# 230500

GM1-GANGLIOSIDOSIS, TYPE I; GM1G1


Alternative titles; symbols

GANGLIOSIDOSIS, GENERALIZED GM1, TYPE I
GANGLIOSIDOSIS, GENERALIZED GM1, INFANTILE FORM
GANGLIOSIDOSIS, GENERALIZED GM1, TYPE 1
BETA-GALACTOSIDASE-1 DEFICIENCY
GLB1 DEFICIENCY


Other entities represented in this entry:

GM1-GANGLIOSIDOSIS, TYPE I, WITH CARDIAC INVOLVEMENT, INCLUDED
GANGLIOSIDOSIS, GENERALIZED GM1, TYPE I, WITH CARDIAC INVOLVEMENT, INCLUDED

Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p22.3 GM1-gangliosidosis, type I 230500 AR 3 GLB1 611458
Clinical Synopsis
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Dwarfism
HEAD & NECK
Face
- Coarse facies
- Full forehead
- Flat nose
Eyes
- Hypertelorism
- Clear cornea
- Cherry-red spot in half the patients
Mouth
- Gingival hyperplasia
Neck
- Short neck
CARDIOVASCULAR
Heart
- Dilated cardiomyopathy (in a subset of patients)
- Hypertrophic cardiomyopathy (in a subset of patients)
- Congestive heart failure (in a subset of patients)
- Valvular heart disease (in a subset of patients)
CHEST
Ribs Sternum Clavicles & Scapulae
- Thick ribs
ABDOMEN
External Features
- Inguinal hernia
Liver
- Hepatomegaly
Spleen
- Splenomegaly
GENITOURINARY
Kidneys
- Glomerular epithelial cytoplasmic vacuolization
SKELETAL
Spine
- Kyphosis
- Scoliosis
- Hypoplastic vertebral bodies
- Beaked vertebral bodies
Limbs
- Joint stiffness
SKIN, NAILS, & HAIR
Skin
- Angiokeratoma corporis diffusum
- Dermal melanocytosis
Hair
- Hypertrichosis
NEUROLOGIC
Central Nervous System
- Mental retardation
- Cerebral degeneration
METABOLIC FEATURES
- No mucopolysacchariduria
- Beta-galactosidase-1 deficiency
IMMUNOLOGY
- Vacuolated lymphocytes
MISCELLANEOUS
- Death in infancy
- Allelic to mucopolysaccharidosis IVB
MOLECULAR BASIS
- Caused by mutation in the beta-1 galactosidase gene (GLB1, 611458.0001)

TEXT

A number sign (#) is used with this entry because GM1-gangliosidosis type I (GM1G1) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-galactosidase-1 (GLB1; 611458) on chromosome 3p22.


Description

GM1-gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. Clinically, patients show variable degrees of neurodegeneration and skeletal abnormalities. There are 3 main clinical variants categorized by severity and variable residual beta-galactosidase activity. Type I, or infantile form (GM1G1), shows rapid psychomotor deterioration beginning within 6 months of birth, generalized central nervous system involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death. Type II, or late-infantile/juvenile form (GM1G2; 230600), has onset between 7 months and 3 years, shows generalized central nervous system involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present. Type III, or adult/chronic form (GM1G3; 230650), shows onset from 3 to 30 years and is characterized by localized skeletal involvement and localized central nervous system involvement, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity (Suzuki et al., 2001).

See also Morquio B disease (253010), an allelic disorder with skeletal anomalies and no neurologic involvement.

The GM2-gangliosidoses include Tay-Sachs disease (272800) and Sandhoff disease (268800).


Clinical Features

Landing et al. (1964) gave the first definitive description of this entity, which had variously been called 'Hurler variant,' 'pseudo-Hurler disease,' and 'Tay-Sachs disease with visceral involvement.' O'Brien et al. (1965) suggested the designation 'generalized gangliosidosis.' Clinical features of the infantile form include severe cerebral degeneration leading to death within the first 2 years of life; accumulation of ganglioside in neurons, hepatic, splenic and other histiocytes, and in renal glomerular epithelium; and the presence of skeletal deformities resembling Hurler disease (607014).

Scott et al. (1967) described affected sibs. Renal biopsy showed storage of an acid mucopolysaccharide rather than a glycolipid in vacuoles of the glomerular epithelium. The vacuoles were thought to represent lysosomes. The authors suggested that generalized gangliosidosis, which they also called 'neurovisceral lipidosis,' may be closely related to the Hurler syndrome, which it resembles clinically and radiologically. Grossman and Danes (1968) demonstrated x-ray features resembling those of Hurler syndrome, increased synthesis and storage of mucopolysaccharides by skin fibroblasts, and marked metachromasia of fibroblasts in both parents. Autosomal recessive inheritance was suggested.

Singer and Schafer (1972) reported a patient who presented at age 3 months due to poor psychomotor development and hepatosplenomegaly. He was later found to have dysplastic changes in the long bones and vertebrae and cherry-red spot on the macula. He died at age 18 months. A female sib had died at age 18 months with autopsy findings consistent with generalized gangliosidosis. Detailed biochemical studies on beta-galactosidase obtained from liver tissue of this patient and a patient with juvenile type II disease suggested that the 2 disorders are related and likely allelic.

Fricker et al. (1976) reported a 3-month-old girl with rapidly progressive psychomotor retardation, hepatomegaly, vacuolated lymphocytes, minimal bone dysplasia, and decreased beta-galactosidase activity. She died at age 16 months. Postmortem examination showed generalized GM1-gangliosidosis.

Giugliani et al. (1985) found that GM1-gangliosidosis was the inborn error of metabolism most often diagnosed on the Pediatrics Service in Porto Alegre, Brazil. From a study of 8 families, they suggested that increased fetal loss and macrosomy are features and that vacuolated lymphocytes are a useful diagnostic clue. Almost all patients had alteration in the lumbar vertebrae and cherry spots on the retina.

Yoshida et al. (1991) reported 4 unrelated Japanese patients with the infantile form of GM1-gangliosidosis. Age at onset ranged from 3 to 5 months. All patients had psychomotor retardation or deterioration, macular cherry-red spots, hepatosplenomegaly, and dysostosis multiplex. Beta-galactosidase activity in leukocytes ranged from 0.65 to 1.58% of control values.

GM1-Gangliosidosis with Cardiac Involvement

Hadley and Hagstrom (1971) reported cardiomyopathy in an infant with GM1-gangliosidosis. EKG showed an incomplete bundle branch block and pathology showed vacuolated and hypertrophied myofibers. The mitral valve leaflets were thick and nodular with vacuolated histiocytes and fibrous tissue. The right coronary artery was partially occluded by an atherosclerotic plaque containing ballooned cells. Benson et al. (1976) reported cardiomegaly in association with GM1-gangliosidosis. Kohlschutter et al. (1982) reported cardiomyopathy in an infant with beta-glucosidase deficiency who died of heart failure at age 8 months. Rosenberg et al. (1985) also described cardiac abnormalities in patients with beta-galactosidase deficiency.


Other Features

Beratis et al. (1989) described angiokeratoma corporis diffusum appearing before the age of 10 months in a boy with GM1-gangliosidosis. The angiokeratomas did not form clusters but were scattered widely over the body and proximal extremities. No angiokeratomas were observed on the penis and scrotum.

Hanson et al. (2003) described 2 infants with extensive dermal melanocytosis in association with GM1-gangliosidosis type I and Hurler syndrome, respectively. Clinically, dermal melanocytosis associated with lysosomal storage disease is characterized by extensive blue cutaneous pigmentation with dorsal and ventral distribution, indistinct borders, and persistent and/or 'progressive' behavior. A literature analysis revealed 37 additional cases. The most common lysosomal storage disease associated with dermal melanocytosis was Hurler syndrome (24 of 39 cases), followed by GM1-gangliosidosis (11 of 39 cases). Hanson et al. (2003) concluded that in the appropriate clinical setting, an unusual presentation of dermal melanocytosis in an infant may be a cutaneous sign of an underlying lysosomal storage disease.

Mishra et al. (2021) reported 6 unrelated Indian patients, aged 3 to 15 months, with GM1G1. All of the patients had extensive dermal melanocytosis distributed over the ventral and dorsal surface of the trunk and extremities. The spots were present since birth and progressively increased in size, number, and pigmentation. All of the patients also had global developmental delay, coarse facial features, hepatosplenomegaly, hypotonia, and dysostosis multiplex. Four of the patients had retinal cherry-red spots.


Biochemical Features

O'Brien et al. (1965) identified the ganglioside stored in this disorder as a GM1 ganglioside distinct from that seen in Tay-Sachs disease. Okada and O'Brien (1968) demonstrated that beta-galactosidase deficiency is the fundamental defect in generalized gangliosidosis. O'Brien (1969) found that all 3 isoenzymes of acid beta-galactosidase, A, B and C, were grossly deficient in all tissues.

Galjaard et al. (1975, 1975) studied complementation in cell hybrids between 4 types of Gm(1)-gangliosidosis. They concluded that types I and II involved the same locus. Complementation studies suggested that types III and IV may result from mutation at a second and separate locus.

Horst et al. (1975) demonstrated transfer of E. coli beta-galactosidase to gangliosidosis fibroblasts by phage transduction.

O'Brien (1975) suggested that the pleiotropic effects of mutations affecting a single locus for beta-galactosidase can be explained by the principle of one gene/one polypeptide/many substrates. Accordingly, different mutations in the same enzyme may have variable phenotypic effects since different mutations may impair one or more substrate specificities much more than others. Sixteen patients with beta-galactosidase deficiency and various phenotypes (i.e., types I, II, or III) were studied and all were found to have cross-reacting positive material to anti-beta-galactosidase antibody. However, all had decreased enzymatic activity. The findings suggested that the various forms of the disorder are due to a mutation at a common locus (reviewed by O'Brien and Norden, 1977).

Hoogeveen et al. (1986) showed that the mutations in the infantile and adult forms of GM1-gangliosidosis interfere with the phosphorylation of precursor beta-galactosidase. As a result, the precursor is secreted instead of being compartmentalized into the lysosomes and further processed.


Clinical Management

Mohamed et al. (2020) tested the effects of 2 derivatives of the chemical chaperone deoxygalactonojirimycin (DGJ), NB (butyl)-DGJ and NN (nonyl)-DGG, in fibroblasts from a patient with GM1-gangliosidosis type I and a homozygous mutation in the GJB gene (D151Y; 611458.0029). NN-DGJ demonstrated affinity to beta-galactosidase but did not show significant enhancement mutant enzyme activity. NB-DGJ both promoted mutant beta-galactosidase maturation and enhanced its enzyme activity in a dose-dependent manner. Mohamed et al. (2020) concluded that NB-DGJ could be a promising therapeutic chaperone for some GLB1 mutations that underlie infantile GM1.


Inheritance

The transmission pattern of GM1G1 in the families reported by Nishimoto et al. (1991) was consistent with autosomal recessive inheritance.


Molecular Genetics

Yoshida et al. (1991) and Nishimoto et al. (1991) independently identified mutations in the GLB1 gene in Japanese patients with various forms of GM1-gangliosidosis. Those with the infantile form had specific mutations (611458.0001; 611458.0002; 611458.0005-611458.0007). Residual enzyme activity in these patients ranged from 0.65 to 1.58% of control values (Yoshida et al., 1991).

In several Italian patients with infantile GM1-gangliosidosis with cardiac involvement, Morrone et al. (2000) identified homozygous mutations in the GLB1 gene (611458.0023-611458.0026). Cardiac involvement took the form of dilated and/or hypertrophic cardiomyopathy. All of these mutations were located in the GLB1 region common to the beta-galactosidase-1 lysosomal protein and ts nonlysosomal splice variant, elastin-binding protein (EBP) or S-Gal, and were shown to impair elastogenesis (Hinek et al., 2000). Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations.

Bidchol et al. (2015) reported molecular findings in 46 Indian patients with GM1-gangliosidosis and 2 pairs of Indian parents who had carrier testing for the disorder. Thirty-three different mutations in the GLB1 gene were identified; 20 of the mutations were novel, including 12 missense, 4 splicing, 3 indels, and 1 nonsense. The most common mutations were c.75+2insT (14% of alleles) and L337P (10% of alleles). None of the novel mutations were observed in the dbSNP or 1000 Genomes Project databases. Forty-one of the patients had homozygous mutations, 25 of whom were born to consanguineous parents. Thirty-two of the patients had GM1-gangliosidosis type I, 13 had GM1-gangliosidosis type II, and 1 had GM1-gangliosidosis type III. No genotype-phenotype correlation was observed.

In a 5-year-old Emirati boy, born to consanguineous parents, with GM1-gangliosidosis type I, Mohamed et al. (2020) identified a homozygous mutation in the GLB1 gene (D151Y; 611458.0029). Testing in patient fibroblasts showed less than 1% residual beta-galactosidase enzyme activity. Immunofluorescence staining in patient fibroblasts demonstrated that the mutant protein was improperly trafficked and processed, resulting in trapping in the endoplasmic reticulum (ER). Enzyme function in the fibroblasts was partially rescued by the presence of glycerol, which acts as a chemical chaperone to rescue misfolded proteins retained in the ER, or reduced temperature, which assists with conformational rescue of misfolded proteins.


Genotype/Phenotype Correlations

Hinek et al. (2000) performed expression studies on 2 nonsense GLB1 mutations resulting in GM1-gangliosidosis with cardiac involvement (see, e.g., R351X; 611458.0019). Both mutations resulted in impairment of the lysosomal and EBP protein regions and showed no EBP expression. Functional studies indicated that mutants showed impaired secretion of tropoelastin and did not assemble elastic fibers, resulting in impaired elastogenesis. In these mutants, coculturing with Chinese hamster ovary cells transfected with S-Gal cDNA resulted in improved deposition of elastic fibers. In contrast, cells from patients with missense mutations resulting in lysosomal beta-galactosidase deficiency, but not in S-Gal deficiency, assembled normal elastic fibers. The study provided validating functional roles of S-Gal in elastogenesis and elucidated an association between impaired elastogenesis and the development of connective tissue disorders in patients with infantile GM1-gangliosidosis with cardiac involvement.


History

Caffey (1951) probably described the first cases, interpreting them as gargoylism with prenatal onset.


Animal Model

O'Brien et al. (1990) performed allogeneic bone marrow transplantation early in life in a case of canine GM1-gangliosidosis. Despite successful engraftment, no benefit was found.

Prieur et al. (1991) described GM1-gangliosidosis in sheep in which deficiency of beta-galactosidase was coupled with a deficiency of alpha-neuraminidase. Skelly et al. (1995) described a new form of ovine GM1-gangliosidosis in which there was a specific deficiency of lysosomal beta-D-galactosidase only.


REFERENCES

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Hilary J. Vernon - updated : 10/14/2021
Hilary J. Vernon - updated : 05/21/2021
Cassandra L. Kniffin - reorganized : 10/1/2007
Cassandra L. Kniffin - updated : 9/27/2007
Victor A. McKusick - updated : 7/16/2004
Gary A. Bellus - updated : 9/3/2003
Victor A. McKusick - updated : 6/10/2003
Victor A. McKusick - updated : 9/5/2001
Ada Hamosh - updated : 10/31/2000
George E. Tiller - updated : 10/17/2000
Victor A. McKusick - updated : 9/11/2000
Victor A. McKusick - updated : 4/19/2000
Victor A. McKusick - updated : 4/15/1997
Orest Hurko - updated : 6/13/1995
Creation Date:
Victor A. McKusick : 6/24/1986
carol : 03/20/2024
carol : 03/22/2022
carol : 10/14/2021
carol : 06/07/2021
carol : 05/22/2021
carol : 05/21/2021
carol : 05/04/2021
carol : 09/09/2016
carol : 07/09/2016
mcolton : 3/4/2015
terry : 11/16/2007
carol : 10/1/2007
carol : 10/1/2007
ckniffin : 9/27/2007
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terry : 2/22/2005
tkritzer : 7/20/2004
terry : 7/16/2004
carol : 3/17/2004
tkritzer : 3/17/2004
terry : 3/15/2004
carol : 9/9/2003
alopez : 9/3/2003
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mcapotos : 5/19/2000
mcapotos : 5/17/2000
terry : 4/19/2000
terry : 6/11/1999
mark : 8/21/1997
jenny : 4/15/1997
terry : 4/9/1997
terry : 5/17/1996
terry : 5/17/1996
terry : 4/30/1996
mark : 2/5/1996
mark : 9/19/1995
mark : 6/13/1995
jason : 7/19/1994
mimadm : 4/17/1994
warfield : 3/30/1994
carol : 12/16/1993

# 230500

GM1-GANGLIOSIDOSIS, TYPE I; GM1G1


Alternative titles; symbols

GANGLIOSIDOSIS, GENERALIZED GM1, TYPE I
GANGLIOSIDOSIS, GENERALIZED GM1, INFANTILE FORM
GANGLIOSIDOSIS, GENERALIZED GM1, TYPE 1
BETA-GALACTOSIDASE-1 DEFICIENCY
GLB1 DEFICIENCY


Other entities represented in this entry:

GM1-GANGLIOSIDOSIS, TYPE I, WITH CARDIAC INVOLVEMENT, INCLUDED
GANGLIOSIDOSIS, GENERALIZED GM1, TYPE I, WITH CARDIAC INVOLVEMENT, INCLUDED

SNOMEDCT: 238025006, 238026007;   ICD10CM: E75.19;   ORPHA: 354, 79255;   DO: 0080502;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p22.3 GM1-gangliosidosis, type I 230500 Autosomal recessive 3 GLB1 611458

TEXT

A number sign (#) is used with this entry because GM1-gangliosidosis type I (GM1G1) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-galactosidase-1 (GLB1; 611458) on chromosome 3p22.


Description

GM1-gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. Clinically, patients show variable degrees of neurodegeneration and skeletal abnormalities. There are 3 main clinical variants categorized by severity and variable residual beta-galactosidase activity. Type I, or infantile form (GM1G1), shows rapid psychomotor deterioration beginning within 6 months of birth, generalized central nervous system involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death. Type II, or late-infantile/juvenile form (GM1G2; 230600), has onset between 7 months and 3 years, shows generalized central nervous system involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present. Type III, or adult/chronic form (GM1G3; 230650), shows onset from 3 to 30 years and is characterized by localized skeletal involvement and localized central nervous system involvement, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity (Suzuki et al., 2001).

See also Morquio B disease (253010), an allelic disorder with skeletal anomalies and no neurologic involvement.

The GM2-gangliosidoses include Tay-Sachs disease (272800) and Sandhoff disease (268800).


Clinical Features

Landing et al. (1964) gave the first definitive description of this entity, which had variously been called 'Hurler variant,' 'pseudo-Hurler disease,' and 'Tay-Sachs disease with visceral involvement.' O'Brien et al. (1965) suggested the designation 'generalized gangliosidosis.' Clinical features of the infantile form include severe cerebral degeneration leading to death within the first 2 years of life; accumulation of ganglioside in neurons, hepatic, splenic and other histiocytes, and in renal glomerular epithelium; and the presence of skeletal deformities resembling Hurler disease (607014).

Scott et al. (1967) described affected sibs. Renal biopsy showed storage of an acid mucopolysaccharide rather than a glycolipid in vacuoles of the glomerular epithelium. The vacuoles were thought to represent lysosomes. The authors suggested that generalized gangliosidosis, which they also called 'neurovisceral lipidosis,' may be closely related to the Hurler syndrome, which it resembles clinically and radiologically. Grossman and Danes (1968) demonstrated x-ray features resembling those of Hurler syndrome, increased synthesis and storage of mucopolysaccharides by skin fibroblasts, and marked metachromasia of fibroblasts in both parents. Autosomal recessive inheritance was suggested.

Singer and Schafer (1972) reported a patient who presented at age 3 months due to poor psychomotor development and hepatosplenomegaly. He was later found to have dysplastic changes in the long bones and vertebrae and cherry-red spot on the macula. He died at age 18 months. A female sib had died at age 18 months with autopsy findings consistent with generalized gangliosidosis. Detailed biochemical studies on beta-galactosidase obtained from liver tissue of this patient and a patient with juvenile type II disease suggested that the 2 disorders are related and likely allelic.

Fricker et al. (1976) reported a 3-month-old girl with rapidly progressive psychomotor retardation, hepatomegaly, vacuolated lymphocytes, minimal bone dysplasia, and decreased beta-galactosidase activity. She died at age 16 months. Postmortem examination showed generalized GM1-gangliosidosis.

Giugliani et al. (1985) found that GM1-gangliosidosis was the inborn error of metabolism most often diagnosed on the Pediatrics Service in Porto Alegre, Brazil. From a study of 8 families, they suggested that increased fetal loss and macrosomy are features and that vacuolated lymphocytes are a useful diagnostic clue. Almost all patients had alteration in the lumbar vertebrae and cherry spots on the retina.

Yoshida et al. (1991) reported 4 unrelated Japanese patients with the infantile form of GM1-gangliosidosis. Age at onset ranged from 3 to 5 months. All patients had psychomotor retardation or deterioration, macular cherry-red spots, hepatosplenomegaly, and dysostosis multiplex. Beta-galactosidase activity in leukocytes ranged from 0.65 to 1.58% of control values.

GM1-Gangliosidosis with Cardiac Involvement

Hadley and Hagstrom (1971) reported cardiomyopathy in an infant with GM1-gangliosidosis. EKG showed an incomplete bundle branch block and pathology showed vacuolated and hypertrophied myofibers. The mitral valve leaflets were thick and nodular with vacuolated histiocytes and fibrous tissue. The right coronary artery was partially occluded by an atherosclerotic plaque containing ballooned cells. Benson et al. (1976) reported cardiomegaly in association with GM1-gangliosidosis. Kohlschutter et al. (1982) reported cardiomyopathy in an infant with beta-glucosidase deficiency who died of heart failure at age 8 months. Rosenberg et al. (1985) also described cardiac abnormalities in patients with beta-galactosidase deficiency.


Other Features

Beratis et al. (1989) described angiokeratoma corporis diffusum appearing before the age of 10 months in a boy with GM1-gangliosidosis. The angiokeratomas did not form clusters but were scattered widely over the body and proximal extremities. No angiokeratomas were observed on the penis and scrotum.

Hanson et al. (2003) described 2 infants with extensive dermal melanocytosis in association with GM1-gangliosidosis type I and Hurler syndrome, respectively. Clinically, dermal melanocytosis associated with lysosomal storage disease is characterized by extensive blue cutaneous pigmentation with dorsal and ventral distribution, indistinct borders, and persistent and/or 'progressive' behavior. A literature analysis revealed 37 additional cases. The most common lysosomal storage disease associated with dermal melanocytosis was Hurler syndrome (24 of 39 cases), followed by GM1-gangliosidosis (11 of 39 cases). Hanson et al. (2003) concluded that in the appropriate clinical setting, an unusual presentation of dermal melanocytosis in an infant may be a cutaneous sign of an underlying lysosomal storage disease.

Mishra et al. (2021) reported 6 unrelated Indian patients, aged 3 to 15 months, with GM1G1. All of the patients had extensive dermal melanocytosis distributed over the ventral and dorsal surface of the trunk and extremities. The spots were present since birth and progressively increased in size, number, and pigmentation. All of the patients also had global developmental delay, coarse facial features, hepatosplenomegaly, hypotonia, and dysostosis multiplex. Four of the patients had retinal cherry-red spots.


Biochemical Features

O'Brien et al. (1965) identified the ganglioside stored in this disorder as a GM1 ganglioside distinct from that seen in Tay-Sachs disease. Okada and O'Brien (1968) demonstrated that beta-galactosidase deficiency is the fundamental defect in generalized gangliosidosis. O'Brien (1969) found that all 3 isoenzymes of acid beta-galactosidase, A, B and C, were grossly deficient in all tissues.

Galjaard et al. (1975, 1975) studied complementation in cell hybrids between 4 types of Gm(1)-gangliosidosis. They concluded that types I and II involved the same locus. Complementation studies suggested that types III and IV may result from mutation at a second and separate locus.

Horst et al. (1975) demonstrated transfer of E. coli beta-galactosidase to gangliosidosis fibroblasts by phage transduction.

O'Brien (1975) suggested that the pleiotropic effects of mutations affecting a single locus for beta-galactosidase can be explained by the principle of one gene/one polypeptide/many substrates. Accordingly, different mutations in the same enzyme may have variable phenotypic effects since different mutations may impair one or more substrate specificities much more than others. Sixteen patients with beta-galactosidase deficiency and various phenotypes (i.e., types I, II, or III) were studied and all were found to have cross-reacting positive material to anti-beta-galactosidase antibody. However, all had decreased enzymatic activity. The findings suggested that the various forms of the disorder are due to a mutation at a common locus (reviewed by O'Brien and Norden, 1977).

Hoogeveen et al. (1986) showed that the mutations in the infantile and adult forms of GM1-gangliosidosis interfere with the phosphorylation of precursor beta-galactosidase. As a result, the precursor is secreted instead of being compartmentalized into the lysosomes and further processed.


Clinical Management

Mohamed et al. (2020) tested the effects of 2 derivatives of the chemical chaperone deoxygalactonojirimycin (DGJ), NB (butyl)-DGJ and NN (nonyl)-DGG, in fibroblasts from a patient with GM1-gangliosidosis type I and a homozygous mutation in the GJB gene (D151Y; 611458.0029). NN-DGJ demonstrated affinity to beta-galactosidase but did not show significant enhancement mutant enzyme activity. NB-DGJ both promoted mutant beta-galactosidase maturation and enhanced its enzyme activity in a dose-dependent manner. Mohamed et al. (2020) concluded that NB-DGJ could be a promising therapeutic chaperone for some GLB1 mutations that underlie infantile GM1.


Inheritance

The transmission pattern of GM1G1 in the families reported by Nishimoto et al. (1991) was consistent with autosomal recessive inheritance.


Molecular Genetics

Yoshida et al. (1991) and Nishimoto et al. (1991) independently identified mutations in the GLB1 gene in Japanese patients with various forms of GM1-gangliosidosis. Those with the infantile form had specific mutations (611458.0001; 611458.0002; 611458.0005-611458.0007). Residual enzyme activity in these patients ranged from 0.65 to 1.58% of control values (Yoshida et al., 1991).

In several Italian patients with infantile GM1-gangliosidosis with cardiac involvement, Morrone et al. (2000) identified homozygous mutations in the GLB1 gene (611458.0023-611458.0026). Cardiac involvement took the form of dilated and/or hypertrophic cardiomyopathy. All of these mutations were located in the GLB1 region common to the beta-galactosidase-1 lysosomal protein and ts nonlysosomal splice variant, elastin-binding protein (EBP) or S-Gal, and were shown to impair elastogenesis (Hinek et al., 2000). Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations.

Bidchol et al. (2015) reported molecular findings in 46 Indian patients with GM1-gangliosidosis and 2 pairs of Indian parents who had carrier testing for the disorder. Thirty-three different mutations in the GLB1 gene were identified; 20 of the mutations were novel, including 12 missense, 4 splicing, 3 indels, and 1 nonsense. The most common mutations were c.75+2insT (14% of alleles) and L337P (10% of alleles). None of the novel mutations were observed in the dbSNP or 1000 Genomes Project databases. Forty-one of the patients had homozygous mutations, 25 of whom were born to consanguineous parents. Thirty-two of the patients had GM1-gangliosidosis type I, 13 had GM1-gangliosidosis type II, and 1 had GM1-gangliosidosis type III. No genotype-phenotype correlation was observed.

In a 5-year-old Emirati boy, born to consanguineous parents, with GM1-gangliosidosis type I, Mohamed et al. (2020) identified a homozygous mutation in the GLB1 gene (D151Y; 611458.0029). Testing in patient fibroblasts showed less than 1% residual beta-galactosidase enzyme activity. Immunofluorescence staining in patient fibroblasts demonstrated that the mutant protein was improperly trafficked and processed, resulting in trapping in the endoplasmic reticulum (ER). Enzyme function in the fibroblasts was partially rescued by the presence of glycerol, which acts as a chemical chaperone to rescue misfolded proteins retained in the ER, or reduced temperature, which assists with conformational rescue of misfolded proteins.


Genotype/Phenotype Correlations

Hinek et al. (2000) performed expression studies on 2 nonsense GLB1 mutations resulting in GM1-gangliosidosis with cardiac involvement (see, e.g., R351X; 611458.0019). Both mutations resulted in impairment of the lysosomal and EBP protein regions and showed no EBP expression. Functional studies indicated that mutants showed impaired secretion of tropoelastin and did not assemble elastic fibers, resulting in impaired elastogenesis. In these mutants, coculturing with Chinese hamster ovary cells transfected with S-Gal cDNA resulted in improved deposition of elastic fibers. In contrast, cells from patients with missense mutations resulting in lysosomal beta-galactosidase deficiency, but not in S-Gal deficiency, assembled normal elastic fibers. The study provided validating functional roles of S-Gal in elastogenesis and elucidated an association between impaired elastogenesis and the development of connective tissue disorders in patients with infantile GM1-gangliosidosis with cardiac involvement.


History

Caffey (1951) probably described the first cases, interpreting them as gargoylism with prenatal onset.


Animal Model

O'Brien et al. (1990) performed allogeneic bone marrow transplantation early in life in a case of canine GM1-gangliosidosis. Despite successful engraftment, no benefit was found.

Prieur et al. (1991) described GM1-gangliosidosis in sheep in which deficiency of beta-galactosidase was coupled with a deficiency of alpha-neuraminidase. Skelly et al. (1995) described a new form of ovine GM1-gangliosidosis in which there was a specific deficiency of lysosomal beta-D-galactosidase only.


See Also:

Emery et al. (1971); Goldman et al. (1981); Hoeksema et al. (1980); Kaback et al. (1973); MacBrinn et al. (1969); Thomas (1969)

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Contributors:
Hilary J. Vernon - updated : 10/14/2021
Hilary J. Vernon - updated : 05/21/2021
Cassandra L. Kniffin - reorganized : 10/1/2007
Cassandra L. Kniffin - updated : 9/27/2007
Victor A. McKusick - updated : 7/16/2004
Gary A. Bellus - updated : 9/3/2003
Victor A. McKusick - updated : 6/10/2003
Victor A. McKusick - updated : 9/5/2001
Ada Hamosh - updated : 10/31/2000
George E. Tiller - updated : 10/17/2000
Victor A. McKusick - updated : 9/11/2000
Victor A. McKusick - updated : 4/19/2000
Victor A. McKusick - updated : 4/15/1997
Orest Hurko - updated : 6/13/1995

Creation Date:
Victor A. McKusick : 6/24/1986

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mark : 6/13/1995
jason : 7/19/1994
mimadm : 4/17/1994
warfield : 3/30/1994
carol : 12/16/1993