Gangliosidosis GM1 - a rare disorder of spingolipid metabolism

Clinical History

One and a half year old girl with shortness of breath, tachypnoea, multiple dysmorphic features, visual failure, and a gross delay in her developmental milestones. On examination she was found to have course crepitations in the region of the left upper lung lobe and oxygen saturations of 88% on air.

Imaging Findings

A one and a half year old girl was brought to paediatric casualty with shortness of breath and deterioration in general condition. The child was blind and had abnormal facies. She was being fed via a nasogastric tube. Notice was made of joint contractures affecting the elbows and knees. The child was noted to have grossly delayed milestones, with minimal head control, no grasping reflex, no babbling or cooing. Multiple dysmorphic features were also evident – coarse facies, depressed nasal bridge and broad nasal tip, gingival hypertrophy and macroglossia. Auscultation of her chest revealed coarse inspiratory crepitations in the region of the left upper lobe, and expiratory rhonchi. The respiratory rate was also tachypnoeic and pulse oximetry showed saturations of 88% on air.

Review of the clinical history revealed multiple admissions with similar complaints in the past months. She was a known case of GM1 gangliosidosis, and was blind since 6 months of age.

The patient was started on intravenous antibiotics and supplemental oxygen.

A plain radiograph of the chest was performed two days following admission since her clinical condition failed to improve significantly. This showed no foci of consolidation. A number of skeletal dysmorphic features were noted, including wide spatula-shaped ribs, thoraco-lumbar kypho-scoliosis, and physeal / diaphyseal widening in both humeri with distal tapering (Fig. 1-3).

The child made an uneventful slow recovery and was discharged back home three weeks after her admission.

Discussion

GM1 gangliosidosis is an autosomal recessive disorder of sphingolipid metabolism secondary to a deficiency of β-galactosidase. β-galactosidase is part of a multi-enzyme lysosomal complex which is necessary for the degradation of certain gangliosides (including GM1 – the major ganglioside in the vertebrate brain), other glycospingolipids and also galactose-containgin oligosaccharides and keratan sulfates [1].

These most severe forms of the disease will exhibit features of a neuronal lipidosis, a mucopolysaccharoidosis, and an oligosaccharidosis. The only definite way to diagnose GM1 gangliosidosis is by obtaining enzyme assays showing deficient β-galactosidase activity.

GM1 gangliosidosis is a rare disorder (estimated incidence is 1 in 100,000-200,000 liver births) [2] but an unusually high incidence has been reported in our institution, which caters for the population of Malta (1 in 3700 live births) [3].

Three clinical subtypes of GM1 gangliosidosis are recognised [1,2]:

1. The typical early infantile form (type 1) – children are hypotonic in the first days or weeks of life, with poor head control. An arrest in neurological development is observed at 3-6 months of age, often resulting in feeding difficulties and a failure to thrive. Dysmorphic features include macroglossia, hypertrophic gums, depressed nasal bridge, ‘chipmunk face’, and macular cherry-red spots on ophthalmoscopy. Visual failure occurs within a few months. Radiological features include hepatomegaly, splenomegaly, thoraco-lumbar kyphoscoliosis and beaking, subperiosteal new bone formation, shortened long bones with diaphyseal widening and distal tapering, widening of the metacarpal shafts with proximal pinching of the four lateral metacarpals, J-shaped enlarged sella turcica, wide spatula shaped ribs, and acetabula dysplasia. The vertebral anomalies seen in GM1 gangliosidosis are similar to those seen in the mucopolysaccharidoses [4]. Death usually occurs by two years of age, often secondary to repeated aspiration pneumonias.

2. Late infantile form (type 2) – onset of symptoms is between 12-18 months with unsteadiness in sitting or standing or difficulty in walking. Regression is rapid and severe, resulting in a spastic quadriparesis and pseudobulbar signs. Most of these patients will have frequent epileptic seizures, which are difficult to manage. No dysmorphic features are present, and death usually occurs by the second decade. Radiographic features include mild anterosuperior hypoplasia of the vertebral bodies at the thoracolumbar junction.

3. Chronic late-onset form (type 3) – onset in late childhood, adolescence or adulthood. These patients commonly present with a progressive dementia (following normal early cognitive development) with parkinsonian features (dysarthria and extrapyramidal signs). Radiological signs are variable.

The radiological features observed in GM1 gangliosidosis are shared with mucopolysaccharidoses of the 'Hurler type'. In fact, GM1 gangliosidosis had variously been called 'Hurler variant,' 'pseudo-Hurler disease,' and 'Tay-Sachs disease with visceral involvement⁵. The term 'gangliosidosis' was first applied to this entity in 1965⁶.

GM1 gangliosidosis is catalogued in the 'Online Mendelian Inheritance in Man (OMIM) project', a database that catalogues all the known diseases with a genetic component. It carries the OMIM ID #230500, with the '#' denoting the mutation in the gene encoding beta-galactosidase-1⁷.

No effective treatment is currently available for patients with GM1 gangliosidosis.

Differential Diagnosis List

Final Diagnosis

Aspiration pneumonia in a patient with Type I GM1 gangliosidosis.

URL:	https://www.eurorad.org/case/8680
DOI:	10.1594/EURORAD/CASE.8680
ISSN:	1563-4086