The Rare Genetic Sandhoffs Disease Biology Essay

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Sandhoff disease is a rare, genetically inherited, glycosphingolipid storage disorder resulting in the progressive deterioration of the central nervous system. The disease appears in three forms: classic infantile - most common and severe, juvenile and late onset Sandhoff disease. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. It is likely to be found in any ethnic group passing from generation to generation through carriers without being expressed in their offspring. Even though the family may not have a history of Sandhoff Disease, it is possible for two individuals to have a child with the disease. Sandhoff disease is classified as a GM2 gangliosidotic disease characterised by severe psycho-motor developmental disorders caused by the inability to properly degrade membrane associated gangliosides of the GM2 family.

Background

GM2 ganglioside (fig. 1) is a component of cell plasma membranes that is especially concentrated in neural cell membranes of the brain and spinal cord. The common location and molecular shape suggests that the sialic acid and carbohydrate head of the molecule extend from the plasma membrane while the fatty acid hydrophobic tails are anchored in the membrane. The exposed polar head of the molecule thereby serves to interact with other membrane constituents or extracellular molecules. GM2 gangliosides have specialized functions in motility, growth control and differentiation of cells through interactions with specific proteins and signal transduction pathways. Cell-cell interactions occur by sialoglycans on one cell binding to complementary binding proteins (lectins) on adjacent cells, bringing about cell-cell adhesion and enabling regulation of intracellular signalling pathways. Based on an abnormal growth of neural cell dendrites in patients with high levels of GM2 gangliosides it has been suggested that these molecules could be associated with dendrite initiation.

Fig 1: Structure of GM2 ganglioside [N-acetyl-neuraminidate (sialic acid).]

Adapted from: http://themedicalbiochemistrypage.org/sandhoffdisease.html

The degradation of GM2 gangliosides takes place in the lysosomes which are membrane-bound organelles in cells which serve as recycling centres. They contain digestive enzymes that are active at acidic pH and break down toxic substances. GM2 ganglioside degradation requires the lysosomal enzyme β-hexosaminidase and the GM2 activator protein. Hexosaminidase is a dimer composed of 2 subunits, either α subunit (encoded by the HEXA gene) and/or the β subunit (encoded by the HEXB gene). The various isoforms of β-hexosaminidase result from the combination of α and β subunits. The HexA is a heterodimer of αβ and HexB is a homodimer of ββ. It is the β-subunit that carries out the catalysis and in particular, beta-hexosaminidase A (HexA form of β-hexosaminidase) forms part of a complex that catalyze the cleavage of GM2 gangliosides (the bond cleaved is shown by the arrow in the Figure below). The GM2 activator first binds to GM2 gangliosides followed by hexosaminidase and then digestion occurs.

Fig. 2 Diagram of HexA and GM2 Activator Action on GM2 Gangliosides

Adapted from: http://themedicalbiochemistrypage.org/sandhoffdisease.html

Causes

Sandhoff disease results from defects in the HEXB gene encoding the β-subunit of β-hexosamindase. As such, patients with Sandhoff disease are defective in both the HexA (αβ) and HexB (ββ) forms of the enzyme. The HEXB gene resides on chromosome 5q13 (chromosome 5 on the long (q) arm in band 13) spanning 36,145 base pairs and composed of 14 exons (expressed regions).

Fig. 3 Molecular location of HEXB gene

At least 26 mutations have been identified in the HEXB gene resulting in Sandhoff disease. These mutations prevent cells from making any β-HexA or β-HexB, or lead to the production of completely non-functional versions of these enzymes. The most common mutation deletes a large segment of DNA near the beginning of the HEXB gene, which results in a total loss of enzyme activity and this mutation is more severe, with symptoms becoming apparent in the infantile stage. Other mutations reduce but do not eliminate the activity of the enzymes; these genetic changes are responsible for the less severe forms of Sandhoff disease, which appear later in life. The malfunctioning or missing enzymes are unable to break down GM2 ganglioside and results in accumulation to toxic levels, particularly in neurons of the brain and spinal cord, where GM2 gangliosides are concentrated. The lysosomes become engorged (fig. 4) filling the cell, and eventually choke off normal cellular functions leading to a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. Because Sandhoff disease impairs the function of lysosomal enzymes and involves the build up of GM2 ganglioside, GM2 gangliosidotic disease is also referred to as a lysosomal storage disease.

Fig. 4 Engorged lysosomes (lipid vacuoles) filling neurons

Signs and Symptoms

Classic infantile Sandhoff disease

Infants with Sandhoff disease appear normal at birth

Mild motor weakness by 3 to 5 months of age. Parents will begin to notice that their afflicted child has a dull response to outside stimuli.

Exaggerated startle response (sudden extension of arms and legs) to sharp sounds.

By 6 to 10 months of age infants will begin to show regression of prior acquired motor and mental skills.

A progressive loss in visual attentiveness may lead to an ophthalmological consultation which will reveal macular pallor and the presence of the characteristic "cherry-red spot" on the fundus of the eye (see Figure below).

Fig. 5 "Cherry red spot" on the eye fundus. The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula and fovea, and posterior pole.

Adapted from: http://themedicalbiochemistrypage.org/sandhoffdisease.html

At around 8 to 10 months of age the symptoms of Sandhoff disease begin to progress rapidly.

Infants are progressively non-responsive to parental stimulation

The exaggerated startle response becomes quite pronounced.

Onset of seizures which become progressively more severe and are very frequent by the end of the first year.

Psycho-motor deterioration increases by the second year and invariably leads to difficulty in swallowing and increased seizure activity

Decerebrate posturing. Decerebrate posture is an abnormal body posture that involves the arms and legs being held straight out, the toes being pointed downward, and the head and neck being arched backwards. The muscles are tightened and held rigidly. This type of posturing usually means there has been severe damage to the brain. (fig. 6)

Fig. 6.-A, characteristic attitude of the patient; the legs were held in full extension and the arms in semi flexion; B, Tonic neck reflex; chin turned to the right produced flexion of the left arm and increased extensor rigidity of the right arm; C, Tonic neck reflex; chin turned to the left produced flexion of the right arm and increase in extensor rigidity of the left arm.

doll-like face

macrocephaly

Myoclonus - contraction of a single muscle or group of muscle

Frequent respiratory infections

Patient will progress to an unresponsive vegetative state with death resulting from bronchopneumonia resulting from aspiration in conjunction with a depressed cough. Death usually occurs around 3 years of age.

Juvenile and Late onset Sandhoff disease have similar signs and symptoms

learning difficulties

emotional lability - "mood swings"

intermittent psychosis, or confusional state

muscle weakness and muscle atrophy

fasciculations - involuntary muscle contractions

supranuclear gaze palsy - paralysis of eye muscles impairing eye movement

hyperreflexia - over responsive reflexes

dysarthria - motor speech disorder

progressive dementia

Diagnosis

The clinical features associated with the infantile forms of Sandhoff disease and Tay-Sachs disease is indistinguishable. The initial discrimination of Sandhoff disease from Tay-Sachs disease is accomplished by biochemical analysis. This involves an enzyme assay to measure β-HexA and β-HexB enzymes. Absence of β-subunit activity indicates Sandhoff disease and if otherwise the patient might have Tay-Sachs disease.

Adult onset Sandhoff disease is also diagnosed by enzyme assay to check for activity of β-HexA and β-HexB in blood.

Treatment and disease management

There is no cure for Sandhoff disease, and treatment is based on lessening the symptoms. Supportive therapy includes hydration, nutrition and keeping the airways open. A 'feeding tube' may be inserted to prevent aspiration of feedings into the lungs. Anticonvulsants may be used to initially control seizures. Emphasis is placed on comfort as symptoms progress with therapist providing positional strategies and devices. Physical therapy may be helpful to maintain muscle tone and skeletal alignment. In ongoing studies, a small number of children have received an experimental treatment using transplants of stem cells from umbilical cord blood.  Although these limited trials have not yet produced a treatment or cure, scientists continue to study these and other investigational approaches. 

Prognosis

The prognosis for individuals with Sandhoff disease is poor. Death of infant patients usually occurs by age 3 and is typically caused by respiratory infections.

http://themedicalbiochemistrypage.org/sandhoffdisease.html

http://ghr.nlm.nih.gov/condition/sandhoff-disease

http://ghr.nlm.nih.gov/gene/HEXB

http://www.ntsad.org/S02/S02sandhoff.htm

http://www.ncbi.nlm.nih.gov/omim/268800

http://newhoperesearch.org/GM2_gangliosidosis.html

http://www.theisaacfoundation.com/nsaidarticle.pdf

http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2003/Holmberg/HEXA.html

http://www.ninds.nih.gov/disorders/sandhoff.htm

http://www.healthline.com/galecontent/sandhoff-disease#ixzz12QXHCeiYh

http://www.wrongdiagnosis.com/s/sandhoff_disease/intro.htm

http://sandhoffdisease.webs.com/whatisit.htm

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