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Neuroimaging Findings in GM1 Gangliosidosis
 
Dinesh S Baviskar, Devang J Desai, Inder Talwar, Sunila T Jaggi
 
We report neuroimaging findings in an 18-month-old baby who presented with progressive spasticity, delayed milestones, facial dysmorphic features and macrocephaly. CT and MRI findings with enzyme level correlation, were suggestive of GM1 gangliosidosis
 
Introduction

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulphate (and their derivatives). Deficiency of the lysosomal hydrolase, acid b-galactosidase, causes GM1 gangliosidosis and Morquio disease type B (i.e., mucopolysaccharidosis type IV-B).

 
 
Case Report

An 18-month-old child presented with history of spasticity, delayed milestones, facial dysmorphic features (depressed nasal bridge) and macrocephaly. Retinoscopy revealed macular cherry red spots.

NECT scan showed high attenuation involving both thalami, with low attenuation in the cerebral white matter. There was no enhancement on the post contrast study.

MRI of the brain showed T1 and T2 shortening in the thalami bilaterally. The white matter appeared diffusely hyperintense on T2 weighted images. No cerebral atrophy was noted.

The skeletal survey was normal.

Enzyme level estimation was carried out which showed reduced levels of acid b-Galactosidase, which is seen in GM1 Gangliosidosis.

 
Discussion

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulphate (and their derivatives).1

Three clinical subtypes of GM1 gangliosidosis exist, classified by age of onset, as follows:

  • Infantile (type 1) : The classic infantile subtype combines the features of a neurolipidosis (i.e., neurodegeneration, macular cherry-red spots) with those of a mucopolysaccharidosis (i.e., visceromegaly, osseous dysplasia, dysmorphic facial features). This form of GM1 gangliosidosis most frequently presents in early infancy and may be evident at birth.
  • Juvenile (type 2) : The juvenile subtype is marked by a slightly later age of onset (1-5 years) and has progressive psychomotor retardation. Seizures, spasticity and movement disorders occur, death ensues within a few years.
  • Adult (type 3) : The adult subtype is marked by normal early neurologic development with no physical stigmata and subsequent development of a slowly progressive dementia with parkinsonian features, extrapyramidal disease, and dystonia.1-3
 
Pathophysiology

Acid b-galactosidase is a lysosomal hydrolase that catalyzes the removal of the terminal b-linked galactose from glycoconjugates (e.g., GM1 ganglioside), generating GM2 ganglioside. It also functions to degrade other b-galactose-containing glycoconjugates, such as keratan sulphate.

Enzyme activity is markedly reduced in patients with GM1 gangliosidosis. Deficiency of acid b-galactosidase results in the accumulation of glycoconjugates in body tissues and their excretion in urine. GM1 ganglioside and its derivative asialo GM1 ganglioside (GA1), glycoprotein-derived oligosaccharides, and keratan sulphate are found to be elevated in the intracellular concentrations.

Gangliosides are normal components of cell membranes, particularly neurons, and GM1 is the major ganglioside in the vertebrate brain.

Accumulation of toxic asialo- and lyso-compound GM1 ganglioside derivatives is believed to be neuropathic.4,5

 

Figs. 1 : (a) Axial NECT scan reveals hyperdense thalami. (b) IR axial image
showing hyperintense thalami.

Figs 2 : (a) FLAIR axial image showing hypointense thalami. (b) T2 weighted coronal image showing hypointense thalami and diffuse white matter hyperintensity
 
Lab Studies
  • Acid b-galactosidase activity : Diagnosis can be confirmed by measurement of acid b-galactosidase activity in peripheral blood leucocytes. Patients with the infantile form have almost no enzyme activity, while patients with the adult form may have residual activity of 5-10% of reference values.
  • 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 : Vacuolation of lymphocytes may be present in patients with GM1 gangliosidosis but is a nonspecific indicator seen in a variety of lysosomal storage disorders.1,6
 
Imaging Studies
  • Neuroimaging : CT studies reveal high attenuation in the thalami and low attenuation in the white matter in early stages, with cerebral and cerebellar atrophy in later stages.
    MRI shows hypointensity involving the thalami on T1 weighted images with hyperintensity on T2 weighted images. Diffuse T2 prolongation is seen in the white matter. The differential diagnosis includes GM2 gangliosidosis, Krabbe’s disease and neonatal hypoxia. Absence of microcephaly differentiates GM1 from Krabbe’s disease. 2,3 The neuroimaging findings of GM1 and GM2 gangliosidoses are similar, and differentiation is on the basis of enzyme level estimation.3
  • Radiography : Skeletal radiographs may reveal changes characteristic of osseous dysplasia (as observed in mucopolysaccharidosis), including thickened calvarium, 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.7
  • Ultrasound : An ultrasound of the abdomen may reveal organomegaly.
 
References
1.
Tegay DH, Fallet S. GM1 gangliosidosis. eMedicine.com, Inc. (web article), 2002.
2.
Chen CY, Zimmerman RA, Lee CC, et al. Neuroimaging findings in late infantile GM1 gangliosidosis. Am J Neuroradiol 1998; 19 : 1628-30.
3.
Barkovich AJ. Toxic and Metabolic Brain Disorders. In: Pediatric Neuroimaging 3rd ed. Lippincott Williams and Wilkins; 2000: 139-141
4.
Suzuki Y, Oshima A, Nanba E. b-Galactosidase deficiency (b-Galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Scriver CR, Sly WS, Valle D, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Professional; 2001: 3775-810..
5.
Suzuki K. Neuropathology of late onset gangliosidoses. A review. Dev Neurosci 1991; 13 (4-5) : 205-10.
6.
Bieber FR, Mortimer G, Kolodny EH, et al. Pathologic findings in GM1 gangliosidosis. Arch Neurol 1986; 43: 736-38.
7.
Ohta K, Tsuji S, Mizuno Y, et al. Type 3 (adult) GM1 gangliosidosis: case report. Neurology 1985; 35 : 1490-94.

 

OMEPRAZOLE 20 MG = 40 MG FOR PRIMARY CARE ACID RELATED DYSPEPSIA

Omeprazole 20 mg is highly effective for treating acid related dyspepsia. There was no advantage to higher doses, and relapse following the initial two week treatment period was common.

BMJ, 2004; 329 : 1058.