Schindler Disease

Schindler disease is a rare autosomal recessive lysosomal storage disorder due to biallelic variants in NAGA, with deficiency of alpha-N-acetylgalactosaminidase. It has three forms: type I (infantile neuroaxonal dystrophy), type II (Kanzaki disease, adult onset with angiokeratoma), and type III (intermediate).

Pathophysiology. Alpha-N-acetylgalactosaminidase removes terminal N-acetylgalactosamine from glycoproteins and glycolipids. Deficiency leads to storage of sialylated and asialo glycopeptides and oligosaccharides.

Neuroaxonal dystrophy with spheroids explains the severe neurological disease in type I.

Adults with type II may have few or no symptoms except skin findings.

• Type I: normal development to 9 to 15 months, then rapid regression, cortical blindness, hypotonia then spasticity, seizures, myoclonus and death in childhood.
• Type II (Kanzaki): angiokeratoma corporis diffusum, mild intellectual impairment, sensorineural hearing loss, and tortuous retinal vessels in adults.
• Type III: variable intellectual disability, seizures, and behavioural problems, with autism features.
• Coarse features and organomegaly are uncommon.
• Peripheral neuropathy in some.

• Alpha-N-acetylgalactosaminidase activity in plasma, leukocytes or fibroblasts: markedly reduced.
• NAGA sequencing with deletion and duplication analysis.
• Urine oligosaccharides: abnormal sialylated and O-linked glycopeptides.
• Brain MRI: atrophy and signal change in the basal ganglia and thalami, and axonal spheroids on biopsy if done.
• Skin biopsy for angiokeratoma histology.
• Ophthalmology and audiology assessment.

Differential diagnosis.

• Fabry disease (angiokeratoma)
• Fucosidosis and GM1 gangliosidosis (angiokeratoma)
• Infantile neuroaxonal dystrophy (PLA2G6)
• Other infantile neurodegenerative storage disorders (Krabbe disease, Tay-Sachs disease)
• Autism spectrum disorder in type III

• Seizures and myoclonus: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily in children (adults 500 mg twice daily increasing to 1500 mg twice daily), and valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Spasticity: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), physiotherapy and orthotics.
• Feeding and respiratory care: gastrostomy for unsafe swallow, omeprazole 0.7 to 1 mg/kg daily, vaccination and prompt antibiotics.
• Skin care in type II: sun protection and reassurance; laser treatment may be used for cosmetic indications.
• Hearing and eyes: hearing aids and low vision support.
• Behavioural and developmental support: behavioural therapy, special education, and melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Palliative care: early involvement in type I.
• Disease modifying therapy: none is established.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Adults with Kanzaki disease: counsel about the benign course, and review hearing and cardiac status.

Monitoring. Seizures and development every 3 to 6 months in type I. Skin and hearing yearly in type II, and eye review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine and neurology. Emergency for status epilepticus or aspiration.