Mucopolysaccharidosis Type III

Mucopolysaccharidosis type III (Sanfilippo syndrome) is a group of autosomal recessive lysosomal disorders due to deficiency of one of four enzymes needed to degrade heparan sulphate: sulfamidase (IIIA, SGSH), alpha-N-acetylglucosaminidase (IIIB, NAGLU), acetyl-CoA alpha glucosaminide N-acetyltransferase (IIIC, HGSNAT) and N-acetylglucosamine 6-sulfatase (IIID, GNS). It causes severe, progressive neurodegeneration with relatively mild somatic features.

Pathophysiology. Accumulated heparan sulphate and secondary storage of gangliosides in neurons cause neuroinflammation and neuronal loss. Type A is usually the most severe.

Children seem normal in the first years.

Behaviour and sleep problems are the main early burden.

• Normal early development with speech delay noted at 2 to 4 years
• Hyperactivity, aggression, destructive behaviour and sleep disturbance in the preschool years
• Progressive loss of speech and skills from 6 to 10 years, with dementia
• Mild coarse features, thick hair and hirsutism
• Recurrent upper respiratory infections and ear infections
• Chronic diarrhoea and hepatosplenomegaly
• Seizures in the later stages
• Hearing loss
• Loss of mobility, dysphagia, and death in the second or third decade (attenuated forms live longer)
• Mild skeletal changes

• Urine glycosaminoglycans: raised heparan sulphate on quantitative analysis and electrophoresis or mass spectrometry. A normal screen does not exclude the disease, so confirm by enzyme assay.
• Enzyme assay in leukocytes or fibroblasts for the four enzymes.
• Sequencing of SGSH, NAGLU, HGSNAT and GNS, with deletion and duplication analysis.
• Brain MRI: ventriculomegaly, atrophy, and white matter change.
• Audiology, sleep study and swallow assessment.
• Newborn screening in some regions using dried blood spots.

Differential diagnosis.

• Autism spectrum disorder and ADHD in early disease
• Other mucopolysaccharidoses (Hurler syndrome, Hunter syndrome)
• Neuronal ceroid lipofuscinosis
• Other causes of childhood dementia (Niemann-Pick disease type C)
• Non-genetic sleep disorder and behavioural disorders

• Disease modifying therapy: no enzyme replacement therapy is licensed. Gene therapy for type IIIA and intrathecal enzyme therapy are being studied, so refer for research where possible.
• Behaviour: structured routines and safe environments, with risperidone 0.25 mg daily increasing to 1 to 2 mg daily for aggression, with metabolic monitoring.
• Sleep: sleep hygiene and melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed). For persistent insomnia add trazodone 25 to 50 mg at night, or clonidine 25 to 50 microgram at night, under specialist supervision.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, 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.
• Hearing and ENT care: grommets, hearing aids, and adenotonsillectomy for obstructive sleep apnoea.
• Diarrhoea and feeding: dietary measures and loperamide 0.1 mg/kg twice daily if troublesome, with gastrostomy for unsafe swallow. Add omeprazole 0.7 to 1 mg/kg daily for reflux.
• Spasticity and mobility: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), and physiotherapy.
• Dental care: early dental review.
• Palliative care: early involvement, with attention to family support and respite.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Children with behavioural change and speech delay but normal appearance: check urine glycosaminoglycans, because diagnosis is often delayed.

Monitoring. Development, behaviour and sleep every 3 to 6 months. Hearing yearly, swallow assessment yearly, and orthopaedic and dental review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, neurology and palliative care. Urgent for aspiration, status epilepticus or caregiver crisis.