1. Genetic testing for GLB1-related disorders

GLB1-related disorders

December 07, 2017

Clinical features

GM1 gangliosidosis is a rare lysosomal storage disorder characterized biochemically by deficient beta-galactosidase activity and clinically by a wide range of variable neurovisceral, ophthalmological and dysmorphic features 1. GM1 gangliosidosis, also known as GLB1 deficiency, is estimated to occur in one in 100,000 to 300,000 individuals 2, 4. The most common of all GM1 gangliosidosis forms is the infantile form.

GM1 gangliosidosis is one of the GLB1-related disorders, along with the mucopolysaccharidosis type IVB (MPS IVB), also known as Morquio disease type B 1, 2, 4. MPS IVB is clinically indistinguishable from MPS IVA; therefore, the recently published MPS IVA clinical diagnostic criteria might be used as an aid in MPS IVB diagnosis 3.

There are three types of GM1 gangliosidosis based on age of onset:

  • Severe rapidly progressive infantile form with onset before six months of age (type 1 GM1 gangliosidosis)
  • Late infantile or juvenile form with onset between seven months and 3 years of age with delayed motor and cognitive development (type 2 GM1 gangliosidosis)
  • Adult, chronic form with late onset between 3 and 30 years of age (type 3 GM1 gangliosidosis), characterized primarily by generalized dystonia.

Disease severity appears to be related to the level of beta-galactosidase activity. GM1 gangliosidosis is caused by pathogenic variants in GLB1 leading to decreased activity of β-galactosidase, a lysosomal enzyme involved in the metabolism of the sphingolipid GM1 ganglioside. When enzyme activity is decreased, sphingolipid intermediates accumulate in the lysosome and interfere with appropriate functioning of the organelle. A hallmark of GM1 gangliosidosis is degeneration of the CNS where ganglioside synthesis is the highest.

Clinical features of GM1 gangliosidosis span a spectrum ranging from severe (infantile) to mild (adult) form 4:

Type I (infantile) GM1 gangliosidosis is characterized by the onset of symptoms prior to age 12 months. In some infants prenatal manifestations include hydrops fetalis (6%) and intrauterine growth retardation (1%) 4. The major clinical finding of infantile GM1 gangliosidosis is severe central nervous system dysfunction which manifest as early developmental delay with hypotonia and an exaggerated startle response, followed by spasticity and rapid regression 3. By the end of the first 12 months of life, most affected infants are without vision or hearing and with severe central nervous system dysfunction leading to decerebrate 3. Common finding in infantile GM1 gangliosidosis are cardiomyopathy, seizures, hepatosplenomegaly and poor feeding. Other findings include a coarsened facial appearance, large low-set ears, gingival hypertrophy with macroglossia, coarse thickened skin, hirsutism, and skeletal dysplasia 1, 3.

Type II (late infantile and juvenile) GM1 gangliosidosis is characterized with the late infantile onset, typically between ages 1-3 until ages 5-10 1. The disease is characterized by motor and cognitive delay, slow regression of previously achieved skills and absence of skeletal deformities 1.

Chronic/adult GM1 gangliosidosis has the onset of symptoms is in late childhood to the third decade 3, typically presenting with generalized dystonia leading to unsteady gait and speech disturbance 1, 3. Most affected patients rapidly develop extrapyramidal signs including akinetic-rigid parkinsonism (64%) 3. Other common findings include gait disturbance (44%), cardiomyopathy (38%), speech difficulties (33%), and dystonia (22%) 3. Skeletal abnormalities are identified in 95% of affected individuals, they are most commonly present in a form of short stature, kyphosis, and scoliosis of varying severity 3.

GM1 gangliosidosis is an allelic disorder to the Morquio B disease (Mucopolysacharoidosis type IVB, MPS IVB). MPS IVB is clinically indistinguishable from MPS IVA, caused by pathogenic variants in GALNS. MPS IVA/IVB is clinically characterized by corneal clouding, cardiac valvular disease, and skeletal abnormalities, including short stature. In general, neurologic function is normal 3, 4. Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years. The attenuated form may not become evident until late childhood or adolescence. While the skeletal changes in MPS IV are the hallmark findings, involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, and hepatomegaly 1, 5.

GM1 gangliosidosis and Mucopolysacharoidosis type IVB are caused by variants in the GLB1 gene coding for beta-galactosidase. To date, more than 215 variants have been identified.

At CENTOGENE we have analyzed several hundred individuals clinically suspected for GM1 gangliosidosis and 14% of GM1 gangliosidosis-susspected individuals had pathogenic variant in GLB1 gene, while 14% were identified as carriers 6.

Out of all GLB1 identified pathogenic variants 81% were identified as substitution, 13% as deletions and 3% as gross/complex rearrangements. Additional 1% of GLB1 variants were duplications and 3% were other types of variants (Figure 1). GLB1 classification of variants on protein level identified 61% missense variants, 14% splicing, 13% frameshift and 10% nonsense variants. Additional 25 of variants were of unknown effect or start loss variants (Figure 2) (CentoMD® 4.1) 6.

Figure 1. GLB1 classified and curated genetic variants types on DNA level identified in cases and carriers (wild type excluded) at CENTOGENE (CentoMD® 4.1) 6.

Figure 2. GLB1 classified and curated genetic variants types on protein level identified in cases and carriers (wild type excluded) at CENTOGENE (CentoMD® 4.1) 6.


Treatment for patients with GM1 gangliosidosis is symptomatic and supportive. Substrate reduction therapy is a potential approach for clinical trials in late-onset forms.

CENTOGENE offers detection of enzymatic activity of the lysosomal enzyme beta-galactosidase, full GLB1 gene sequencing and deletion/duplication testing of the GLB1 gene. GLB1 is also part of these gene panels:


Differential diagnosis

The differential diagnosis of GLB1-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • GM2 gangliosidosis (hexosaminidase A deficiency) caused by pathogenic variant in HEXA
  • Galactosialidosis sialidosis (mucolipidosis I) caused by pathogenic variant in CTSA
  • Sialidosis caused by pathogenic variant in NEU1
  • Mucopolysaccharidosis Type I H/S; H; S, caused by pathogenic variant in IDUA
  • Mucolipidosis II/III caused by pathogenic variant in GNPTAB.

Testing strategy

To confirm/establish the diagnosis, we offer beta-galactosidase enzymatic activity testing, full GLB1 gene sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels which are designed for the molecular genetic diagnosis of GM1 gangliosidosis and related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for GLB1 gene testing:

Step 1: Tandem-MS-based determination of enzymatic activity of the lysosomal enzyme beta-galactosidase

Step 2: GLB1 full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter

Step 3: Deletion/duplication analysis/pathogenic variant scanning of GLB1

Step 4: If no pathogenic variant is identified after analysis of the GLB1 gene, panel testing with related genes or further genetic testing of related genes can be done

Step 5: If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology


Referral reasons

The following individuals are candidates for GLB1 gene testing:

  • Individuals with a family history GM1 gangliosidosis and presentation of the most common symptoms
  • Individuals without a positive family history of GM1 gangliosidosis, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of GM1 gangliosidosis, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Tandem-MS-based assessment of beta-galactosidase enzyme activity, sequencing and deletion/duplication of GLB1 and related genes should be performed in all individuals suspected of having GM1 gangliosidosis. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of reduced/abnormal enzymatic activity and/or GLB1 pathogenic variants, due to the overlap in many clinical features caused by genes associated with various clinically overlapping forms of GM1 gangliosidosis. Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct the management.

Genetic counseling can provide a patient and/or family with the natural history of GM1 gangliosidosis to identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s genetic tests for GM1-gangliosidosis can be found in our genetic test catalogue.