

Treatment

• None available

Recent research

5 important facts

Not to be confused with

• Sandhoff disease:
  • Recall that

Questions and answers

• started here on 03/24/10.

• Discussed the quiz.
  • Note that heterogeneity (as in allele, locus, or clinical) is strictly limited to the condition that the differences are associated with a different phenotype.

Tay Sachs

• presented by Helen Cuffe
• http://www.curetay-sachs.org/Alternate names
• Every phenotype is associated with one gene!
• GM2 gangliosidosis
  • There are two other diseases of this type, also.
• Hexosaminidase A deficiency
• Abbreviated TSD

Discovered by Warren Tay and Bernard Sachs

• They didn't know what they had discovered at the time.
• Warren Tay - 1881
  • British ophthalmologist that noticed red spots on retina
• Bernard Sachs - 1887
  • American neurologist that noticed cellular changes and high incidence in Ashkenazi Jews

Incidence

• A single gene disorder.
• Autosomal recessive.
• Homozygous patients don't live to reproduction.
• Carriers
  • 1/250-300 of general population are carriers
  • 1/27-30 of Ashkenazi Jewish and French Canadian populations are carriers
• Occurrence
  • 1/3600 babies born in Ashkenazi Jew populations
  • 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.

Tay Sachs affects the CNS

• 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

Tay Sachs leads to a progressive loss of CNS function

• 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!

Diagnosis

• 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.

Caused by HexA mutation

• Mutation in the Hexosaminidase A gene
  • Both the gene and the protein are called HexA.
  • Encodes the α subunit of the β-Hexosaminidase A enzyme
• Location
  • 15q23-q24
  • 70,422,832 to 70,455,392 bp
• Many different mutations known

Inheritance

• Autosomal recessive
• Can be due to compound heterozygosity
  • Because of the hundreds of different mutations you can have.
  • This is also responsible for the variability of symptoms.
• Haplosufficient
• You can test carriers by enzymatic activity because they have decreased enzymatic activity.

Hexosaminidase A functions to remove and break down GM2 gangliosides from the neuron

• 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.

Genotype to phenotype correlation: GM2 gangliosides are retained in the lysosome

• 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

Workflow

• GM2 accumulation -> Neuron Cell body distension -> Neuronal cell death -> Eventual brain atrophy

Common mutations that cause Tay Sachs

• 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

Other types of Tay Sachs

• 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.

Sandhoff disease and AB variant Are related to Tay Sachs

• Sandhoff disease
  • 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 ...?

Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay–Sachs disease

• Hypothesis: Inflammation caused by an immune response to GM2 gangliosidosis plays a role in the pathophysiology of Tay Sachs

Followed progression of Tay Sachs disease in a Child from 15 months till 3 years

• Child originally came in with seizures and infections
• Was diagnosed with Tay Sachs due to low β-hexosaminidase A activity
• Followed progression with MRIs and measuring the level of cytokines

MRIs showed progressive white matter lesions

• Increasing of white areas (dense areas) which are the build up of GM2.
• Stop the swelling, stop the seizure.

MRI

• Magnetic resonance imaging
• Useful for looking at the soft tissues
• Muscles, brain etc
• It uses strong magnetic fields and non-ionizing radiation
• First used in 1977
• Different tissues have different densities and the density causes ....
  • http://www.howstuffworks.com/mri.htm

Cytokines levels were slightly elevatedPro-inflammatory cytokines were elevated

• TNF-α
  • Produced primarily by macrophages
  • Promotes inflammation
  • Went up.
• IL-5
  • Stimulates B cell growth and antibody secretion
  • Mediated eosinophils
  • Went way up.
• IL-10
  • Anti-inflammatory
  • Actually opposes TNF- α
  • Went way down.

Conclusion: Inflammation is important in the pathophysiology of Tay Sachs

• Level of swelling and cytokines show ....
• Elevation of Cytokines relate to the occurrence of seizures in Tay Sachs Patient
  • Seizures are an important part of the disease process
• Medication to reduce brain inflammation helps to stop the seizures
• Patient shows progressive swelling and lesions in the white matter of the Brain

Treatments

• 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.

Screening Programs

• 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.

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

Test questions

• 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