Alpha Galactosidase B Deficiency - Schindler disease
Schindler Disease is one of seven identified Glycoprotein storage diseases. These inherited diseases are part of a larger group of disorders called Lysosomal storage diseases. Lysosomes are membrane-bound compartments found in the cells of the body. These compartments contain enzymes, which are responsible for the breakdown of many different oligosaccharides (long sugar chains.) These sugar chains are continuously made and broken down in our bodies, and this process is necessary for the appropriate mental and physical development. Each enzyme in the lysosome is responsible for a certain step in the breakdown of the sugar chains.
When an enzyme is not working, it leads to the build up of the sugar chains in the lysosome. In Schindler Disease, the specific enzyme that is absent is called alpha-N-acetylgalactosaminidase (previously known as alpha-galactosidase B.) The build up of oligosaccharide sugars that is caused, is gradual and interferes with the correct function of the cell. ItThis build up is gradual and eventually leads to the clinical features of Schindler Disease. Features may progress in severity over time.
In Schindler Disease, the specific enzyme that is absent is called alpha-N- acetylgalactosaminidase (previously known as alpha-galactosidase B.) (1)
Genetic: Gene map locus 22q11 -
NAGA encodes the lysosomal enzyme alpha-N-acetylgalactosaminidase, which cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA have been identified as the cause of Schindler disease types I and II (type II also known as Kanzaki disease).
Diagnosis of Schindler disease is based on the symptoms the individual has, as well as the age the symptoms began. A urine test, blood test, or skin sample (biopsy) may help confirm the diagnosis. In Schindler disease, the blood or skin sample will show decreased activity of alpha-NAGA.
Teleangiectasia (widening of groups of blood vessels which causes skin redness), excess urinary sialylglycoaminoacids, warty discolorations on skin, mildly coarse facial features, mild intellectual impairment, edema/lymphedema, loss of previously acquired physical skills, loss of previously acquired mental abilities, progressive neurological symptoms (seizures)
Supportive - no treatment for underlying disorder, multidisciplinary approach (Peadiatrics, Neurology, Ophthalmology, Orthopedics), Genetic counselling (normal sib of an affected patient has a 67% risk of being a carrier).
June 11, 2008
Alternative titles; symbolsALPHA-GALACTOSIDASE B; GALBGene map locus 22q11
Alpha-N-acetylgalactosaminidase (EC 18.104.22.168) is a lysosomal glycohydrolase that cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates.
Wang et al. (1990) isolated a full-length 2.2-kb NAGA cDNA and a genomic cosmid clone containing the entire NAGA gene from a human fibroblast cDNA library. The cDNA encodes a 411-amino acid protein with a 17-residue signal peptide and 6 putative N-glycosylation sites. Northern blot analysis detected 2 mRNA transcripts of 3.6 and 2.2 kb. Sequence analysis revealed striking similarities between the NAGA gene and exons 1-6 of the alpha-galactosidase A gene (GLA; 300644), suggesting that the 2 genes evolved by duplication and divergence from a common ancestral locus. Wang and Desnick (1991) also pointed to remarkable amino acid identity between the NAGA and GLA genes.
Wang et al. (1998) isolated the mouse Naga cDNA from a fibroblast cDNA library and found that the deduced human and mouse proteins share 81.9% sequence identity.
Wang and Desnick (1991) determined that the NAGA gene contains 9 exons.
De Groot et al. (1978) assigned the human N-acetyl-alpha-D-galactosaminidase gene to chromosome 22 by human-rodent somatic cell hybridization. The authors suggested that 'alpha-NAGA' was a more appropriate designation for this enzyme than alpha-galactosidase B.
In human-rodent cell hybrids, Geurts van Kessel et al. (1979, 1980) studied chronic myeloid leukemia cells to determine the site of the break on 22q relative to markers assigned to chromosomes 22 and 9. Alpha-NAGA remained with the Ph-1 chromosome, whereas the aconitase gene (ACO2; 100850) went with chromosome 9. Alpha-NAGA was located to band 22q11 and ACO2 was located between it and 22qter.
Wang et al. (1994) generated a mouse model of Schindler disease by targeted disruption of the Naga gene. Naga-null mice appeared clinically normal, survived into adulthood, and were fertile. Consistent with the human disease, the mice had no Naga activity and showed lysosomal pathology, including vacuolated peripheral lymphocytes.
Desnick and Schindler (2001) reported that Naga-null mice developed widespread lysosomal storage of abnormal material in the central nervous system and other organs, as well as focal axonal swellings or spheroids in the brain and spinal cord.
In the 2 German boys first described with Schindler disease (609241) (11,12:van Diggelen et al., 1987, 1988), Wang et al. (1990) identified a homozygous 973G-A transition in exon 8 of the NAGA gene, resulting in a glu325-to-lys (E325K) substitution. Keulemans et al. (1996) identified a distant affected relative of the 2 boys who had the E325K homozygous mutation. The boys had approximately 1% residual NAGA activity.
Bakker et al. (2001) reported homozygosity for the E325K mutation in a 3-year-old Moroccan boy with alpha-NAGA deficiency. He was born of consanguineous parents. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. The parents had alpha-NAGA activity consistent with heterozygosity. Mutation analysis revealed homozygosity for the E325K mutation in the proband and his healthy brother, whereas a third sib and both parents were heterozygous. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms.
In a Japanese woman with disseminated angiokeratoma (609242) reported by Kanzaki et al. (1989), Wang et al. (1990, 1994) identified a homozygous 985C-T transition in the NAGA gene, resulting in an arg329-to-trp (R329W) substitution. The base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Wang et al. (1994) showed that in transiently expressed COS-1 cells, both the infantile-onset E325K (104170.0001) and the adult-onset R329W precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.
Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with manifestations of Kanzaki disease (609242) described by Chabas et al. (1994) were homozygous for a 5371G-T transversion in exon 5 of the NAGA gene (numbering according to Yamauchi et al., 1990), resulting in a glu193-to-ter (E193X) substitution, premature truncation, and complete loss of the NAGA protein.
In a Dutch girl with type III NAGA deficiency (609241) reported by de Jong et al. (1994), Keulemans et al. (1996) identified compound heterozygosity for 2 mutations in the NAGA gene: E325K (104170.0001) and a 4969C-G transversion in exon 4 (numbering according to Yamauchi et al., 1990), resulting in a ser160-to-cys (S160C) substitution. The same genotype was found in the clinically unaffected 3-year-old brother of the proband, and the authors suggested that the brother might be a preclinical case of NAGA deficiency; the brother's twin sister did not have the genotype. Residual enzyme activity in the proband was approximately 4% of controls. The S160C allele was not identified in 80 Dutch control alleles.
In a Japanese woman with Kanzaki disease (609242), Kodama et al. (2001) identified a homozygous 986G-A transition in the NAGA gene, resulting in an arg329-to-gln (R329Q) substitution. The patient had angiokeratoma corporis diffusum, Meniere syndrome, and no mental retardation. Her parents were consanguineous.
PubMed ID : 2243144
Kniffin - updated : 5/11/2005
Cassandra L. Kniffin - updated : 4/6/2005
Cassandra L. Kniffin - reorganized : 4/1/2005
Cassandra L. Kniffin - updated : 3/8/2005
Michael B. Petersen - updated : 8/21/2001
Iosif W. Lurie - updated : 7/10/1996
Victor A. McKusick : 6/4/1986
carol : 3/28/2007
Blood group B glycosphingolipids in
deficiency (Fabry disease): influence of secretor status.
Ledvinova J, Poupetova H, Hanackova A, Pisacka M, Elleder M.
Institute of Inherited Metabolic Diseases, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Defect in degradation of blood group B-immunoactive glycosphingolipids in Fabry disease (deficiency of lysosomal alpha-galactosidase EC 22.214.171.124) has been studied using highly sensitive and specific TLC-immunostaining analysis of urinary sediments and tonsillar tissues of blood group B patients and healthy controls, secretors and nonsecretors. The B glycolipid antigens with hexasaccharide chains were consistently found increased (25- to 100-fold) in the urinary sediments of three Fabry patients, blood group B or AB secretors. Conversely, they were absent in the urinary sediment of one blood group B nonsecretor patient. In normal secretors, B glycosphingolipids were present only in traces. Moreover, significant increase in B glycolipid antigens (8-fold) was found in the tonsillar tissue of a Fabry patient blood group B secretor. We conclude that the secretor status is responsible for increased concentration of blood group B glycosphingolipids in both urinary cells and tonsils in alpha-galactosidase deficiency. The quantity of stored B-immunoactive glycosphingolipids, however, is much lower than that of the mainly accumulated glycosphingolipid Gb(3)Cer. The results clearly indicate that active or silent Se gene, which controls synthesis of B-antigen precursors, is responsible for notable difference in B-glycosphingolipids expression in Fabry patients - secretors and nonsecretors. Whether this novel aspect may be of prognostic significance, remains to be established.
PMID: 9106497 [PubMed - indexed for MEDLINE]
Defects in degradation of blood group A
and B glycosphingolipids in Schindler and Fabry diseases.
Asfaw B, Ledvinova J, Dobrovolny R, Bakker HD, Desnick RJ, van Diggelen OP, de Jong JG, Kanzaki T, Chabas A, Maire I, Conzelmann E, Schindler D.
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, 128 08 Prague, Czech Republic. email@example.com
Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, alpha-N-acetylgalactosaminidase (alpha-NAGA) and alpha-galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (GalNAc (alpha 1-->3)[Fuc alpha 1-->2]Gal(beta1-->4)GlcNAc(beta 1-->3)Gal(beta 1--> 4)Glc (beta 1-->1')Cer, IV(2)-alpha-fucosyl-IV(3)-alpha-N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(alpha 1-->3)[Fuc alpha 1--> 2] Gal (beta 1-->4)GlcNAc(beta 1-->3)Gal(beta 1-->4)Glc(beta 1-->1')Cer, IV(2)- alpha-fucosyl-IV(3)-alpha-galactosylneolactotetraosylceramide), and globoside (GalNAc(beta 1-->3)Gal(alpha 1-->4)Gal(beta 1-->4)Glc(beta 1-->1') Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the alpha-NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary excretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to alpha-galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones. Relatively high-degree degradation of substrates with alpha-D-Galactosyl moieties hints at a possible contribution of other enzymes.
PMID: 12091494 [PubMed - indexed for MEDLINE]
Schindler disease: the molecular lesion in
the alpha-N-acetylgalactosaminidase gene that causes an infantile
Wang AM, Schindler D, Desnick R.
Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.
Schindler disease is a recently recognized infantile neuroaxonal dystrophy resulting from the deficient activity of the lysosomal hydrolase, alpha-N-acetylgalctosaminidase (alpha-GalNAc). The recent isolation and expression of the full-length cDNA encoding alpha-GalNAc facilitated the identification of the molecular lesions in the affected brothers from family D, the first cases described with this autosomal recessive disease. Southern and Northern hybridization analyses of DNA and RNA from the affected homozygotes revealed a grossly normal alpha-GalNAc gene structure and normal transcript sizes and amounts. Therefore, the alpha-GalNAc transcript from an affected homozygote was reverse-transcribed, amplified by the polymerase chain reaction (PCR), and sequenced. A single G to A transition at nucleotide 973 was detected in multiple subclones containing the PCR products. This point mutation resulted in a glutamic acid to lysine substitution in residue 325 (E325K) of the alpha-GalNAc polypeptide. The base substitution was confirmed by dot blot hybridization analyses of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Furthermore, transient expression of an alpha-GalNAc construct containing the E325K mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity.
PMID: 2243144 [PubMed - indexed for MEDLINE]
Schindler Disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA). The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. In individuals with Schindler Disease, deficiency of the alpha-NAGA enzyme leads to an abnormal accumulation of certain complex compounds (glycosphingolipids) in many tissues of the body.
There are two forms of Schindler Disease. The classical form of the disorder, known as Schindler Disease, Type I, has an infantile onset. Affected individuals appear to develop normally until approximately 1 year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe mental retardation, hearing and visual impairment, and a lack of response to stimuli in the environment.
Schindler Disease, Type II, which is also known as Kanzaki Disease, is the adult-onset form of the disorder. Associated symptoms may not become apparent until the second or third decade of life. In this milder form of the disease, symptoms may include the development of clusters of wart-like discolorations on the skin (angiokeratomas); permanent widening of groups of blood vessels (telangiectasia), causing redness of the skin in affected areas; relative coarsening of facial features; and mild intellectual impairment. The progressive neurological degeneration characteristically seen in the infantile form of the disease has not occurred in association with Schindler Disease, Type II.
Both forms of Schindler Disease are inherited as autosomal recessive traits. According to investigators, different changes (mutations) of the same gene are responsible for the infantile- and adult-onset forms of the disease. The gene has been mapped to the long arm (q) of chromosome 22 (22q11).
Organizations related to Schindler Disease
5223 Brookfield LaneCLIMB (Children Living with Inherited Metabolic Diseases)
Sylvania OH 43560-1809
Phone #: 419-885-1497
800 #: --
Home page: N/A
Crewe Intl CW2 6BG
Phone #: 44 -870- 7700 325
800 #: --
3210 Batavia Ave, Baltimore, MD, 21214
Baltimore MD 21214
Phone #: 410-254-4903
800 #: N/A
PO Box 5801
Bethesda MD 20824
Phone #: 301-496-5751
800 #: 800-352-9424
National Lipid Diseases Foundation
1201 Corbin StreetNational Tay-Sachs and Allied Diseases Association, Inc.
Elizabeth NJ 07201
Phone #: 908-527-8000
800 #: 800-527-8005
Home page: N/A
2001 Beacon StreetVaincre Les Maladies Lysosomales
Boston MA 02135
Phone #: 617-277-4463
800 #: 800-906-8723
9 Place du 19 Mars 1962,
Evry Cedex None 91035
Phone #: 016-091-7500
800 #: --
Schindler disease - Webmd
Schindler disease - Pedbase.org
Schindler Disease - Developmental Disorders of the Lymphatics
Classification and Codes:
ICD 10 code - E74.2
N-ACETYL-ALPHA-D-GALACTOSAMINIDASE; NAGA 104170
SCHINDLER DISEASE, TYPE I 609241
KANZAKI DISEASE 609242
Join us as we work for lymphedema patients everywhere:
Advocates for Lymphedema
Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.
Lymphedema People / Advocates for Lymphedema
For information about Lymphedema
For Information about Lymphedema Complications
For Lymphedema Personal Stories
For information about How to Treat a Lymphedema Wound
For information about Lymphedema Treatment
For information about Exercises for Lymphedema
For information on Infections Associated with Lymphedema
For information on Lymphedema in Children
Lymphedema People - Support Groups
The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.
No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.
Come join, be a part of the family!
MEN WITH LYMPHEDEMA
If you are a
man with lymphedema; a man with a loved one with lymphedema who you are
to help and understand come join us and discover what it is to be the
instead of the sufferer of lymphedema.
Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.
Disorders Support Group @ Yahoo Groups
While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.
Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.
Lymphedema People New Wiki Pages
Have you seen
our new “Wiki”
yet? Listed below
are just a sample
of the more than 140 pages now listed in our Wiki section. We are also
on hundred more. Come
and take a
not for Lymphedema
People Online Support Groups
Lymphatic Drainage (MLD) and Complex Decongestive Therapy (CDT)
Associated with Lymphedema
How to Treat a
Infections Associated with Lymphe dema
para-aortic lymph node dissection (EPLND)
Needle Biopsy - Fine Needle Aspiration
Lymphedema Gene VEGFC
Lymphedema Gene SOX18
Home page: Lymphedema People
Page Updated: Dec. 14, 2011