Glb1-Related Disorders
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 testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.
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 [Regier et al 2016].
Table 1.
Clinical, Skeletal, Neuroimaging, and Biochemical Findings in GLB1-Related Disorders
| Finding | GM1 Gangliosidosis | MPS IVB | |||
|---|---|---|---|---|---|
| Type I | Type II | Type III | |||
| Infantile | Late Infantile | Juvenile | Chronic/Adult | ||
| Onset of symptoms | <1 yr | 1-3 yrs | 3-10 yrs | 10+ yrs | 3-5 yrs |
| Eye findings | CRS | CC | CC | +/– CC | CC |
| Motor abnormalities | + | + | + | Extrapyramidal | See footnote 1 |
| Hepatosplenomegaly | + | +/– | +/– | – | – |
| Cardiac involvement | +/– | +/– | +/– | +/– | + |
| Coarse facial features | +/– | – | – | – | See footnote 1 |
| Skeletal findings | + | +/– | +/– | – | + |
| Neuroimaging | PA | PA | PA | +/– mild atrophy | See footnote 1 |
| Urine glycosaminoglycans (GAG) | See footnote 2 | See footnote 2 | See footnote 2 | See footnote 2 | Keratan sulfate 3 |
– = negative finding; + = positive finding; +/ – = variable finding in patient population; CC = corneal clouding; CRS = cherry red spot; 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. 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. The odontoid process is under ossified (white arrow). The vertebral bodies are flattened (black arrow).
- 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. At age 3 years 6 months: T2-weighted axial view showing minimal atrophy
Brain MR spectroscopy (MRS) has shown patient-specific changes documented in case reports [Erol et al 2006] and described as a marker of disease progression by Regier et al [2016].
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 Gangliosidosis | MPS IVB | ||||
|---|---|---|---|---|---|
| Type I | Type II | Type III | |||
| Infantile | Late infantile | Juvenile | Chronic/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.
Santamaria et al [2007]
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.
Molecular Genetic Testing Used in GLB1-Related Disorders
| Gene 1 | Method | Variants Detected 2 | Variant Detection Frequency by Method 3 |
|---|---|---|---|
| GLB1 | Sequence analysis 4 | Sequence variants | >99% 5 |
| Deletion/duplication analysis 6 | Exon or whole-gene deletions | <1% 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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. 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.
Santamaria et al [2007], Brunetti-Pierri & Scaglia [2008]
- 6.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include 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.
Published natural history studies for GM1 gangliosidosis have been limnited; however, there have been several case reports [Hofer et al 2010, Caciotti et al 2011], including extensive documentation of more than 200 affected individuals [Brunetti-Pierri & Scaglia 2008]. Regier et al [2016] followed juvenile and late-infantile affected individuals and Jarnes Utz et al [2017] described the natural history of affected infants.
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]. Ou et al [2019] have recently published a genotype-phenotype in silico tool that has been helpful in the prediction of disease severity.
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