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GM2 gangliosidoses

This is part of Rare diseases.

Diagnosis: GM2 gangliosidoses

Synonyms: Hexosaminidase A deficiency, Tay-Sachs disease, Hexosaminidase B deficiency, Sandhoff disease, Activator protein deficiency, AB variant

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Date of publication: 2010-04-26
Version: 1:0

ICD 10 code

E75.0

The disease 

Three different forms of encephalopathies (any diffuse disease of the brain that alters brain function or structure) make up the group of GM2 gangliosidoses: Tay-Sachs disease, Sandhoff disease and the AB variant. The GM2 gangliosidoses are all lysosomal diseases. Lysosomes are small units (organelles) found in all cells of the body, except for red blood cells. Their role is to deal with and break down large molecules with the help of enzymes (a sort of protein). All lysosomal diseases are the result of a malfunction in the lysosomes. This malfunction is caused either by an enzyme not functioning properly, or by a fault in one of the proteins transporting substances in and out of the lysosomes. In GM2 gangliosidoses, lysosomes are not able to degrade GM2 ganglioside in the brain.

Tay-Sachs disease was named after the English opthamologist Warren Tay and the American neurologist Bernard Sachs. In 1881 Warren Tay was the first to describe the cherry-red spot on the retina characteristic of the disease. Some years later Bernard Sachs described the clinical symptoms and the pathological changes which distinguish the classic, infantile form of the disease. Sandhoff disease takes its name from the German biochemist Konrad Sandhoff, who in 1968 described the underlying cause of the disease. Ten years later, he and Ernst Conzelmann identified the AB variant.

Today we know of over fifty lysosomal diseases. Examples include Fabry disease, Gaucher disease, Krabbe disease, mannosidosis, metachromatic leukodystrophy, mucopolysaccharidoses I, II, III, IV, VI and VII, Pompe disease and Salla disease. Separate information on these disorders can be found in the Swedish National Board of Health and Welfare database of rare diseases.

Occurrence

The occurrence of GM2 gangliosidoses in the population is not fully known, but international studies have estimated the combined incidence of Tay-Sachs disease and Sandhoff disease at approximately 3 per million live births. AB variant is extremely rare.

Tay-Sachs disease and Sandhoff disease occur more frequently in certain population groups than others. In the Jewish population with genetic roots in Central and Eastern Europe, and in the French-Canadian population of east Quebec, Tay-Sachs disease is much more common than average. Sandhoff disease is more common in the Lebanon, in the Creole population of northern Argentina and among the Métis Indians of Canada.

In Sweden over the last few years an average of one child per year has been diagnosed with the infantile form of Tay-Sachs disease.

Cause

Lysosomes function as the cells’ re-cycling machinery. The degradation process means that the “building blocks” which make up different macromolecules become available for re-cycling. Proteins, for example, are broken down into amino acids in this way. Once this process has taken place the building blocks are transported out of the lysosomes and become available to the cell for the building up of new macromolecules.

GM2 gangliosidoses are caused by a deficiency in one of the lysosome enzymes, hexosaminidase, which is necessary for the degradation of GM2 gangliosides in the nerve cells of the brain. The GM2 ganglioside is a glycosphingolipid, which is an important constituent of the plasma membranes of nerve cells. The accumulation of the GM2 ganglioside leads to a subsequent breakdown of nerve cells, leading in turn to the development of progressive neurological symptoms. For the GM2 ganglioside to be broken down, the enzymes hexosaminidase A and hexosaminidase B, and the GM2 activator protein (which acts as an intermediary between hexosaminidase A and GM2 gangliosides) all need to function normally.

Both hexosaminidase A och hexosaminidase B are made up of a combination of two subunits, alfa and beta. Hexosaminidase A consists of one alpha subunit and one beta subunit, while hexosaminidase B consists of two beta subunits. The gene which controls the production of (codes for) the alfa subunit is HEXA (15q23-q24), while HEXB (5q13) codes for the beta subunit.

Tay-Sachs disease is caused by mutations in HEXA, leading to a dysfunction in hexosaminidase A. Most of the mutations result in an absence of the enzyme and a severe infantile form of Tay-Sachs disease. More unusual mutations are associated with some remaining degree of enzyme activity and a milder form of the disease, characterised by a later onset of symptoms and a more varied progression.

Mutations in HEXB result in Sandhoff disease, as they lead to dysfunctions of both hexosaminidase A and hexosaminidase B. The most common mutation in Sandhoff disease is a deletion, where part of the HEXB gene is absent. Point mutations in HEXB give rise to later onset forms of the disease.

Mutations in the GM2A gene (5q31.3-q33.1) lead to diminished functionality of the GM2 activator protein and result in the AB variant of GM2 gangliosidoses. Only a few mutations have been identified in this gene to date.

Heredity

The inheritance pattern of GM2 gangliosidoses is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene

Figure: Autosomal recessive inheritance of genetic traits

Symptoms

GM2 gangliosidoses can be divided into three types depending on the age the symptoms first appear: infantile, juvenile or adult. Progression and severity are dependent on the amount of remaining enzyme activity in the lysosomes and are often, but not always, linked to the age when symptoms first present.

Despite the similarity in symptoms, Tay-Sachs disease, Sandhoff disease and AB variant are caused by different gene dysfunctions. In rare cases of Sandhoff disease, symptoms may also occur in the liver, spleen and skeleton.

Children with the infantile form have no symptoms when they are born but become ill first between the ages of three and six months. Early symptoms are increased irritability and over-sensitivity to sounds. One characteristic symptom is that their muscles jerk (myoclonus) if, for example, someone claps loudly in their proximity. Initially their muscles are flaccid, but with time they become increasingly stiff. Changes to the retina, presenting as a cherry-red spot in the macula (the yellow spot near the centre of the retina) are accompanied by lack of eye contact and abnormal eye movements.

After normal development in the first months, at around six to ten months the child’s development stagnates. After this, the child begins to lose motor and mental functions. Voluntary movements become less frequent and the child becomes less and less responsive. Sight deteriorates quickly and eventually the child becomes blind. In addition, epileptic seizures become more frequent.

During the second year the condition deteriorates further, with the child displaying symptoms including swallowing difficulties, an increasing number of seizures and lowered levels of consciousness. Around the age of eighteen months a characteristic enlargement of the head may be noted. This is not hydrocephalus but the result of a type of scar tissue resulting from the growth of astrocytes, the brain’s support cells (reactive gliosis). During the second year the condition deteriorates, with the child displaying symptoms including swallowing difficulties, an increasing number of seizures and lowered levels of consciousness. Children with the disease often die between the ages of three and five, usually as a result of pneumonia brought on by breathing difficulties.

The juvenile form usually presents between the ages of one and nine years of age. This variant of the disease is much less common than the infantile form and its course is more variable, both in terms of signs and symptoms and the rate of progression. Common early signs are that the child has problems with coordination (ataxia) and speech (dysartria), and learning becomes increasingly difficult. Spasticity is also frequently an early sign. In some individuals hand tremors, involuntary muscle contractions (dystonia) and involuntary abnormal movements (choreoathetosis) are the main symptoms. Others may include increasing muscle weakness and atrophy, twitching (fasciculations) and changes to the skeleton.

Approximately half the patients develop epileptic seizures. In their early teens some individuals experience symptoms of mental disorder which affect behaviour. Sight is retained longer than in the infantile form of the disease. The characteristic cherry red spot on the retina is not present in all, but a wasting away (atrophy) of the optic nerve, and disease of the retina (retinitis pigmentosa) can present late in the progression of the disease. Other symptoms may include difficulties swallowing, urinary and faecal incontinence, as well as diarrhoea and/or constipation. Brain function deteriorates gradually and in the final years only the child’s basic bodily functions are working (vegetative state). Most individuals with this late infantile or juvenile form of the disease die before the age of twenty, but sometimes the disease progresses more slowly (chronic encephalopathy).

The adult form of Tay-Sachs disease is very rare and usually presents when the individual is between 20 and 30. The disease develops slowly and displays highly varied symptoms and signs which can appear individually or in different combinations. Symptoms of mental disorders are common and may be the first sign of illness, meaning that some individuals are first diagnosed, wrongly, with schizophrenia. Between 30 and 50 per cent develop a psychosis and more than a quarter of individuals display symptoms of depression. Difficulties in learning (cognitive disability) are less pronounced and not as common as in the forms of the disease which start earlier. Nevertheless, they are found in just over one fifth of patients. In approximately half the number of individuals affected by the disease hand tremor, abnormal body posture and involuntary abnormal movements occur. About one third have balance and coordination problems. Other common symptoms include difficulties when speaking and swallowing, muscle weakness and atrophy, twitching (fasciculations) and unstable gait and spasticity. Many become wheelchair users. With the correct treatment, those who develop the adult form of Tay-Sachs disease frequently have a normal life span.

As the severity of the disease does not always correspond to the person’s age at the onset of the disease, different groupings are sometimes used: infantile, acute encephalopathic (equivalent to the classic infantile form), sub-acute encephalopathic (including late infantile and juvenile forms, with a slower progression and mortality in childhood or early adulthood) and chronic encephalopathic (which includes juvenile and adult forms with high survival rates).

Diagnosis

In the classic infantile form an eye examination is often crucial for arriving at a diagnosis. A cherry-red spot in the macula is characteristic of the disease. CT (computed tomography) and MRI (magnetic resonance imaging) scans of the brain can show early changes in the thalamus, located near the centre of the brain. In the juvenile form atrophy of the cerebellum and the cerebrum, and changes in white matter of the brain, can be seen.

The diagnosis is made by measuring enzyme activity in hexosaminidase A and hexosaminidase B, in white blood cells or fibroblasts. In Sandhoff disease it is possible to test for the presence of oligosaccharides in the urine. To diagnose the AB variant, it is first necessary to establish the level of GM2 ganglioside in the cerebrospinal fluid.

Diagnosis can be carried out with the help of DNA analysis. Pre-natal diagnosis is possible using enzyme analysis or DNA testing, if the mutation in the family is previously known.

At the same time that the diagnosis of one of the GM2 gangliosidoses is made, genetic information should be made available to the family.

Treatment/interventions

As yet there is no treatment which can cure this disease or prevent its progression. Attempts have been made to make up for the enzyme deficit, and to reduce the accumulation of gangliosides, by medication. So far this has been unsuccessful. Instead, treatment focuses on alleviating symptoms, compensating for disabilities and creating a good quality of life. Regular medical check-ups are important.

When the diagnosis is made it is important that support is available from a team consisting of the supervising doctor, nurse, psychologist and social worker. Treatment during the early stages of the disease can take place in the local paediatric clinic with the same team of professionals, at a habilitation facility, or at home with the support of the local hospital. Parents may need contact with a speech therapist and a dietician as it can be difficult for children to eat. In larger hospitals there are specialist nutrition teams. Nutrition or nutritional supplements can be given by a tube through the nose, or using a procedure called PEG (percutaneous endoscopic gastrostomy) where a tube is inserted into the stomach through the abdominal wall. It is important that the child does not become constipated.

Epilepsy can be treated with medication.

Where muscles governing breathing are affected, breathing exercises and different respiratory aids may be required.

The family needs advice on care and available help, as well as information about the rights of children with severe disabilities and progressive diseases. It is also important that the family is offered relief, and that their needs for continuous psychological and social care are met. Information and support are provided by the team described above, in paediatric clinics, at home in association with the local hospital, or during habilitation.

Children/families requiring long-term habilitation should be offered contact with a habilitation team, which includes professionals with expertise on disabilities and their effects on health, development and everyday life. For children with a form of the disease resulting in impaired vision, appropriate habilitation is required.

Habilitation teams are responsible for providing medical, educational, psychological, social and technical support and treatment. Help includes assessment, treatment, assistance with aids, information on the specific disability, and counselling. It also includes information on all available support offered in the community, as well as advice on adjustments to the home environment and other places where the child spends time. As well as support for the child/young person, parents and siblings should also be offered support.

Support should be based on existing needs. It should always be planned in close collaboration with adults in the child’s/young person’s immediate environment, and is likely to vary over time. Families with a child with a severe, progressive disease are in special need of help in coordinating the various efforts.

It is important that measures are taken to maintain functionality as long as is possible, to prevent deformities which can result from muscle weakness and spasticity. From an early age attention should be paid to the child’s capacity to communicate and engage with his/her surroundings. Adjustments should be made to the immediate environment in order to compensate for disabilities.

The local authority can offer different forms of support to make the family’s day-to-day life easier. Relief in the form of personal assistance, the provision of a contact family or short-term respite care, are examples of such initiatives.

For children with the classic infantile form of the disease, palliative care can be offered in the final stages of the disease. “Palliative” means a remedy that alleviates pain without curing the illness, and its goal is to make the final period for the child as comfortable and pain-free as possible. This requires close and intensive collaboration between parents, other relatives and personnel with different expertise.

Many parents wish to care for their child at home as long as possible, with the help of professionals. Often the child is cared for partly at home and partly in the hospital. At this time it is important that parents and siblings receive the psychological and social support which they need.

Older teenagers and adults require continuing and regular medical check-ups and individually designed habilitation measures. Those who have a late-onset form of the disease, where symptoms present later, should maintain close contact with a neurology clinic. Psychiatric symptoms can be treated with medication.

The respiratory muscles may also be affected, meaning that some individuals require breathing exercises and assistance with breathing (e.g. mask and ventilator). A physiotherapist may give advice on suitable activities and exercises to preserve functionality as long as possible. Muscle weakness can affect daily activities, in which case physical aids and appropriate adjustments to the immediate environment may be required. Adjustments may also be required when it comes to, for example, getting dressed and undressed, eating and mobility.

As the need for practical help in daily life can be great, accommodation in a specially-adapted apartment with personal assistants is one of several appropriate solutions.

Practical advice

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National and regional resources in Sweden

Diagnostic expertise may be found in the paediatric neurology units of university hospitals where all the relevant specialist evaluations can be carried out while the child is an in-patient. Sometimes the diagnosis is made in the local hospital instead. If necessary, a university clinic may be consulted.

The bio-chemical analyses are made at the Neurochemistry laboratory, Sahlgrenska University Hospital /Mölndal, SE 431 80 Mölndal, Sweden, ( contact person Professor Jan-Erik Månsson) and the Center for Inherited Metabolic Diseases, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. (contact person Associate Professor Ulrika von Döbeln.) When required, tests for DNA analysis are sent to departments of clinical genetics at Swedish university hospitals.

Resource personnel

Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden. Tel: +46 31 343 40 00, email: niklas.darin@vgregion.se.

Professor Jan-Eric Månsson, Department of Clinical Chemistry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE- 431 80 Mölndal, Sweden. Tel: +46 31 343 10ÿ 00.

Paediatric Neurologist Karin Naess, Paediatric Neurology and Habilitation, The Astrid Lindgren Children’s Hospital, SE-141 86 Stockholm, Sweden. Tel: +46 31 343 10ÿ 00.

Associate Professor Ulrika von Döbeln, The Center for Inherited Metabolic Diseases, (CMMS), Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities. Gävlegatan 18 C, Stockholm. Mailing address: Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax +46 8 508 866 66, email: fub@fub.se, www.fub.se.

RBU, The Swedish National Association for Disabled Children and Young People. St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax +46 8 677 73 09, Email: info@riks.rbu.se, www.rbu.se.

The National Tay Sachs & Allied Diseases Association can be found in the US. email: info@ntsad.org, www.ntsad.org

Courses, exchanges of experience for personnel

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Research and development (R&D)

Research into different treatments is continuing internationally, including collaborative efforts at Auburn University, Boston College, Cambridge University and Massachusetts General Hospital/Harvard Medical School.

Information material

An information leaflet on GM2 gangliosidos that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2009-126-1248). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Information in English is available on the National Tay-Sachs and Allied Diseases Association’s homepage. www.ntsad.org.

Literature

Cachon-Gonzalez MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox TM. Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc Natl Acad Sci U S A 2006; 103: 10373-10378.

Cordeiro P, Hechtman P, Kaplan F. The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci. Genet Med 2000; 2: 319-327.

Conzelmann E, Sandhoff K. AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc Natl Acad Sci U S A 1978; 75: 3979-3983.

Fernandes Filho JA, Shapiro BE. Tay-Sachs disease. Arch Neurol 2004; 61: 1466-1468.

Frey LC, Ringel SP, Filley CM. The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis. Arch Neurol 2005; 62: 989-994.

Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K, Suzuki K. The GM2 gangliosidoses. In: Scriver CR, Beaudet A, Sly WS, Valle D, editors. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. p. 3827-3876.

Hendriksz CJ, Corry PC, Wraith JE, Besley GT, Cooper A, Ferrie CD. Juvenile Sandhoff disease—nine new cases and a review of the literature. J Inherit Metab Dis 2004; 27: 241-249.

MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. J Neuropsychiatry Clin Neurosci 1998; 10: 10-19.

Maegawa GH, Stockley T, Tropak M, Banwell B, Blaser S, Kok F et al. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 2006; 118: e1550-1562.

Meek D, Wolfe LS, Andermann E, Andermann F. Juvenile progressive dystonia: a new phenotype of GM2 gangliosidosis. Ann Neurol 1984; 15: 348-352.

Sandhoff K, Andreae U, Jatzkewitz H. Deficient hexosaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs. Life Sci 7, 1968: 283-288.

Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH. Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med 2009; 11: 425-433.

Database references

OMIM (Online Mendelian Inheritance in Man),
www.ncbi.nlm.nih.gov/omim
search: Tay-Sachs disease, TSD, Sandhoff disease

GeneReviews,
www.genetests.org (select Genereviews, then Titles)
search: hexosaminidase A deficiency

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with Gothenburg University, approved the material prior to publication.

Date of publication: 2010-04-26
Version: 1:0
Publication date of the Swedish version: 2009-12-16

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.