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Case details

A boy was born normal but started flinching at loud noises (enhanced startle response) at the age of 6 months. The child initially could sit up, but then regressed so that he could not roll over or recognize his parents.

Ophthalmological examination revealed a central red area of the retina surrounded by white tissue (Cherry red spot).

What is the treatment for this disease?

Case Discussion

The child is suffering from Tay Sach’s disease (GM2 Gangliosidosis). The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population

Basic Concept

Gangliosides have been isolated from the ganglion cells, neuronal bodies, dendrites, spleen and RBC stroma. The highest concentration is found in the grey matter of brain. Structurally they contain a long chain fatty acid, alcohol sphingosine, a carbohydrate moiety which is usually glucose/ and or galactose, and at least one molecule of N-acetyl –Neuraminic acid (NANA)(Figure-1). Four important types of Gangliosides are GM-1, GM-2, GM-3 and GD-3.GM-1 is more complex ganglioside and is known to be the receptor for cholera toxin in human intestine. Gangliosides are mainly components of membranes. They also serve as receptors for circulating hormones and thereby influence various biochemical processes in the cells.

Case details

The GM2 Gangliosidosis  also called Tay-Sach’s disease results from the deficiency of ß-hexosaminidase activity and the lysosomal accumulation of GM2 gangliosides, particularly in the central nervous system, causing severe effects (neurodegeneration).The child in the given case was born normal but developed progressive deterioration of the neurological functions. This is characteristic of this disease

Tay-Sachs disease

Biochemical defect

There is deficiency of ß hexosaminidase A enzyme. This Lysosomal enzyme removes amino hexose groups from Gangliosides, Subsequently the other components are hydrolyzed by other specific enzymes. In its deficiency the gangliosides are  not degraded  thus accumulate in various tissues especially nervous tissue.


[ß-Hexosaminidase occurs as two isozymes: ß-hexosaminidase A, which is composed of one a and one ß subunit, and ß-hexosaminidase B, which has two ß subunits. ß-hexosaminidase deficiencyA results from mutations in the a subunit and causes Tay-Sachs disease, whereas mutations in the ß-subunit gene result in the deficiency of both ß-hexosaminidase A and B and cause Sandhoff disease.]

 t (Small)

Figure-2- Cherry red spot on the macula


It is inherited as an autosomal recessive traits, with a predilection in the Ashkenazi Jewish population, where the carrier frequency is about 1/25.

Clinical symptoms and Classification

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.

Infantile TSD patients with this disease are born normal, but they develop loss of motor skills, increased startle reaction, macular pallor and retinal cherry red spot(Figure-2).Affected children develop normally till the age of 5-6 months, then decreased eye contact, hyperacusis (Exaggerated startle response) to noise are noted. Progressive development of idiocy and blindness are diagnostic of this disease and they are due to wide-spread injury to ganglion cells, in brain and retina. The cherry red spot about the macula is due to destruction of retinal ganglion cells exposing the underlying vasculature(Figure-2). Macrocephaly not associated with hydrocephalus may be there. Convulsions are seen in severe cases.

Juvenile TSD. Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.

Adult/Late Onset TSD. A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis.


The diagnosis of infantile Tay-Sachs disease is usually suspected in an infant with neurologic features and a cherry-red spot.

Enzymatic Assays-Definitive diagnosis is by determination of the level of ß-hexosaminidase A in isolated blood leukocytes.

Fine needle Aspiration Cytology of brain tissue – can show the degree of neuronal degeneration. FNAC has a great potential for diagnosis and follow-up of Tay-Sachs disease

Prenatal screening-Future at-risk pregnancies for both disorders can be monitored by prenatal diagnosis by amniocentesis or chorionic villus sampling.

Carrier screening– Identification of carriers within families is also possible by ß-hexosaminidase A and B determination. Indeed, for Tay-Sachs disease, carrier screening of all couples in whom at least one member is of Ashkenazi Jewish descent is recommended before the initiation of pregnancy to identify couples at risk. These studies can be conducted by the determination of the level of ß-hexosaminidase A activity in peripheral leukocytes or plasma.


No cure for this disease. Symptomatic treatment is given. Enzyme replacement therapy and Gene therapy are under trial. Although experimental work is underway, no current medical treatment exists for infantile TSD. Patients receive palliative care to ease the symptoms. Infants are given feeding tubes when they can no longer swallow. Improvements in palliative care have somewhat lengthened the survival of children with TSD, but no current therapy is able to reverse or delay the progress of the disease.


Prognosis is bad and death occurs in early years of life.


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Case Details

A 25 –year-old women presents, with a history that includes-

a) Hepatosplenomegaly with eventual removal of spleen

b) Bone and joint pains with several fractures of femur.

c) A liver biopsy that shows wrinkled looking cells with accumulation of Glucosyl ceramide,

What would be the likely diagnosis for this patient?

Case discussion

The patient is suffering from Gaucher disease. It is an inherited disorder of Cerebroside metabolism.

Basic concept

Cerebrosides occur in large amount in the white matter of brain and in the myelin sheath of nerves. Structurally, Cerebrosides contain a carbohydrate which is generally galactose or sometimes glucose, a high molecular weight fatty acid, an alcohol which is sphingosine or Dihydro sphingosine (See the structure below-figure-1).There is no glycerol, no phosphoric acid and no nitrogenous base. Individual cerebrosides are differentiated by the type of fatty acid present in them.

Figure-1- showing structure of Glucocerebroside(Glucosyl Ceramide). Sphingosine+ Fatty acid(Oleic acid in the given structure) is Ceramide. Ceramide can be further attached with either Glucose or Galactose.

Gaucher disease

This disease is a multisystem lipidosis characterized by hematological changes, organomegaly and skeletal involvement, the latter is usually manifested in the form of bone pains and multiple fractures. It is the most common genetic disorder among Ashkenazi Jews. It is the commonest Lysosomal storage disease.


It is Autosomal recessive in nature.

Biochemical defect

Gaucher’s disease results from deficient activity of Lysosomal Hydrolase, β- Glucocerebrosidase. The enzyme defect results in accumulation of undegraded glycolipid in the form of Glucosyl ceramide in the cells of reticuloendothelial system (figure-2). This progressive accumulation results in infiltration of bone marrow, hepatosplenomegaly and skeletal complications.

Figure-2- showing the formation of Gaucher cell

Clinical features

There are three clinical sub types depending upon the presence of, absence of or progression of neurological complications-

1)Type-1- It accounts for 99 % of cases. The age of onset is variable, from early childhood to late adulthood. The patients present with easy bruising due to thrombocytopenia, chronic fatigue due to anemia, hepatomegaly with or without impaired liver functions. Progressive enlargement of spleen is there which can become massive. Clinical bone involvement is apparent which is manifested in the form of bone pains, or pathological fractures.  The hall-mark of Gaucher’s disease is gaucher cells in the reticuloendothelial system, particularly in the bone marrow. These cells have a typical appearance, they are 20-100μm in diameter, wrinkled looking due to the presence of intracytoplasmic inclusion bodies(figure-2 and 3). The presence of these cells is highly diagnostic of Gaucher’s disease.

Figure3– showing Gaucher cell

2) Type 2 is less common, it is characterized by neurodegeneration, extreme visceral involvement and death within 2 years of life. The death is due to respiratory compromise.

3) Type 3- is intermediate in presentation to type 1 and 2. Neurological involvement is there but occurs later in life with decreased severity as compared to Type 2.

Laboratory Diagnosis

The following studies are indicated in gaucher disease:

  • Enzyme activity testing: Diagnosis can be confirmed  through measurement of Glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean  normal activity is diagnostic.
  • Genotype testing: Molecular diagnosis  can be helpful, especially in Ashkenazi patients, in whom 6 GBA mutations account for most disease alleles.
  • CBC count: Obtain CBC count and differential to assess the degree of cytopenia.
  • Liver function enzyme testing: Minor elevations of liver enzyme levels are common, even in patients who are mildly affected with Gaucher disease; however, the presence of jaundice or impaired hepatocellular synthetic function merits a full hepatic evaluation. 

Imaging Studies

  • Ultrasonography: Ultrasonography of the abdomen can reveal the extent of organomegaly.
  • MRI
    • MRI is more accurate than ultrasonography in determining organ size.
    • Hip MRI may be useful in revealing early avascular necrosis.
    • MRI may be useful in delineating the degree of marrow infiltration and evaluating spinal involvement.
  • Radiography
    • Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease.
    • Perform chest radiography to evaluate pulmonary manifestations.
  • Bone marrow examination for the presence of Gaucher’s cells is diagnostic.
  • Liver biopsy – Liver biopsy is occasionally performed to assess unexplained hepatomegaly.


 1) Enzyme replacement therapy (ERT) by recombinant β- Glucocerebrosidase is currently done. This preparation is highly effective in reversing the visceral and hematologic manifestations of gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme.

2) Surgical Care

Partial and total Splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.

3) Bone marrow transplant is also helpful.

4) Gene replacement is the permanent cure.


  • Many individuals with Gaucher disease have few manifestations and a normal life expectancy without any intervention.
  • The prognosis for symptomatic patients with type 1 or type 3 Gaucher disease who receive treatment is very good, with a decrease in organomegaly and an eventual rise in hemoglobin levels and platelet counts.
  • Skeletal disease is slow to respond to ERT and widely varies.
  • Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.
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