Sialidosis

Sialidosis is an autosomal recessive lysosomal storage disorder due to biallelic variants in NEU1, with deficiency of neuraminidase-1 and storage of sialylated glycoproteins and oligosaccharides. Type I (the cherry red spot myoclonus syndrome) is milder and starts in adolescence or early adult life; type II (dysmorphic) starts in infancy or before birth.

Pathophysiology. NEU1 removes terminal sialic acid from glycoconjugates in the lysosome. Neuraminidase-1 also forms a complex with beta galactosidase and protective protein/cathepsin A, so its loss secondarily destabilises that complex.

Residual enzyme activity determines severity.

Storage in neurons and the retina explains the myoclonus and the cherry red spot.

• Type I: onset in the second or third decade with action myoclonus, ataxia, progressive visual loss, cherry red spot, and generalised seizures; intelligence is usually preserved.
• Type II infantile and congenital forms: coarse facial features, dysostosis multiplex, hepatosplenomegaly, hypotonia, intellectual disability, and corneal clouding.
• Congenital sialidosis: non-immune hydrops foetalis, ascites, and neonatal death.
• Hearing loss, angiokeratomas and recurrent respiratory infection in some.
• Peripheral neuropathy in some adults.

• Urine oligosaccharides: raised sialyloligosaccharides on thin layer chromatography or mass spectrometry.
• Neuraminidase activity in cultured fibroblasts: markedly reduced.
• NEU1 sequencing with deletion and duplication analysis.
• Ophthalmology: cherry red spot and cataract.
• EEG and EMG: giant somatosensory evoked potentials in myoclonus.
• Brain MRI: cerebellar atrophy in later disease.
• Radiographs for dysostosis multiplex in type II.
• Prenatal ultrasound for hydrops.

Differential diagnosis.

• Galactosialidosis (CTSA), where beta galactosidase and neuraminidase activities are both low
• GM1 and GM2 gangliosidosis
• Other progressive myoclonus epilepsies (Unverricht-Lundborg disease, Lafora disease, MERRF)
• Mucolipidosis and mucopolysaccharidoses
• Non-immune hydrops from other lysosomal disorders

• Myoclonus and seizures: levetiracetam 500 mg twice daily increasing to 1500 mg twice daily (maximum 3 g daily), valproate 500 mg twice daily increasing to 1000 mg twice daily, and clonazepam 0.5 mg at night increasing to 2 mg three times daily (maximum 8 mg daily). Avoid phenytoin, carbamazepine and oxcarbazepine, which can worsen myoclonus. In children use levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily and buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Ataxia and function: physiotherapy, gait aids, and occupational therapy.
• Vision: low vision aids, and cataract surgery when it improves vision.
• Hearing: hearing aids or cochlear implants.
• Respiratory care: vaccination, chest physiotherapy and prompt antibiotics.
• Type II infantile disease: feeding support, gastrostomy for unsafe swallow, omeprazole 0.7 to 1 mg/kg daily, and palliative care involvement.
• Disease modifying therapy: no licensed treatment; haematopoietic stem cell transplantation has been tried in few patients with uncertain benefit.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis by enzyme assay or variant testing.

Special groups.

• Women of child bearing age on valproate need contraception and counselling on foetal risk.

Monitoring. Myoclonus, seizures and drug side effects at each visit. Visual acuity and fundus yearly, hearing yearly, and neurological examination every 6 to 12 months.

Referral and escalation. Refer to clinical genetics, metabolic medicine and neurology. Urgent for status epilepticus or rapid neurological decline.