Gangliosidosis generalized GM1- type 1

Synonyms

1

Overview

A rare biochemical disorder involving a deficiency of an enzyme (beta-galactosidase A) which results in the accumulation of harmful chemicals (GM1 gangliosides) in the central nervous system and other body tissues. Type 1 is a severe infantile form of the disorder and involves a greater degree of accumulation than type II or III. Mutations in the GLB1 gene cause GM1 gangliosidosis. The GLB1 gene provides instructions for making an enzyme called beta-galactosidase (β-galactosidase), which plays a critical role in the brain. This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. 

Individuals with GM1 gangliosidosis type I usually do not survive past early childhood.

Symptoms

  • Severe psychomotor retardation
  • Reduced muscle tone
  • Decerebrate rigidity
  • Hyperreflexia
  • Muscle weakness
  • Exaggerated startle reaction to loud noises
  • Profound intellectual disability
  • Clouding of the clear outer covering of the eye (the cornea)

Causes

Mutations in the GLB1 gene cause GM1 gangliosidosis. The GLB1 gene provides instructions for making an enzyme called beta-galactosidase (β-galactosidase), which plays a critical role in the brain. This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Within lysosomes, β-galactosidase helps break down several molecules, including a substance called GM1 ganglioside. GM1 ganglioside is important for normal functioning of nerve cells in the brain.

Mutations in the GLB1 gene reduce or eliminate the activity of β-galactosidase. Without enough functional β-galactosidase, GM1 ganglioside cannot be broken down when it is no longer needed. As a result, this substance accumulates to toxic levels in many tissues and organs, particularly in the brain. Progressive damage caused by the buildup of GM1 ganglioside leads to the destruction of nerve cells in the brain, causing many of the signs and symptoms of GM1 gangliosidosis. In general, the severity of GM1 gangliosidosis is related to the level of β-galactosidase activity. Individuals with higher enzyme activity levels usually have milder signs and symptoms than those with lower activity levels because they have less accumulation of GM1 ganglioside within the body.

Conditions such as GM1 gangliosidosis that cause molecules to build up inside the lysosomes are called lysosomal storage disorders.

Read more about the GLB1 gene.

Diagnosis

  • Acid β -galactosidase activity: Diagnosis of G M1 gangliosidosis can be confirmed by measurement of acid β -galactosidase activity in peripheral blood leukocytes. Patients with the infantile form have almost no enzyme activity, whereas patients with the adult form may have residual activity of 5-10% of reference values. Overlap is often present between homozygotes without GM1 gangliosidosis and heterozygote carriers; therefore, screening for heterozygote carriers using enzyme analysis is not reliable.

  • Urine: Galactose-containing oligosaccharides are excreted in the urine. Their presence may be used as an ancillary diagnostic test, and the concentration of the metabolites is proportional to disease severity.

  • CBC count: Vacuolation of lymphocytes may be present in patients with GM1gangliosidosis but is a nonspecific indicator seen in a variety of lysosomal storage disorders.

  • Dried blood spots: Diagnosis of GM1 gangliosidosis has been made based on dried blood spots from newborn screening filter paper, even after 15 months in storage.

  • Molecular analysis: Molecular analysis of the β -1 galactosidase gene (GLB1) is clinically available.

  • Radiography: Skeletal radiographs may reveal changes characteristic of dysostosis multiplex (as observed in mucopolysaccharidosis), including thickened calvaria, J-shaped enlarged sella turcica, wide spatula-shaped ribs, flared ilia, acetabular dysplasia and flat femoral heads, wide wedge-shaped metacarpals, shortened long bones with diaphyseal widening, and hypoplastic and anteriorly beaked thoracolumbar vertebrae. Delayed bone age also may be demonstrated. In the adult form, only mild vertebral changes may be observed.

  • CT and MRI: Neuroimaging using CT scan or MRI generally reveals diffuse atrophy and white matter demyelination with or without basal ganglia changes. Bilateral T2-weighted hyperintensities in the putamen are a frequently reported MRI finding in adult-onset disease. Mild cerebral atrophy may also be observed in the adult form. MR spectroscopy has demonstrated increased striatal myoinositol.

  • Ultrasound: An ultrasound of the abdomen may reveal organomegaly.

  • Echocardiography: Signs of cardiomyopathy or valvulopathy may be observed.