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GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB / Morquio Type B via the GLB1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7683 GLB1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7683GLB181479 81479,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Jana Paderova, PhD

Clinical Features and Genetics

Clinical Features

GM1 gangliosidosis and mucopolysaccharidosis Type IVB (MPS IVB, Morquio B disease) are two clinically distinct lysosomal storage disorders due to deficiency of the lysosomal beta-galactosidase (beta-gal), which hydrolyzes terminal beta-linked galactose residues from GM1 gangliosides, glycoproteins, oligosaccharides, and keratan sulfate. GM1 gangliosidosis results from beta-gal deficiency with respect to all substrates and their subsequent accumulation, mainly in neuronal tissues. MPS IVB is due to selective beta-gal deficiency with respect to keratan sulfate and its subsequent storage in the cartilage and cornea (Neufeld and Muenzer 2001; Hofer et al. 2010).

GM1 gangliosidosis is a neurodegenerative disorder with three clinical forms based on the age of onset of symptoms, severity, and residual beta-gal activity (Suzuki et al. 2014):

GM1 gangliosidosis Type 1 or Infantile form is the most common and most severe of the three. It is characterized by onset during the first year of life, rapidly progressive central nervous system involvement and psychomotor deterioration. Symptoms include dysmorphism, cerebral degeneration, skeletal dysplasia, gingival hypertrophy, macular cherry-red spots, vision and hearing loss, abnormally pronounced startle reflex, epilepsy, spasticity, hepatosplenomegaly, and cardiomyopathy. Death occurs before the age of two years.

GM1 gangliosidosis Type 2 or Juvenile form is characterized by age of onset between 2 and 5 years, a milder course compared to the infantile form, and survival into early adulthood.

GM1 gangliosidosis Type 3 or Adult form is characterized by a later age of onset, usually during the second decade of life, and more prolonged clinical course. The central nervous system involvement is restricted to the extrapyramidal tract. Symptoms include dysarthria, gait disturbance and dystonia.

GM1 gangliosidosis affects people worldwide with an estimated prevalence of 1:100,000 to 3:100,000 live births (Suzuki et al. 2014).

MPS IVB belongs to the mucopolysaccharidoses (MPS), which are a group of seven inherited disorders (Types I, II, III, IV, VI, VII, and IX) caused by defects in lysosomal enzymes involved in the degradation of various glycosaminoglycans (GAGs). Based on the biochemical and genetic defects, MPS IV is further divided in two subtypes: MPS IV-A and MPS IV-B, also known as Morquio A and B diseases. The clinical features are identical in both subtypes. They are distinguished from other MPS by normal intelligence and skeletal dysplasia that results in short stature and skeletal abnormalities with secondary effects on the central nervous system. Various parts of the body may be affected including the wrists, knees, hips, ribs, chest and spine. Odontoid hypoplasia is a characteristic feature. Additional features include osteoporosis; coarse traits; corneal clouding leading eventually to loss of vision; widely spaced teeth with multiple cavities; repeated upper respiratory and ear infections that result in apnea and hearing loss; hernia; and hepatomegaly (Hughes et al. 1997; O’Brien et al. 1976).

In the classical and most severe form, symptoms begin during early childhood. If not treated, death occurs by the third decade of life, usually from complications as the result of spinal cord compression and airway obstruction. A milder form of MPS IV is characterized by a later age of onset; slow progression; mild bone and somatic involvement; and survival into late adulthood (Montaño et al. 2007; Solanki et al. 2013; Nelson et al. 1988).

MPSIV affects people worldwide with various incidences, ranging from 1:76,000 in Northern Ireland to 1:640,000 in Western Australia (Tomatsu et al. 2005). An incidence of 0.38:100,000 was reported in Germany (Baehner et al. 2005).

Genetics

GM1 Gangliosidosis and MPS IVB are inherited with an autosomal recessive manner. They are caused by pathogenic variants in the GLB1 gene (Nishimoto et al.; Oshima et al. 1991). Over 150 variants have been detected in patients with GM1 Gangliosidoses, and include all types. GLB1 mutations in patients with MPS IVB are mostly of the missense type. Out of 22 MSP IVB-causative variants, 21 are missense and only one is a frameshift located near the 5' end of the gene (Human Gene Mutation Database).

Although several GLB1 pathogenic variants may be predictive of the resulting clinical phenotype (Santamaria et al. 2006; Hofer et al. 2010), there are no clear genotype-phenotype correlations. In particular, the same variants have been reported in patients with GM1 gangliosidoses types I, II, III and MPS IVB (Caciotti et al. 2011; Moore et al. 2013).

The GLB1 gene encodes lysosomal beta-galactosidase, which hydrolyzes terminal beta-linked galactose residues from GM1 gangliosides, glycoproteins, oligosaccharides, and keratan sulfate.

Clinical Sensitivity - Sequencing with CNV PG-Select

Using Sanger sequencing, several studies identified pathogenic variants in about 99% of the analyzed mutant alleles (Santamaria et al. 2006; Santamaria et al. 2007; Brunetti-Pierri and Scaglia 2008).

Large pathogenic deletions in GLB1 appear to be rare (Santamaria et al. 2007).

Testing Strategy

This test provides full coverage of all coding exons of the GLB1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with clinical features and radiological findings suggestive of either GM1 gangliosidoses or MPS IV and reduced beta-galactosidase activity; and potential heterozygous carriers. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GLB1.

Gene

Official Gene Symbol OMIM ID
GLB1 611458
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, Kohlschütter A, Kampmann C, Beck M. 2005. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 28: 1011–1017. PubMed ID: 16435194
  • Brunetti-Pierri N, Scaglia F. 2008. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol. Genet. Metab. 94: 391–396. PubMed ID: 18524657
  • Caciotti A, Garman SC, Rivera-Colón Y, Procopio E, Catarzi S, Ferri L, Guido C, Martelli P, Parini R, Antuzzi D, Battini R, Sibilio M, et al. 2011. GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812: 782–790. PubMed ID: 23430499
  • Hofer D, Paul K, Fantur K, Beck M, Roubergue A, Vellodi A, Poorthuis BJ, Michelakakis H, Plecko B, Paschke E. 2010. Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations. Clin. Genet. 78: 236–246. PubMed ID: 20175788
  • Hughes DG, Chadderton RD, Cowie RA, Wraith JE, Jenkins JP. 1997. MRI of the brain and craniocervical junction in Morquio’s disease. Neuroradiology 39: 381–385. PubMed ID: 9189888
  • Human Gene Mutation Database (Bio-base).
  • Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. 2007. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J. Inherit. Metab. Dis. 30: 165–174. PubMed ID: 17347914
  • Moore T, Bernstein JA, Casson-Parkin S, Cowan TM. 2012.  β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype. Epub 2012 Apr 22.
  • Nelson J, Broadhead D, Mossman J. 1988. Clinical findings in 12 patients with MPS IV A (Morquio’s disease). Further evidence for heterogeneity. Part I: Clinical and biochemical findings. Clin. Genet. 33: 111–120. PubMed ID: 3129221
  • Neufeld EF, Muenzer J. 2001. The Mucoploysaccharidoses. 136: 3421-3452.
  • Nishimoto J, Nanba E, Inui K, Okada S, Suzuki K. 1991. GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients. American journal of human genetics 49: 566. PubMed ID: 19911909089
  • Oshima A, Yoshida K, Shimmoto M, Fukuhara Y, Sakuraba H, Suzuki Y. 1991. Human beta-galactosidase gene mutations in morquio B disease. American journal of human genetics 49: 1091. PubMed ID: 1928092
  • O’Brien JS, Gugler E, Giedion A, Wiessmann U, Herschkowitz N, Meier C, Leroy J. 1976. Spondyloepiphyseal dysplasia, corneal clouding, normal intelligence and acid beta-galactosidase deficiency. Clin. Genet. 9: 495–504. PubMed ID: 817853
  • Santamaria R, Chabas A, Callahan JW, Grinberg D, Vilageliu L. 2007. Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients. The Journal of Lipid Research 48: 2275–2282. PubMed ID: 17309651
  • Santamaria R, Chabás A, Coll MJ, Miranda CS, Vilageliu L, Grinberg D. 2006. Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. Hum. Mutat. 27: 1060. PubMed ID: 16941474
  • Solanki GA, Martin KW, Theroux MC, Lampe C, White KK, Shediac R, Lampe CG, Beck M, Mackenzie WG, Hendriksz CJ, Harmatz PR. 2013. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. Journal of Inherited Metabolic Disease 36: 339–355. PubMed ID: 23385297
  • Suzuki Y, Nanba E, Matsuda J, Higaki K, Oshima A. 2014. β-galactosidase deficiency (β-Galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID).Chap 151. New York, NY: McGraw-Hill.
  • Tomatsu S, Montaño AM, Nishioka T, Gutierrez MA, Peña OM, Tranda firescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T. 2005. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Human Mutation 26: 500–512. PubMed ID: 16287098

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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