Related Terms: Alpha-N-acetylgalactosaminidase deficiency type 2, Alpha-N-acetylgalactosaminidase deficiency adult onset, NAGA deficiency type 2, Schindler disease type 2, Lymphedema, -N-acetylgalactosaminidase deficiency, Kanzaki disease, Homology modeling, Tn-antigen, angiokeratoma corporis diffusum-glycopeptiduria, lysosomal glycoaminoacid storage disease-angiokeratoma corporis diffusum, neuroaxonal dystrophy, Schindler type neuronal axonal dystrophy, Schindler type
A very rare inherited metabolic disorder where deficiency of an enzyme (alpha-N-acetylgalactosaminidase) causes glycoplids to accumulate in body tissues and result in various symptoms. Type 2 occurs during the second or third decade of life and is milder than type I and doesn\'t involve neurological degeneration. (1) It is one of seven inherited identified Glycoprotein storage diseases.
Kansaki Disease (Shindler Type 2) occurs generally during the second or third decades of life. It is milder then Shindler Type I and does not involve neurological degeneration.
Kanzaki diease is one of three tyeps of the inherited disorder called Schindler disease.
There are three types of Schindler disease. Schindler disease type I, also called the infantile type, is the most severe form. Babies with Schindler disease type I appear healthy at birth, but by the age of 8 to 15 months they stop developing new skills and begin losing skills they had already acquired (developmental regression). As the disorder progresses, affected individuals develop blindness and seizures, and eventually they lose awareness of their surroundings and become unresponsive. People with this form of the disorder usually do not survive past early childhood.
Schindler disease type II, also called Kanzaki disease, is a milder form of the disorder that usually appears in adulthood. Affected individuals may develop mild cognitive impairment and hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). They may experience weakness and loss of sensation due to problems with the nerves connecting the brain and spinal cord to muscles and sensory cells (peripheral nervous system). Clusters of enlarged blood vessels that form small, dark red spots on the skin (angiokeratomas) are characteristic of this form of the disorder.
Schindler disease type III is intermediate in severity between types I and II. Affected individuals may exhibit signs and symptoms beginning in infancy, including developmental delay, seizures, a weakened and enlarged heart (cardiomyopathy), and an enlarged liver (hepatomegaly). In other cases, people with this form of the disorder exhibit behavioral problems beginning in early childhood, with some features of autism spectrum disorders. Autism spectrum disorders are characterized by impaired communication and socialization skills. (1)
Symptoms: Telangiectasia, excess urinary sialylglycoaminoacids, warty discolorations on skin (angiokeratosis), mildly coarse facial features, mild intellectual impairment, lymphedema,
Other sites list these additional symptoms:
Peripheral nerve symptoms, Enlarged nose tip, Depressed nose bridge, Thickened lips, Meniere syndrome, Dry skin, Lymphedema, Vertigo. Hand muscle weakness, Foot muscle weakness,
The diagnostic workup is based on the conditions symptoms, as well as the age. A urine test to show increased oligosaccharides, blood test or skin biopsy may help confirm the diagnosis. The blood or skin sample should show decreased activity of the enzyme alpha-N-acetylgalactosaminidase.
For families who have had a child diagnosed with Schindler Disease, prenatal diagnosis is available in future pregnancies by looking at alpha-N- acetylgalactosamindase activity through Chorionic Villus Sampling (CVS) or amniocentesis. Prenatal diagnosis by detection of alpha-N- acetylgalactosaminidase gene changes is also available for families in which the responsible gene changes have been identified. (3)
Kanzaki disease is caused by mutations in the gene for alpha-N-galactosaminidase (NAGA).
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. (2)
Gene Test Information:
Emory University School of Medicine Emory Biochemical Genetics Laboratory (click here to go to Laboratory Web site) Atlanta, GA
There is no cure for Kanzaki disease and treatments will focus on the comorbidities or complications.
For example, manual decongestive therapy with the use of compression garments should be used for the treatment and management of lymphedema. While sclerotherapy might be used to help or treat the telangiectasia.
Doctors involved in the care of the patient may include:
A neurologist for the seizures, ophthalmologist (eye doctor) and geneticist. A certified lymphedema therapist should be involved to treat/manage the lymphedema. A physical therapist and/or an occupational therapist to help with muscle difficulties.
Alternative titles; symbols ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, TYPE II, ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, ADULT-ONSET NAGA DEFICIENCY, TYPE II, SCHINDLER DISEASE, TYPE II
A number sign (#) is used with this entry because Kanzaki disease is caused by mutation in the gene encoding alpha-N-galactosaminidase (NAGA; 104170).
See also the more severe infantile and childhood forms of the disorder (609241), which are also caused by mutation in the NAGA gene.
Description Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder with atypical features. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy (609241); type II, also known as Kanzaki disease, is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder (see 609241) with mild to moderate neurologic manifestations (Desnick and Schindler, 2001).
Clinical Features Kanzaki et al. (1989) described a 46-year-old Japanese woman with disseminated angiokeratoma, and demonstrated numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates were normal in leukocytes and fibroblasts. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid. No information was provided on the patient's family. The enzyme studies excluded Fabry disease (301500), fucosidosis (230000), galactosialidosis (256540), and the various mucolipidoses and mucopolysaccharidoses. Kanzaki et al. (1991) determined that the enzymatic defect in this patient was a deficiency of alpha-N-acetylgalactosaminidase. The findings confirmed that there are 2 forms of alpha-N-acetylgalactosaminidase deficiency with sialopeptiduria: a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions (609241), and an adult-onset form with angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides, and the absence of detectable neurologic involvement.
Kanzaki et al. (1993) gave an extensive description of the patient originally described in 1989 (Kanzaki et al., 1989). The angiokeratomas first appeared on her lower torso when she was 28 years old and later became diffusely distributed. Her 2 unaffected children had half-normal enzyme levels, consistent with autosomal recessive inheritance. The woman had mild intellectual impairment and peripheral neuroaxonal degeneration. She was the product of a first-cousin marriage and worked in a hospital as a nurse's aide. Endoscopic examination demonstrated telangiectasia on the gastric mucosa. Dilated blood vessels were present on the ocular conjunctiva and dilated vessels with corkscrew-like tortuosity were observed in the fundi.
Umehara et al. (2004) presented neurologic findings in the patient reported by Kanzaki et al. (1989). The 59-year-old woman reported progressive distal muscle weakness and numbness beginning at age 40 years. She also developed recurrent vertigo attacks and bilateral sensorineural hearing loss. Physical examination showed impairment of all sensory modalities in the distal upper and lower extremities. Sural nerve biopsy showed decreased density of myelinated fibers and axonal degeneration. Brain MRI showed cerebral atrophy and posterior periventricular white matter abnormalities. Umehara et al. (2004) concluded that Kanzaki disease involves both the central and peripheral nervous systems.
Chabas et al. (1994) reported 2 adult Spanish sibs with angiokeratoma, lymphedema, and vacuolization in dermal cells, but no neurologic signs. Fibroblast activity of alpha-NAGA was decreased to 0.6 to 2% of normal controls. Urinary analysis showed abnormal excretion of sialyloligosaccharides. The patients were clinically similar to the patient described by Kanzaki et al. (1989).
Kodama et al. (2001) reported a 47-year-old Japanese woman, born of consanguineous parents, with Kanzaki disease confirmed by genetic analysis (104170.0005). She developed angiokeratoma corporis diffusum on her lower trunk at age 28 years, which spread to her entire body and oral mucosa. Her conjunctiva and fundi showed mildly dilated blood vessels. After experiencing bilateral tinnitus, hearing difficulty, and vertigo for many years, she was diagnosed with Meniere syndrome (see 156000) and wore a hearing aid. Neurologic examination showed normal IQ with no mental deficits, and some peripheral sensory loss. Echocardiogram revealed partial hypertrophy of the interventricular septum with normal cardiac function. Biochemical studies showed decreased alpha-NAGA activity at 0.77% of control values, and she had urinary excretion of O-linked glycoaminoacid. Kodama et al. (2001) suggested that Meniere syndrome may be another manifestation of Kanzaki disease.
Molecular Genetics In the Japanese woman with disseminated angiokeratoma reported by Kanzaki et al. (1989), Wang et al. (1990, 1994) identified a homozygous mutation in the NAGA gene (104170.0002).
Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with Kanzaki disease described by Chabas et al. (1994) were homozygous for a mutation in the NAGA gene (104170.0003).
Neurologic manifestations of Kanzaki disease. May 2004
Umehara F, Matsumuro K, Kurono Y, Arimura K, Osame M, Kanzaki T.
Department of Neurology and Geriatrics, Graduate School of Medicine and Dental Sciences, Kagoshima University, Japan. firstname.lastname@example.org
We describe the neurologic findings in a patient with alpha-N-acetylgalactosaminidase deficiency (Kanzaki disease). Clinical and electrophysiologic studies revealed sensory-motor polyneuropathy, and sural nerve pathology showed decreased density of myelinated fibers with axonal degeneration. The patient had mildly impaired intellectual function with abnormal brain MRI and sensory-neuronal hearing impairment with repeated episodes of vertigo attacks. These findings suggest that Kanzaki disease may develop neurologic complications in the CNS and peripheral nervous system.
Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease). 2004
Sakuraba H, Matsuzawa F, Aikawa S, Doi H, Kotani M, Nakada H, Fukushige T, Kanzaki T.
Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. email@example.com
Keywords: -N-acetylgalactosaminidase deficiency, Schindler disease, Kanzaki disease, Homology modeling, Tn-antigen
Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki disease) is a clinically and pathologically heterogeneous genetic disease with a wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) and late onset angiokeratoma corporis diffusum (Kanzaki disease). In alpha-NAGA deficiency, there are discrepancies between the genotype and phenotype, and also between urinary excretion products (sialyl glycoconjugates) and a theoretical accumulated material (Tn-antigen; Gal NAcalpha1-O-Ser/Thr) resulting from a defect in alpha-NAGA. As for the former issue, previously reported genetic, biochemical and pathological data raise the question whether or not E325K mutation found in Schindler disease patients really leads to the severe phenotype of alpha-NAGA deficiency. The latter issue leads to the question of whether alpha-NAGA deficiency is associated with the basic pathogenesis of this disease. To clarify the pathogenesis of this disease, we performed structural and immunocytochemical studies. The structure of human alpha-NAGA deduced on homology modeling is composed of two domains, domain I, including the active site, and domain II. R329W/Q, identified in patients with Kanzaki disease have been deduced to cause drastic changes at the interface between domains I and II.
The structural change caused by E325K found in patients with Schindler disease is localized on the N-terminal side of the tenth beta-strand in domain II and is smaller than those caused by R329W/Q. Immunocytochemical analysis revealed that the main lysosomal accumulated material in cultured fibroblasts from patients with Kanzaki disease is Tn-antigen. These data suggest that a prototype of alpha-NAGA deficiency in Kanzaki disease and factors other than the defect of alpha-NAGA may contribute to severe neurological disorders, and Kanzaki disease is thought to be caused by a single enzyme deficiency.
Three dimensional structural studies of alpha-N-acetylgalactosaminidase (alpha-NAGA) in alpha-NAGA deficiency (Kanzaki disease): different gene mutations cause peculiar structural changes in alpha-NAGAs resulting in different substrate specificities and clinical phenotypes. Jan. 2005
Keywords: α-N-acetylgalactosaminidase deficiency, Kanzaki disease, Homology modeling
Characterization of gana-1, a Caenorhabditis elegans gene encoding a single ortholog of vertebrate alpha-galactosidase and alpha-N-acetylgalactosaminidase. Jan 2005
Full Text Article
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ICD - 10 E77.9
H00146 Alpha-N-acetylgalactosaminidase deficiency