Kanzaki Disease

A number sign (#) is used with this entry because of evidence that Kanzaki disease is caused by homozygous mutation in the gene encoding alpha-N-galactosaminidase (NAGA; 104170) on chromosome 22q13.

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).