GM1 gangliosidosis

The disease is characterized by a deficiency of β-galactosidase, an enzyme of lysosomes involved in the catabolism of derivatives of fatty acids and glycosaminoglycans - ganglioside GM ₁ , glycoproteins and keratan sulfate .

Beta-galactosidase is a vital hydrolytic enzyme found in lysosomes that breaks down lipids and glycoproteins . In the case of a genetically determined deficiency or defect, when β-galactosidase does not function properly, lipids and keratan sulfate accumulating in the nervous tissue cause the manifestation of characteristic clinical symptoms . Most variants of GM ₁ gangliosidosis develop at the beginning of life (when the brain rapidly develops) and is accompanied by neurodegeneration. Except for rare late-onset forms, GM ₁ gangliosidoses are fatal.

This group of diseases is inherited, like the vast majority of lysosomal storage diseases , according to the autosomal recessive type of inheritance ^{[2] [3]} . Thus, it occurs with equal frequency in both men and women .

The autosomal recessive type of inheritance in practice means that the defective gene is located on one of two homologous autosomes . A disease clinically manifests itself only when both autosomes, obtained one from the father and mother, are defective in this gene. As in all cases of autosomal recessive inheritance, if both parents carry a defective gene, then the probability of inheriting the disease in the offspring is 1 out of 4. In the diagram, blue indicates healthy carriers, purple indicates carriers of the defective gene, and red indicates GM ₁ gangliosidosis (two defective alleles GLB1 of one gene 3q 21.3). A normal allele is marked with a blue circle and a defective one with a red circle.

There are three forms of the disease ^[2] :

• early childhood (infantile),
• late childhood (juvenile),
• adult (mature).

According to the International classification of diseases of the tenth revision ( ICD-10 ), distinguish:

• E 75. Disorders of sphingolipid metabolism and other diseases of lipid accumulation.
  • E 75.1 Other gangliosidoses. Gangliosidosis: NOS (without further specification) , GM ₁ , GM ₃ , Mucolipidosis IV .

The early childhood form of GM ₁ gangliosidosis is the most severe form of this subtype of gangliosidosis, which manifests itself shortly after the birth of the baby. Symptoms of early childhood GM ₁ gangliosidosis may include manifestations of neurodegeneration, convulsions , enlarged liver ( hepatomegaly ) and spleen ( splenomegaly ), roughening of facial features, skeletal disorders, joint stiffness, bloating, muscle weakness, excessive reaction to sound (startling) and disturbance gait. Approximately half of the patients develop characteristic cherry red spots on the fundus. Such children, upon reaching the age of 1 year, can become blind and deaf and often die at the age of 3 years from cardiovascular complications or pneumonia .

Among the clinical manifestations of this form of the disease, an early violation of the child's psychomotor development is characteristic: a decrease in activity and lethargy in the first weeks of life, problems of feeding - poor weight gain. At the age of 6 months, nystagmus is noted, children do not start to sit, and initial hypotension is subsequently replaced by the development of spasticity with the presence of pyramidal signs , secondary microcephaly , decerebral rigidity at 1 year and death at the age of 1-2 years develop ^[2] (as a result of pneumonia and respiratory failure ).

In some cases, hyperacusia develops - an excessive reaction of the infant to the sound, manifested by trembling. In 50% of cases between the ages of 6 and 10 months, characteristic cherry-red spots on the fundus in the macular region, corneal opacity are revealed. There are signs of facial dysmorphism: frontal thickening, wide nose, swelling of the face (puffy eyelids), peripheral edema, epicanth , long upper lip, microretrognathia, gingival hypertrophy (excessive thickness of the alveolar ridges), macroglossia . Usually hepatomegaly is noted from 6 months, and splenomegaly develops later. Some patients show signs of heart failure and skeletal deformity: flexion contractures are observed from 3 months, signs of premature subperiosteal bone formation (can occur in newborns ), epiphyses form later, diffuse demineralization of bone tissue, hypoplasia and sharpening of vertebral bodies from the thoracic to lumbar region - 3-6 months of age, fixed kyphosis forms at the junction of the thoracic vertebrae with the lumbar. Pronounced hypoplasia of the dentoid process can provoke the development of torticollis and cause compression of the spinal cord of varying severity. The characteristic shape of the vertebrae (“fish vertebrae”) and other skeletal deformities (as in the case of mucopolysaccharidoses ) are noted. The intracellular accumulation of mucopolysaccharides resembles the picture of Gurler's syndrome : vacuolization is noted in 10–80% of peripheral lymphocytes , foamy histiocytes in the bone marrow . The accumulation of GM ₁ ganglioside in the gray matter of the brain is 10 times higher than usual, and a 20-50-fold increase in internal organs is due to intracellular accumulation of galactose- containing oligosaccharides and moderate accumulation of keratan sulfate as in Morcio Type B syndrome : mutations with a higher residual beta-galactosidase activity in relation to GM ₁ substrate than for keratan sulfate and other glycosaminoglycans containing oligosaccharides, which is clinically manifested by minimal neurological impairment against the background of initial deformations of the skeleton and resembles Morkio syndrome ( mucopolysaccharidosis IV ) ^[3] .

The late infantile form of GM ₁ gangliosidosis manifests itself later _{than the} early one (usually aged 1 to 3 years). It is characterized mainly by neurological symptoms: ataxia , the presence of seizures , the development of dementia and speech disorders.

The adult form of GM ₁ gangliosidosis develops between the ages of three and thirty years of life. Clinical symptoms are characterized by muscle atrophy, the development of neurological complications, which, in contrast to childhood forms, are less severe and slower progression, clouding of the cornea (in some patients), dystonia (intrusive muscle contractions that cause torsion dystonia , repetitive movements or abnormal postures) . Angiokeratoma may develop on the lower body as a result of metabolic glycolipid disturbances. Most patients have normal sizes of the liver and spleen .

• GM2 gangliosidosis

• Harrison's principles of internal medicine