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N-of-1 trial of thymoquinone and vorinostat in a patient with sialidosis type 1
  1. Christina Liang1,
  2. D Peach,
  3. Samantha Stark2,
  4. Michael Fietz3
  1. 1Royal North Shore Hospital, St Leonards, NSW, Australia
  2. 2National Referral Laboratory, Genetics and Molecular Pathology, SA Pathology Women’s and Children’s Hospital, North Adelaide, SA, Australia
  3. 3Diagnostic Genomics, Pathwest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia

Abstract

Objectives Sialidosis type 1 is an autosomal recessive disorder causing neuraminidase deficiency, leading to sialic acids accumulation in tissues. Clinically, patients have cherry red spots, normal intelligence, and a progressive cerebellar ataxia, with intention myoclonus and tremor. Currently there is no disease-modifying treatment. Thymoquinone is an agonist of Neu 4 sialidase activity and a weak histone deacetylase inhibitor. Vorinostat is a more potent histone deacetylase inhibitor. It is unclear if these may have an effect on patients with sialidosis.

Methods A 31 year old caucasian man presenting with a mild ataxic syndrome was diagnosed with sialidosis type 1. After initial dose-finding over 3 months, he was commenced on 3 months on-vs-off cycles of oral thymoquinone between 0.5-2g daily. At 3 months intervals, he was assessed by the scale for the assessment and rating of ataxia (SARA), Archimedes spiral-drawing, balance tests and targeting exercises. Urinary oligosaccharides were assessed semi-quantitatively by thin-layer chromatography. Physiological parameters and routine blood tests were monitored.

Results There was a consistent reduction in the patient’s urinary oligosaccharides after periods of being on thymoquinone from 0.5–2g/day, with gastrointestinal side effects reported at doses beyond 2 g/day. The summed time for balance tests showed a significant improvement in balance after periods on thymoquinone (p=0.047), while the SARA score and tests for dysmetria showed no significant change (p=0.34). There was no change from baseline in the urinary oligosaccharides after periods on vorinostat, with asymptomatic neutropenia noted at the standard 300 mg/day dose.

Conclusions There is a clear physiological effect of thymoquinone on this patient with sialidosis type 1, which is not evident with vorinostat. Thymoquinone at <2 g/day appeared safe but the clinical effect size over the short period of the trial on a minimally affected patient was small. A further pilot study into a larger patient cohort will be helpful.

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