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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

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GLB1-Related Disorders

, MD, PhD and , MD, PhD.

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Summary

Clinical characteristics.

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB).

GM1 gangliosidosis includes phenotypes that range from severe to mild. Type I (infantile) begins before age one year; progressive central nervous system dysfunction leads to spasticity, deafness, blindness, and decerebrate rigidity. Life expectancy is two to three years. Type II can be subdivided into the late-infantile form and juvenile form. Type II, late-infantile form begins between ages one and three years; life expectancy is five to ten years. Type II, juvenile form begins between ages three and ten years with insidious plateauing of motor and cognitive development followed by slow regression. Type II may or may not include skeletal dysplasia. Type III begins in the second to third decade with extrapyramidal signs, gait disturbance, and cardiomyopathy; and can be misidentified as Parkinson disease. Intellectual impairment is common late in the disease; skeletal involvement includes short stature, kyphosis, and scoliosis of varying severity.

MPS IVB is characterized by skeletal changes, including short stature and skeletal dysplasia. Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, and the attenuated form in late childhood or adolescence. In addition to skeletal involvement, significant morbidity can result from respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, and spinal cord compression. Intellect is normal unless spinal cord compression leads to central nervous system compromise.

Diagnosis/testing.

The diagnosis of GLB1-related disorders is suspected in individuals with characteristic clinical, neuroimaging, radiographic, and biochemical findings. The diagnosis is confirmed by either deficiency of β-galactosidase enzyme activity or biallelic pathogenic variants in GLB1.

Management.

Treatment of manifestations: Best provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology and therapists knowledgeable about GLB1-related disorders; surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders; occupational therapy to optimize activities of daily living (including adaptive equipment) and physical therapy to optimize gait and mobility (including orthotics and bracing); early and ongoing interventions to optimize educational and social outcomes.

For those with GM1 gangliosidosis: Adequate nutrition to maintain growth; speech therapy to optimize oral motor skills; aggressive seizure control; routine management of risk of aspiration, risk of chronic urinary tract infection, and cardiac involvement; when disease is advanced: hospice services for supportive in-home care.

Prevention of secondary complications: Anesthetic precautions to anticipate and manage complications relating to skeletal involvement and airway compromise; routine immunization; bacterial endocarditis prophylaxis in those with cardiac valvular disease.

Surveillance:

  • GM1 gangliosidosis: Routine monitoring of growth and nutrition. Assess yearly: quality of life including history and physical examination; seizure risk by a neurologist; cervical spine stability; and hip dislocation risk. Perform every one to three years: electrocardiogram and echocardiogram; eye examination.
  • MPS IVB: Yearly: perform endurance tests to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems; assess lower extremities for malalignment, hips for dysplasia/subluxation, thoracolumbar spine for kyphosis, and cervical spine for instability; perform eye examination and audiogram. Perform electrocardiogram and echocardiogram every one to three years depending on disease course; assess for obstructive sleep apnea and restrictive lung disease; monitor nutritional status using MPS IVA-specific growth charts.

Agents/circumstances to avoid: Psychotropic medications because of the risk of worsening neurologic disease; obesity in those with skeletal dysplasia

Genetic counseling.

GLB1-related disorders are inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

GeneReview Scope

GLB1-Related Disorders: Included Phenotypes
  • GM1 gangliosidosis
  • Mucopolysaccharidosis type IVB

For synonyms and outdated names see Nomenclature.

Diagnosis

GLB1-related disorders comprise two phenotypically unique disorders, GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB).

Formal diagnostic criteria have not been established for GLB1-related disorders.

Since MPS IVB is clinically indistinguishable from MPS IVA, it may be appropriate to use the recently published MPS IVA clinical diagnostic criteria as an aid in MPS IVB diagnosis [Wood et al 2013].

Suggestive Findings

The diagnosis of GLB1-related disorders is suspected in individuals with the clinical, neuroimaging, radiographic, and biochemical findings summarized by phenotype in Table 1.

Table 1.

Clinical, Skeletal, Neuroimaging, and Biochemical Findings in GLB1-Related Disorders

FindingGM1 GangliosidosisMPS IVB
Type IType IIType III
InfantileLate InfantileJuvenileChronic/Adult
Onset of symptoms<1 year1-3 years3-10 years10+ years3-5 years
Eye findingsCRSCCCC+/– CCCC
Motor abnormalities+++ExtrapyramidalSee footnote 1
Hepatosplenomegaly++/–+/–
Cardiac involvement+/–+/–+/–+/–+
Coarse facial features+/–See footnote 1
Skeletal findings++/–+/–+
NeuroimagingPAPAPA+/– mild atrophySee footnote 1
Urine glycosaminoglycans (GAG)See footnote 2See footnote 2See footnote 2See footnote 2Keratan sulfate 3
+

= positive finding

– = negative finding

+

/ – = variable finding in patient population

CRS = cherry red spot

CC = corneal clouding

PA = progressive atrophy

1.

Secondary to bony changes

2.

Oligosaccharide with terminal galactose sugar

3.

False negative results can be observed.

Clinical Findings

GM1 gangliosidosis

  • Type I (infantile; onset age <1 year) is the most common phenotype. Infants have macular cherry-red spots, developmental delay followed by regression generally observed by age six months, hepatosplenomegaly, cardiac involvement, coarse facial features, and generalized skeletal dysplasia of varying severity.
  • Type II includes:
    • Late infantile (onset age 1-3 years). These children typically have corneal clouding (Figure 1), motor abnormalities, and progressive and diffuse atrophy on brain imaging; they may have hepatosplenomegaly, cardiac involvement, and/or skeletal abnormalities.
    • Juvenile (onset age 3-10 years). These children typically have motor regression and consistent brain MRI findings of progressive atrophy. Overall, the disease progression is slower than in the late-infantile type.
  • Type III (chronic/adult) is the mildest form of the disease spectrum with dystonia leading to gait or speech difficulty as the first symptom.
Figure 1. . Image obtained with a slit lamp demonstrating mild to moderate corneal clouding in an adolescent with the juvenile form of GM1 gangliosidosis Picture courtesy of Dr.

Figure 1.

Image obtained with a slit lamp demonstrating mild to moderate corneal clouding in an adolescent with the juvenile form of GM1 gangliosidosis Picture courtesy of Dr. Wahdi Zein, National Eye Institute, National Institutes of Health, Bethesda, MD

Mucopolysaccharidosis type IVB (MPS IVB) is characterized by corneal clouding, cardiac involvement, severe skeletal abnormalities, and short stature [reviewed in Suzuki et al 2014]. Developmental milestones, cognitive function, and neurologic function are normal unless neurologic complications (e.g., spinal cord impingement) develop secondary to severe skeletal dysplasia [reviewed in Tomatsu et al 2011].

Radiographic Findings

GM1 gangliosidosis (Figure 2)

Figure 2. . Radiographs of the late infantile form of GM1 gangliosidosis A.

Figure 2.

Radiographs of the late infantile form of GM1 gangliosidosis A. The odontoid process is under ossified (white arrow). The vertebral bodies are flattened (black arrow). B. Hip x-rays showing dysostosis multiplex. The infero-lateral portions of the ilia (more...)

  • Type I and type II. Findings observed in many, but not all, persons include: dysostosis multiplex with thickened calvaria, J-shaped enlarged sella turcica, hypoplastic/anteriorly beaked thoracolumbar vertebrae, wide spatula-shaped ribs, flared ilia, acetabular dysplasia with flat femoral heads, shortened long bones with diaphyseal widening, pectus carinatum, and/or wide wedge-shaped metacarpals [reviewed in Suzuki et al 2014].
  • Type III. Only mild vertebral changes may be observed.

MPS IVB. See Note. Findings on skeletal survey that suggest the diagnosis of MPS IVB include the following:

  • Odontoid hypoplasia with subsequent risk for cervical instability
  • Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
  • Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
  • Scoliosis
  • Pectus carinatum or excavatum

Note: (1) Based on wide variations and subtleties of the radiographic findings in MPS IV, multiple body regions should be evaluated. (2) While the radiographic findings in MPS IVA (caused by biallelic GALNS pathogenic variants) and MPS IVB are extensive and can be diagnostic, they cannot distinguish MPS IVA from MPS IVB. (See Mucopolysaccharidosis Type IVA for a detailed discussion of the radiographic findings.)

Neuroimaging

GM1 gangliosidosis. Brain MRI can show the following:

  • Diffuse atrophy and white matter abnormalities
  • T2-weighted hypointensity in the basal ganglia/globus pallidus that is not specific (Figure 3).
  • In individuals with adult-onset disease: hyperintensity in the putamen and/or mild cerebral atrophy [reviewed in Erol et al 2006, Steenweg et al 2010]
Figure 3. . Brain MRI findings in a child with the late infantile form of GM1 gangliosidosis A.

Figure 3.

Brain MRI findings in a child with the late infantile form of GM1 gangliosidosis A. At age 3 years 6 months: T2-weighted axial view showing minimal atrophy B and C. At age 6 years 10 months: T2-weighted axial view showing progressive atrophy as evidenced (more...)

Brain MR spectroscopy (MRS) has shown patient-specific changes documented in case reports [Erol et al 2006].

Urine Glycosaminoglycans (GAG) Analysis

GM1 gangliosidosis. Although a specific GAG pattern in urine is noted in persons with GM1 gangliosidosis, enzyme activity or molecular genetic testing is necessary for diagnosis [Suzuki et al 2014].

MPS IVB. Excretion of keratan sulfate in the urine can be diagnostic of MPS IV; however, the presence of keratan sulfate in the urine does not distinguish MPS IVA from MPS IVB; thus, additional studies are warranted (see To Confirm/Establish the Diagnosis in a Proband).

A glycosaminoglycan screen can be falsely negative; thus, testing to confirm the diagnosis should be performed if there is clinical suspicion (see To Confirm/Establish the Diagnosis in a Proband).

To Confirm/Establish the Diagnosis in a Proband

The diagnosis of a GLB1-related disorder in a proband relies on either β-galactosidase enzyme analysis or GLB1 molecular genetic testing. Despite the availability of molecular genetic testing, the mainstay of diagnosis of GLB1-related disorders will likely continue to be enzyme activity because of cost and difficulty in interpreting variants of unknown significance.

β-galactosidase enzyme analysis. The definitive diagnosis of a GLB1-related disorder can be made by measuring β-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts.

The diagnosis of MPS IVB can be confirmed by the combination of keratan sulfate in the urine and decreased enzyme activity for β-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts in the absence of intellectual disability.

Table 2.

β-Galactosidase Enzyme Activity in GLB1-Related Disorders by Phenotype

GM1 GangliosidosisMPS IVB
Type IType IIType III
InfantileLate InfantileJuvenileChronic/Adult
β-galactosidase
enzyme activity 1, 2
Negligible~1%-5%~3%-10%5%-10%2%-12% 3
1.

Relative values (% of normal activity)

2.

Although the percent of residual enzyme activity correlates generally with phenotype, it cannot predict the type of GM1 gangliosidosis. The lack of direct correlation between enzyme activity and disease severity may be due to the use of artificial substrates in the in vitro enzyme assay, which may not exactly replicate in vivo enzyme activity with natural substrates. Modifier genes could theoretically alter enzyme activity and, thus, disease severity.

3.

Note: Enzyme activity may not be predictive of carrier status in family members of individuals with a GLB1-related disorder.

Molecular genetic testing. The definitive diagnosis of a GLB1-related disorder can be made by identification of biallelic pathogenic variants in GLB1 if enzyme analysis is not available and/or results are not definitive (see Table 3).

Table 3.

Summary of Molecular Genetic Testing Used in GLB1-Related Disorders

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
GLB1Sequence analysis 4Sequence variants>99% 5
Deletion/duplication analysis 6Exon or whole-gene deletions<1% 7
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7.

One individual had a deletion of exon 5 [Santamaria et al 2007]. See Molecular Genetics.

Clinical Characteristics

Clinical Description

GLB1-related disorders comprise two phenotypically distinct disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB).

GM1 Gangliosidosis

The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late infantile and juvenile) to mild (chronic/ adult). Although classification into these types is arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, symptoms, rate of progression, and longevity.

No prospective natural history studies have been published for GM1 gangliosidosis; however, several case series have been published [Hofer et al 2010, Caciotti et al 2011], as has extensive documentation of more than 200 affected individuals [Brunetti-Pierri & Scaglia 2008].

Type I (infantile) GM1 gangliosidosis. Onset of symptoms is prior to age 12 months. In some infants prenatal manifestations include hydrops fetalis (6%) and intrauterine growth retardation (1%) [Brunetti-Pierri & Scaglia 2008].

The primary findings are severe central nervous system dysfunction [Suzuki et al 2014] manifest as early developmental delay with hypotonia and an exaggerated startle response, followed by spasticity and rapid regression. By the end of the first year, most infants are blind and deaf with severe central nervous system dysfunction leading to decerebrate rigidity [Suzuki et al 2014].

Cardiomyopathy and seizures are common. Some infants manifest hepatosplenomegaly and poor feeding.

Other findings include a coarsened facial appearance (often including frontal bossing, depressed nasal bridge with a broad nasal tip, long philtrum), large low-set ears, gingival hypertrophy with macroglossia, coarse thickened skin, and hirsutism.

Skeletal dysplasia can be seen at the time of diagnosis and may become clinically important over time.

Disease progression is rapid with blindness often by age one year and death by age two to three years frequently secondary to aspiration pneumonia.

Type II (late infantile and juvenile) GM1 gangliosidosis

  • The onset of the late infantile form is typically between ages one and three years with life expectancy until ages five to ten years.
  • The onset of the juvenile form is typically between ages three and ten years and often initially manifests in a school-age child as inability to achieve expected milestones. Disease progression is notable for plateauing of motor and cognitive development followed by slow regression of skills. The juvenile form may or may not have skeletal dysplasia. Life expectancy is well into the second decade.

Chronic/adult GM1 gangliosidosis has been best characterized in the Japanese population. Onset of symptoms is in late childhood to the third decade [Suzuki et al 2014], typically presenting with generalized dystonia leading to unsteady gait and speech disturbance. However, within a short period of time, most (64%) have extrapyramidal signs including akinetic-rigid parkinsonism. The symptom cluster is similar to the extrapyramidal signs in Parkinson disease, which is a common misdiagnosis [Roze et al 2005]. Other common findings are: gait disturbance (44%), cardiomyopathy (38%), speech difficulties (33%), and dystonia (22%) [Suzuki et al 2014].

Although intellectual impairment is common in late stages of the disease, it may be only mild at time of initial diagnosis.

Skeletal abnormalities, found in 95% of individuals, are most commonly short stature, kyphosis, and scoliosis of varying severity.

Prognosis is directly related to the degree of neurologic impairment. Most affected individuals have a shortened life span compared to their unaffected relatives [Suzuki et al 2014].

Neuropathology. All individuals with GM1 gangliosidosis have post-mortem neural changes; specifically, meganeurites and ectopic dendritogenesis have been observed. The extent of ganglioside deposition correlates with age of onset and rate of disease progression [Steenweg et al 2010].

Mucopolysaccharidosis Type IVB

MPS IVB is clinically indistinguishable from MPS IVA. Prior to the availability of molecular testing, natural history studies of MPS IV included both MPS IVA (>95% of affected individuals) and MPS IVB (<5% of affected individuals). The following information is relevant to both MPS IVA and MPS IVB.

MPS IV is characterized by corneal clouding, cardiac valvular disease, and skeletal abnormalities, including short stature. In general, neurologic function is normal. 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 [Montaño et al 2007].

The initial presentation in both severe and attenuated MPS IV can vary. Kyphoscoliosis, knocked knees (genu valgum), and pectus carinatum are the most common initial manifestations of the severe form [Montaño et al 2007]. In contrast, hip problems including pain, stiffness, and Legg-Perthes disease are common initial manifestations of the attenuated form [Hecht et al 1984, Wraith 1995].

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.

Spinal cord compression can result in neurologic compromise, especially in persons with severe disease or delayed diagnosis [reviewed in Neufeld & Muenzer 2001, Tomatsu et al 2011].

Coarse facial features can develop later in life, but the changes are milder than those observed in other mucopolysaccharidoses (see Differential Diagnosis).

Children with MPS IV typically have normal intellectual ability. Ligamentous laxity and joint hypermobility are distinctive features of MPS IV, and are rare among storage disorders.

Pathophysiology

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, thus, interfere with appropriate functioning of the organelle. A hallmark of GM1 gangliosidosis is degeneration of the CNS where ganglioside synthesis is the highest.

GLB1 pathogenic variants leading to MPS IVB result in the accumulation of keratan sulfate, the suspected causative agent for the bone findings in MPS IVB. Note: In MPS IVA (caused by biallelic GALNS pathogenic variants) and MPS IVB (caused by biallelic GLB1 pathogenic variants), keratan sulfate accumulation is thought to be the cause of severe skeletal abnormalities.

Genotype-Phenotype Correlations

GM1 gangliosidosis. More than 150 GLB1 pathogenic variants have been found in GM1 gangliosidosis. Common variants have been identified for each subtype; however, since the vast majority of affected individuals are compound heterozygotes, the same pathogenic variants have been identified in more than one phenotype [Santamaria et al 2007; Caciotti et al 2011; Author, unpublished results], making phenotype/genotype correlation difficult [reviewed in Higaki et al 2011].

Current structure/enzyme activity studies indicate that GM1 gangliosidosis is caused by GLB1 pathogenic variants that result in impaired function of the β-galactosidase enzyme towards its high affinity substrate, the glycosphingolipid GM1 ganglioside. In contrast, specific GLB1 variants that cause MPS IVB are proposed to affect the catabolism of keratan sulfate but have little effect on GM1 gangliosides [reviewed in Suzuki et al 2014].

Mucopolysaccharidosis type IVB. Unique pathogenic variants have been found in MPS IVB. Based on the crystal structure, most of these variants map to the surface or protein core of the enzyme [Ohto et al 2012], likely stabilizing the secondary, tertiary, and/or quaternary structure. However, two MPS IVB common variants are located in the ligand binding pocket.

Nomenclature

In the past GM1 gangliosidosis was referred to as beta-galactosidase-1 deficiency or beta-galactosidosis; mucopolysaccharidosis type IVB was referred to as Morquio syndrome type B. These terms should be used when searching for older literature on GM1 gangliosidosis.

Prevalence

GM1 gangliosidosis of all types is estimated to occur in one in 100,000 to 300,000 [Suzuki et al 2014]. The most common is the infantile form. The prevalence in Brazil (1:17,000), in persons of Roma ancestry (1:10,000), and in the Maltese Islands (1:3,700) is much higher than in other areas and likely represents founder effects [reviewed in Brunetti-Pierri & Scaglia 2008].

The prevalence of chronic/adult GM1 gangliosidosis is higher in the Japanese population, likely due both to a founder effect and possibly a greater awareness of the disorder among Japanese healthcare providers [Higaki et al 2011].

MPS IVB. Prior to 1980, MPS IVA and IVB were indistinguishable. The overall prevalence of MPS IV was reported as 1:75,000 to 1:640,000 [reviewed in Ohto et al 2012]. Subsequently the prevalence of MPS IVB has been reported as 1:250,000-1:1,000,000 [Baehner et al 2005, Enns et al 2009].

Differential Diagnosis

Disorders to consider in the differential diagnosis of the GLB1-related disorders include the following.

MPS IVB

Mucopolysaccharidosis IVA (MPS IVA) and MPS IVB are clinically indistinguishable. Of individuals with the MPS IV phenotype, MPS IVA accounts for more than 95% of affected individuals and MPS IVB accounts for fewer than 5% of affected individuals. The diagnosis of MPS IVA is confirmed by detection either of deficient N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity or of biallelic GALNS pathogenic variants.

GM1 Gangliosidosis

GM2 gangliosidosis (also known as hexosaminidase A deficiency) also presents similarly with a range of severity, including infantile, juvenile, and adult forms. Onset of CNS symptoms in GM1 and GM2 gangliosidosis is similar between each of the forms. The infantile forms of both disorders feature cherry red maculae. However, individuals with GM2 gangliosidosis do not have skeletal changes or other non-CNS findings.

Galactosialidosis and sialidosis (mucolipidosis I) need to be considered in the differential diagnosis of GM1 gangliosidosis. Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with β-galactosidase. This high molecular-weight complex includes β-galactosidase (GM1 gangliosidosis), cathepsin A encoded by CTSA (galactosialidosis), and neuramidase 1 encoded by NEU1 (sialidosis/mucolipidosis I). Note that in galactosialidosis the activities of the enzymes β-galactosidase and neuramidase 1 are reduced, respectively, to about 15% and less than 1% of normal values secondary to a primary deficiency of the protective protein/cathepsin A. Therefore, the activities of cathepsin A and neuraminidase 1 in fibroblasts should be measured to definitively rule out galactosialidosis in an individual with partial deficiency of β-galactosidase.

Galactosialidosis. Three forms are distinguished by the age of onset and disease course.

  • Early-infantile galactosialidosis is associated with hydrops fetalis, inguinal hernia, growth abnormality, and hepatosplenomegaly. Dysostosis multiplex, coarse facial features, corneal clouding, cardiomegaly, cherry-red spot of the macula, and kidney failure are also common. Angiokeratomas have been observed. Affected infants typically die by age one year.
  • Late-infantile galactosialidosis is associated with short stature, dysostosis multiplex, cardiac valvulopathy, hepatosplenomegaly, intellectual disability, and coarse facial features. Cherry-red spot of the macula, angiokeratomas, corneal clouding, and hearing loss can be observed. Life expectancy depends on disease severity.
  • Juvenile/adult galactosialidosis is associated with a variable age of onset (average 16 years, range 1-40 years). Symptoms include ataxia, myoclonus, seizures, corneal clouding, and progressive intellectual disability. Angiokeratomas, spine abnormalities, cherry red spot of the macula, and vision and hearing loss are common. Life expectancy varies. The highest prevalence has been noted in the Japanese population.

Sialidosis (mucolipidosis I). Accumulation of sialylated oligo- and polysaccharides in tissues and body fluids are likely the cause of widespread cellular damage. Two forms determined by the level of neuramidase I enzyme activity have been identified. The features of sialidosis II more closely resemble GM1 gangliosidosis than sialidosis I.

  • Both sialidosis type II and GM1 gangliosidosis have a range of severity from congenital to juvenile onset. All have dysostosis multiplex, cherry red spot of the macula, and intellectual disability.
    • The congenital form has prenatal onset with ascites or hydrops fetalis.
    • The infantile form has onset in the first year of life with hepatosplenomegaly, developmental regression, and coarse facial features. Over time, affected children can have myoclonus, hearing loss, gingival hyperplasia, and abnormal spacing of the dentition. Life expectancy is into childhood or adolescence.
    • The juvenile form has onset in late childhood. Coarse facial features, myoclonus, and angiokeratomas are observed. Life expectancy is symptom-dependent with more mildly affected individuals living into adulthood.
  • Sialidosis type I is also known as cherry-red spot myoclonus syndrome. Onset is in the teens and twenties. Gait disturbances and reduced visual acuity are the most common presenting symptoms. With time, myoclonus, ataxia, and reduced vision worsen, but are not life threatening. Intellect is normal.

Mucopolysaccharidosis type I (MPS I). Dysostosis multiplex and corneal clouding are seen in both MPS I and GLB1-related disorders; however, MPS I has more severe dysostosis multiplex, contractures, and prominent hepatosplenomegaly and does not have cherry red spot of the macula.

Mucopolysaccharidosis type II (MPS II). Children with MPS II have developmental delay and dysostosis multiplex, also seen in the juvenile form of GM1 gangliosidosis. At the time of diagnosis, prominent hepatosplenomegaly, joint contractures, dermal pebbling, clear corneae, and a coarse facial appearance distinguish MPS II from GLB1-realated disorders. Furthermore, MPS II, an X-linked disorder, is observed in males only, whereas GM1 gangliosidosis, an autosomal recessive disorder, is observed in males and females.

Mucolipidoses

  • Mucolipidosis II (ML II) (I-cell disease) includes skeletal dysplasia, global developmental delay, and growth abnormalities similar to GM1 gangliosidosis type I. ML II has more severe and earlier onset skeletal dysplasia than GM1 gangliosidosis. ML II can present prenatally with low birth weight or in the neonatal period with skeletal dysplasia, global development delay, and coarse facial features. In comparison, children with GM1 gangliosidosis can be normal as neonates and present in early infancy.
  • Mucolipidosis III (both Mucolipidosis III Alpha/Beta and Mucolipidosis III Gamma) (pseudo-Hurler polydystrophy) includes onset of clinical features in the preschool years (corneal clouding, cardiac valvular abnormalities, developmental delay, dysostosis multiplex) similar to those observed in the juvenile form of GM1 gangliosidosis. In contrast with GM1 gangliosidosis, ML III usually presents with hand and shoulder arthritis, significant short stature, and/or claw hand deformity.

The differential diagnosis of chronic/adult GM1 gangliosidosis includes Parkinson disease, adult-onset spinal muscular atrophy, spinal cerebellar ataxia, adult-onset GM2 gangliosidosis, juvenile Huntington disease, and Wilson disease.

Note: Positive testing for anti-GM1 ganglioside antibodies is not indicative of a diagnosis of GM1 gangliosidosis. These test results are associated with multifocal motor neuropathy or Guillain-Barré syndrome [reviewed in Kornberg 2000].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a GLB1-related disorder (GM1 gangliosidosis or MPS IVB), the following evaluations are recommended:

  • Developmental history and assessment to document past and current motor and cognitive function, as a baseline in the event of future psychomotor and/or cognitive regression
  • Physical examination for evidence of hepatosplenomegaly
  • Ophthalmologic examination, especially for evidence of corneal clouding and cherry red spot of the macula
  • Evaluation by a pediatric cardiologist (including electrocardiogram and echocardiogram) to assess for cardiac involvement
  • Skeletal survey to determine the extent of skeletal involvement
  • Flexion and extension x-rays of the cervical spine to assess for atlanto-axial instability
  • Electroencephalogram to assess for seizure disorder, if indicated
  • Clinical genetics consultation with genetic counseling

Treatment of Manifestations

Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology, and therapists knowledgeable about GLB1-related disorders.

  • Surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders.
  • Occupational therapy to optimize activities of daily living (including adaptive equipment)
  • Physical therapy to optimize gait, comfort, and mobility including orthotics and bracing to improve mobility and flexibility
  • Early and ongoing interventions to optimize educational and social outcomes are recommended.

GM1 gangliosidosis

  • For patients with GM1 gangliosidosis type I or II, physiatry for appropriate mobility interventions, such as strollers and wheelchairs
  • Speech therapy to optimize oral motor skills and manage aspiration risk
  • Maintenance of adequate hydration and adequate calories for growth. Consider gastrostomy (G-) tube or naso-gastric (NG) tube placement as needed.
  • Routine management of secretions and risk of aspiration with attention to risk for pulmonary sequelae
  • Routine management of chronic urinary tract infections secondary to incontinence and chronic dehydration
  • Aggressive seizure control
  • Medical management of cardiac involvement
  • When disease is advanced, provide access to hospice services for supportive in-home care

MPS IVB

Since MPS IVA and IVB are clinically indistinguishable, details of interventions are based on those recommended for MPS in general or specifically MPS IVA.

Prevention of Secondary Complications

Immunizations. All individuals with GLB1-related disorders should receive routine immunizations. Influenza and pneumococcal immunizations should be administered on schedule because of the low pulmonary reserve of individuals with MPS IVB and the risk for secondary infections due to chronic disease in children with GM1 gangliosidosis.

Bacterial endocarditis prophylaxis is recommended for all high-risk patients, including those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis [Wilson et al 2007].

Anesthesia. Because children with MPS IVB and those with GM1 gangliosidosis with skeletal involvement (spine anomalies, short neck, large head, and atlantoaxial instability) are at increased risk for complications of anesthesia, the following are recommended [Walker et al 2013]:

  • Preoperative evaluation should include a history of complications with previous anesthetics, as well as any ongoing problems with airway obstruction, the heart, and respiratory function.
  • Obtain flexion/extension x-rays of the lateral cervical spine [Muhlebach et al 2011; Tomatsu et al 2011; Author, unpublished observations].
  • Fiber-optic bronchoscopy and smaller than expected endotracheal tubes are often required [Muhlebach et al 2011].
  • For procedures lasting greater than 45 minutes, intraoperative spinal cord monitoring may be necessary to detect exacerbation of pre-existing spinal stenosis.
  • Post-operative management may be complicated by pre-existing sleep apnea and/or pulmonary edema [Morgan et al 2002].

Surveillance

GM1 Gangliosidosis

Assessment of quality of life by a physiotherapist; yearly and before/after major medical events

Musculoskeletal

  • Yearly history and physical examination to evaluate for new skeletal abnormalities that might lead to decreased quality of life
  • Yearly evaluation for cervical spine instability including detailed physical examination and assessment for new neurologic findings, followed by imaging if indicated
  • Monitoring of hip joint stability re risk of hip dislocation. Obtain straight and frog-leg imaging if there is pain with movement or a change in mobility (which in neurologically compromised patients can present as inability to ambulate, unexplained crying, or pain).

Cardiac. Electrocardiogram and echocardiogram every one to three years, if there is a history of cardiac dysfunction and/or new symptoms

Growth. Monitoring of growth and nutrition by a nutritionist with knowledge of neurodegenerative or metabolic disease

Eye. Evaluation for visual acuity and corneal clouding every 1-3 years

Seizures. Yearly evaluation by a neurologist; consideration of EEG if there is an acute change in mental status, a sudden decline in activity/milestones, or abnormal movements

MPS IVB

Note: The recommendations for MPS IVA are appropriate for MPS IVB since MPS IVA and MPS IVB are clinically indistinguishable.

Assessment of quality of life by a physiotherapist:

  • Yearly: track progress and optimize ambulation
  • Yearly, before and after surgical procedures, and as clinically indicated: endurance tests including six-minute walk test (6MWT) and three-minute stair climb test (3MSC) to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal and nervous systems

Musculoskeletal. Assessment for the following:

  • Lower-extremity misalignment: yearly clinical examinations to assess lower extremity alignment
  • Hip dysplasia/subluxation: yearly radiographs of the hips, as clinically warranted
  • Cervical spine instability
  • Note: Solanki et al [2013] recommend the following guidelines for monitoring spinal involvement in those with MPS IVA:
    • Neurologic examination every six months
    • Plain x-rays of the cervical spine (AP, lateral, neutral, and flexion/extension) every six months
    • Plain x-rays of the spine (AP and lateral thoracolumbar) every two to three years if there is evidence of kyphosis and/or scoliosis
    • MRI neutral position: whole spine every year
    • MRI: flexion/extension of the cervical spine every one to three years
      These guidelines can be modified as appropriate.

Cardiac. Electrocardiogram and echocardiogram every one to three years depending on disease course [Hendriksz et al 2013]

Respiratory. Assessment for the following:

  • Obstructive sleep apnea: yearly history focused on sleep patterns and sounds. Evaluation by an otolaryngologist for adenotonsillectomy. Polysomnography if any clinical suspicion exists.
  • Restrictive lung disease: assessment of pulmonary function when age-appropriate at diagnosis and then yearly. Note: The benefit of non-invasive pulmonary function tests, impulse oscillometry, and thoracoabdominal motion analysis has been demonstrated in children with MPS IV [Rodriguez et al 2010].

Growth. Use of MPS IVA-specific growth charts to monitor nutritional status [Montaño et al 2007, Montaño et al 2008]

Eye

  • Yearly: measurement of visual acuity, refractive error, and intraocular pressure; slit lamp examination of cornea; examination of the posterior segment
  • For those with rod and cone retinal dystrophy: Retinal examination and electroretinography (ERG) under scotopic and photopic conditions at onset, then every five years [Hendriksz et al 2013]

Dental. Evaluation every six months

Hearing. Yearly audiogram

Agents/Circumstances to Avoid

Because psychotropic medications have been associated with worsening neurologic disease in adults with Tay-Sachs disease (which is caused by deficiency of the second enzyme in the β-galactosidase pathway) [Shapiro et al 2006], use of these medications in individuals with a GLB1-related disorder should be avoided whenever possible [Shapiro et al 2006].

For persons with MPS IVB, excessive weight gain causes undue stress on the axial skeleton and may decrease the ability to ambulate independently. Thus, it is important that nutrition optimize growth while maintaining a lean habitus.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

No FDA-approved treatments for GLB1-related disorders exist.

While there is currently no effective treatment for GM1 gangliosidosis, multiple interventions are promising, based on in vitro studies and animal models.

Although many lysosomal storage diseases have positive outcomes with hematopoietic stem cell transplantation (HSCT), in one individual with the juvenile form of GM1 gangliosidosis diagnosed prior to onset of symptoms, HSCT did not prevent the development of manifestations. This failure was attributed to the inability of sufficient stem cells to cross the blood-brain barrier rapidly enough to affect lipid accumulation in the central nervous system (CNS) [Shield et al 2005].

Due to the inability of large molecular-weight enzymes to cross the blood-brain barrier, investigators have been studying small molecules as possible chaperones for partially functioning β-galactosidase in the CNS. These chaperones are thought to stabilize the residual endogenous enzyme and facilitate transport to the lysosome.

  • In an in vitro study using fibroblasts from an affected individual, N-octyl-4-epi-B-valienamine stabilized β-galactosidase, reduced lipid accumulations, and improved lipid trafficking [Higaki et al 2011]. Furthermore, oral administration of this compound to mice with GM1 gangliosidosis led to increased enzyme activity and reduced substrate levels [reviewed in Brunetti-Pierri & Scaglia 2008].
  • A second chaperone compound, the imino sugar N-butyl deoxynojirimycin (miglustat), also showed promising outcomes in a murine model of GM1 gangliosidosis [Elliot-Smith et al 2008]. Miglustat, which is FDA approved for the treatment of Gaucher disease, has been used in a few individuals with the juvenile form of GM1 gangliosidosis of whom some showed improvement [Author, unpublished observation].
  • In addition, other imino sugar derivatives have shown increased enzyme activity, facilitated localization of β-galactosidase to lysosomes in fibroblasts of affected individuals [Fantur et al 2012], and shown improved enzyme activity in a mouse model of GM1 gangliosidosis [Takai et al 2013].

Considerable progress has been made in gene therapy in a murine model of GM1 gangliosidosis. See animal model.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

GLB1-related disorders (i.e., GM1 gangliosidosis and MPS IVB) are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Individuals with a severe GLB1-related disorder do not reproduce.
  • The offspring of an individual with a mild GLB1-related disorder are obligate heterozygotes (carriers) for a pathogenic variant in GLB1.
    Note: No studies addressing fertility in individuals with a mild GLB1-related disorder have been published.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Biochemical genetic testing. Enzyme activity may not be predictive of carrier status in family members of individuals with a GLB1-related disorder.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GLB1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for a GLB1-related disorder are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
    Email: info@ntsad.org
  • Canadian Society for Mucopolysaccharide and Related Diseases, Inc.
    PO Box 30034
    North Vancouver British Columbia V7H 2Y8
    Canada
    Phone: 800-667-1846 (toll free); 604-924-5130
    Fax: 604-924-5131
    Email: info@mpssociety.ca
  • Medline Plus
  • Metabolic Support UK
    United Kingdom
    Phone: 0845 241 2173
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
    Email: info@mpssociety.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: 0345 389 9901
    Email: mps@mpssociety.co.uk
  • The Carol Ann Foundation & The International Morquio Organization
    8164 West Circulo De Los Morteros
    PO Box 64184
    Tucson AZ 85743
    Phone: 520-744-2531
    Email: mbs85705@yahoo.com; tomatsus@slu.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

GLB1-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
GLB13p22​.3Beta-galactosidaseGLB1 databaseGLB1GLB1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for GLB1-Related Disorders (View All in OMIM)

230500GM1-GANGLIOSIDOSIS, TYPE I
230600GM1-GANGLIOSIDOSIS, TYPE II
230650GM1-GANGLIOSIDOSIS, TYPE III
253010MUCOPOLYSACCHARIDOSIS, TYPE IVB; MPS4B
611458GALACTOSIDASE, BETA-1; GLB1

Molecular Genetic Pathogenesis

GLB1-related disorders comprise two phenotypically distinct disorders: GM1 gangliosidosis with varying degrees of neurologic involvement and mucopolysaccharidosis type IVB (MPS IVB), a progressive skeletal dysplasia.

GM1 gangliosidosis results from accumulation of glycoconjugates with a terminal β-galactose as a result of deficiency of the enzyme β-galactosidase. An inverse ratio of enzyme activity and substrate storage has been observed, with the lowest amounts of enzyme activity and highest amounts of storage material noted in neural tissue from individuals with the most severe form: infantile GM1 gangliosidosis.

GLB1 is conserved among species. GM1 gangliosidosis has been documented in cats, dog, sheep, calves, and mice [Suzuki et al 2014].

Gene structure. The longest transcript variant NM_000404.2 has 16 exons spanning more than 60 kb.

Multiple transcript variants give rise to different isoforms. Two alternatively spliced mRNA variants are a 2.5-kb transcript that encodes the canonical, lysosomal β-galactosidase enzyme precursor and a minor 2.0-kb transcript in which exons 3, 4, and 6 are deleted and exon 5 is translated from a different reading frame [Morreau et al 1989]. The alternatively spliced exon 5 encodes a unique 32 amino-acid peptide that contains a tropoelastin-binding domain [Privitera et al 1998]. This shorter, catalytically inactive β-galactosidase isoform, named the ‘elastin binding protein’ (EBP), plays an important role in elastogenesis [Privitera et al 1998]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A deletion of exon 5 secondary to unequal crossover between intronic Alu sequences is the largest reported deletion [Santamaria et al 2007].

Table 4.

GLB1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change 1
(Alias 2)
Predicted Protein Change 1Ethnicity / PhenotypeReference Sequences
c.152T>Cp.Ile51ThrJapanese / GM1 adult formNM_000404​.2 NP_000395​.2
c.601C>Tp.Arg201CysJapanese / GM1 juvenile form
c.602G>Ap.Arg201HisMPS IVB, GM1 juvenile form
c.622C>Tp.Arg208CysAmerican / GM1 infantile form
c.817_818delTGinsCT
(851-852 TG>CT)
p.Trp273LeuNorthern European origin / MPS IVB
c.1445G>Ap.Arg482HisItalian / GM1 infantile form
c.1577_1578dupG 3
(1622_1627insG)
p.Trp527LeufsTer5 4Brazilian / GM1
c.176G>Ap.Arg59HisRoma, Brazilian / GM1 infantile and juvenile forms

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Variant designation that does not conform to current naming conventions

3.

Duplication results in the addition of another G to a series of six G nucleotides.

4.

"fsTer#" indicates a frameshift beginning at codon 527Leu with the new frame ending in a stop (Ter). The ‘#’ indicates the position of the stop in the new reading frame, calculated starting at the first changed amino acid that is created by the frame shift, and ending at the first stop codon (fsTer#). The total length of the new shifted frame is 5 (p.Trp527LeufsTer5).

Normal gene product. GLB1 encodes an 88-kd precursor protein, the 677 amino-acid protein (β-galactosidase) which includes an N-terminal 23 amino-acid signal peptide that allows for lysosome localization. The mature protein is formed by proteolytic cleavage of the C-terminus to make a heterodimer of the cleavage products [van der Spoel et al 2000].

The crystal structure shows a TIM barrel domain, the functional domain of the glycoside hydrolase activity of the enzyme. Within this domain, the glycosidase activity depends on a pair of carboxylic acids (one as the catalytic nucleophile and the other as the acid/base catalyst). In human β-galactosidase, the carboxylic acids are located in the Glu-268 and Glu-188 residues, in the fourth and seventh strands of the TIM barrel, respectively. For this reason β-galactosidase is a member of the 4/7 superfamily of enzymes.

Based on crystal structures the protein forms a dimer; some of the pathogenic variants on the surface of the molecule are hypothesized to destabilize this dimerization and thus affect enzymatic activity [Ohto et al 2012].

Multiple studies have demonstrated that β-galactosidase forms a high molecular-weight complex with other two lysosomal enzymes:

Although the crystal structure of the purified protein did not reveal the surface residues required for interaction with PPCA and NEU1, variants in the surface residues in the quaternary structure of β-galactosidase are pathogenic and, thus, may represent sites of such interaction.

Abnormal gene product. The abnormal gene products with pathogenic variants in GLB1 make β-galactosidase with abnormal function.

  • Single nucleotide variants either directly affect the catalytic domain or result in protein misfolding and subsequent mistargeting or degradation through the endoplasmic reticulum-associated protein degradation pathway.
  • Variants in amino acid residues at the surface of the protein may be pathogenic due to destabilization of the dimerization of the enzyme, thus altering enzymatic activity [Ohto et al 2012].

Most GLB1 variants alter the tertiary structure, leading to changes in the ligand-binding pocket. A few variants reside in the ligand-binding pocket [Ohto et al 2012].

  • Changes that alter the overall structure of the TIM barrel domain, responsible for catalysis, are the most detrimental, leading to the infantile form of GM1 gangliosidosis.
  • In contrast, surface or solvent-exposed pathogenic variants tend to be associated with the juvenile and chronic/adult forms of GM1 gangliosidosis.
    Note: While the study of Ohto et al [2012] was instrumental in understanding structure/function relationships of individual pathogenic variants, it offered less insight into the phenotype-genotype correlations in persons with compound heterozygous variants.

Current structure/enzyme activity studies [reviewed in Suzuki et al 2014] indicate that:

  • GM1 gangliosidosis is caused by pathogenic variants in GLB1 that impair the activity of β-galactosidase toward its high-affinity substrate, the glycosphingolipid GM1 ganglioside;
  • MPS IVB is caused by pathogenic variants that impair the catabolism of keratan sulfate, and have little effect on GM1 gangliosides.

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  • Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management. Arch Dis Child. 1995;72:263–7. [PMC free article: PMC1511064] [PubMed: 7741581]

Suggested Reading

  • Norman RM, Urich H, Tingey AH, Goodbody RA. Tay-Sachs’ disease with visceral involvement and its relationship to Niemman-Pick disease. J Pathol Bacteriol. 1959;78:409. [PubMed: 14427628]

Chapter Notes

Author Notes

The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with GM1. Careful phenotyping and advanced imaging facilitate the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions. The laboratory is also engaged in studying biomarkers of disease progression in clinical samples, particularly CSF. Careful, repeated observations especially in later-onset patients have identified significantly decreased bone density and an increased incidence of odontoid hypoplasia, particularly in juvenile patients [Author, unpublished observations]. These findings may impact surgical decision making and the activities of daily living.

Acknowledgments

Dr. Alessandra d’Azzo provided editorial comments and important insights included in this GeneReview.

Dr. Jürgen Spranger is instrumental in the current natural history studies being conducted at the National Human Genome Research Institute at the National Institutes of Health. His findings regarding odontoid hypoplasia are included in the current studies section of this GeneReview.

Revision History

  • 17 October 2013 (me) Review posted live
  • 24 January 2013 (ct) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReviewGLB1-Related Disorders’ is in the public domain in the United States of America.

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Bookshelf ID: NBK164500PMID: 24156116

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