| Disease entity / phenotype | Common names / synonyms | Key molecular cause | Defining clinical features | Notable variants cited | Key reference (year, journal, DOI/URL) | Evidence |
|---|---|---|---|---|---|---|
| NAGA deficiency spectrum | Schindler disease; α-N-acetylgalactosaminidase deficiency; α-NAGA deficiency; Schindler/Kanzaki disease | Biallelic pathogenic variants in **NAGA** causing deficient lysosomal **α-N-acetylgalactosaminidase (α-NAGA)** activity and impaired glycopeptide/glycolipid degradation | Broad spectrum from severe infantile neuroaxonal disease to mild adult angiokeratoma/lymphoedema phenotypes; marked genotype-phenotype variability and possible incomplete penetrance | **E325K, R329W, R329Q, E193X, c.577G>T (p.Glu193\*)** | Groopman et al., 2024, *Molecular Genetics and Metabolism*, https://doi.org/10.1016/j.ymgme.2024.108593 | (pqac-00000008, pqac-00000010, pqac-00000011, pqac-00000012) |
| Type I phenotype | Schindler disease type I; infantile neuroaxonal dystrophy form | **NAGA / α-NAGA** deficiency | Early-onset severe phenotype; infantile neuroaxonal dystrophy with profound neurologic involvement; classically the most severe end of the spectrum | **E325K** homozygosis classically associated; severity not absolute | Wang et al., 1990, *J Clin Invest*, https://doi.org/10.1172/JCI114901; Sakuraba et al., 2004, *J Hum Genet*, https://doi.org/10.1007/s10038-003-0098-z | (pqac-00000012, pqac-00000013, pqac-00000014) |
| Type II phenotype | Schindler disease type II; Kanzaki disease; adult-onset angiokeratoma form | **NAGA / α-NAGA** deficiency | Adult-onset mild phenotype with **angiokeratoma corporis diffusum**, vacuolization, lymphoedema, peripheral neuropathy, sensorineural hearing loss, often without overt central neurologic manifestations | **R329W, R329Q, E193X, c.577G>T (p.Glu193\*)** | Wang et al., 1994, *J Clin Invest*, https://doi.org/10.1172/JCI117404; Castro et al., 2019, *EJCRIM*, https://doi.org/10.12890/2019_001269 | (pqac-00000010, pqac-00000012, pqac-00000013, pqac-00000016) |
| Type III phenotype | Schindler disease type III; NAGA deficiency type III; intermediate Schindler phenotype | **NAGA / α-NAGA** deficiency | **Intermediate phenotype** between type I and type II; literature describes variable neurologic/developmental involvement, seizures/behavioral problems/psychomotor delay in some reports, with possible systemic findings such as growth retardation, cardiomyopathy, or hepatomegaly in broader summaries | No single type III-specific recurrent variant established; variants reported across the spectrum include **E325K, E193X** and others | Bakker et al., 2001, *Eur J Hum Genet*, https://doi.org/10.1038/sj.ejhg.5200598; Sakuraba et al., 2004, *J Hum Genet*, https://doi.org/10.1007/s10038-003-0098-z | (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000012) |
| Molecular genetics / genotype-phenotype paradox | NAGA-related Schindler spectrum | **NAGA** gene; lysosomal hydrolase deficiency | Same or null alleles can present with dramatically different severity; asymptomatic or minimally affected individuals have been reported despite enzyme deficiency | **E193X** is a null allele yet reported in mild disease; **E325K** linked both to severe disease and apparently unaffected relatives; **R329W** causes inactive but immunoreactive protein | Keulemans et al., 1996, *J Med Genet*, https://doi.org/10.1136/jmg.33.6.458; Bakker et al., 2001, *Eur J Hum Genet*, https://doi.org/10.1038/sj.ejhg.5200598 | (pqac-00000002, pqac-00000011, pqac-00000013, pqac-00000014) |


*Table: This table summarizes how NAGA deficiency type III maps onto the Schindler/Kanzaki disease spectrum, highlighting the shared molecular cause, phenotype distinctions across types I–III, and the main variants and references cited in the literature.*