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Table 2 Summary of design and parameters measured in natural history studies in MPS III

From: Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

Reference Geographical region(s) Subtype(s) (n) Design Parameters measured
Meyer et al.
(2007)
[29]
Germany MPS IIIA (71)
MPS IIIB (14)
MPS IIIC (4)
Retrospectively collected data based on family interviews using a questionnaire and FPSS Questionnaire: Family history, onset of symptoms, diagnostic tests, physical symptoms, developmental delay, behavioural problems, sleep disturbance, neurological symptoms, physical development/puberty, therapies and medications, social care, developmental regression, death
FPSS: motor function, speech abilities, cognitive function; assessed retrospectively over course of disease at 3–6 month intervals
Ruijter et al.
(2008)
[28]
Netherlands MPS IIIC (29) Retrospectively collected data based on paediatrician and geneticist interview with family using a questionnaire, or case note review for deceased patients Questionnaire: pregnancy, first clinical signs and symptoms, mental and motor milestones, behavioural and sleep problems, medical history
DNA sequencing
HGSNAT activity in fibroblasts
Malm et al.
(2010)
[2]
Sweden MPS IIIA (15)
MPS IIIB (1)
MPS IIIC (5)
Retrospective case notes review with completion of missing data by interview with families Motor function and loss of ability, speech development and loss of ability, mental development using IQ measures from locally applied neuropsychological tests (not specified), clinical symptoms and somatic features including behavioural problems, sleep, epilepsy, umbilical or inguinal hernia, orthopaedic problems
Enzyme assay in leukocytes or fibroblasts
Valstar et al.
(2010)
[64]
Netherlands MPS IIIB (52)
(majority with attenuated phenotype)
Retrospectively collected data based on clinician interview with family using a questionnaire, or case note review for deceased patients Questionnaire: pregnancy and delivery, first clinical signs and symptoms, mental and motor milestones, behavioural problems, sleeping problems, medical history
Clinical examination
DNA sequencing
Valstar et al.
(2010)
[30]
Netherlands MPS IIIA (110) Retrospectively collected data based on clinician interview with family using a questionnaire, or case note review for deceased patients Questionnaire: pregnancy, first clinical signs and symptoms, mental and motor milestones, behavioural problems, sleeping problems, medical history
FPSS as used in Meyer et al. (2007)
Clinical examination
DNA sequencing
Heron et al.
(2011)
[5]
France, UK, Greece France
- MPS IIIA (76)
- MPS IIIB (16)
- MPS IIIC (13)
- MPS IIID (6)
UK
- MPS IIIA (89)
- MPS IIIB (22)
- MPS IIIC (7)
- MPS IIID (2)
Greece
- MPS IIIB (16)
- MPS IIIC (3)
France, Greece: retrospectively collected data from participating physicians without direct contact with families using pre-established form
UK: retrospectively collected data from telephone interview with families conducted by UK MPS Society using pre-established form
Pre-established form: Presence of specified clinical features at diagnosis and occurrence during follow up, e.g. early language, loss of walking, cognitive delay, abnormal behaviours, school level
Enzyme activity in leukocytes or fibroblasts
DNA sequencing
Grant et al.
(2013)
[81]
UK Parents (23) of children with MPS III (19)
Parents (23) of children with ID (20)
Child behaviour and parental psychological functioning. Questionnaire packs sent out to families and completed at a single time point. Behaviour: LDCMS, ECBI
Parental psychological functioning: Resilience Scale for Adults, Multidimensional Scale of Perceived Social Support, coping techniques (Brief COPE questionnaire), Paediatric Inventory for Parents, parental anxiety and depression (General Health Questionnaire, GHQ-12)
Delgadillo et al. (2013)
[24]
Spain MPS IIIA (34)
MPS IIIB (11)
MPS IIIC (10)
Retrospectively collected data using a questionnaire answered by physicians and parents Questionnaire: early psychomotor development, age at diagnosis, first clinical symptoms, somatic features, speech, behavioural and sleep disturbance, evolution of neurodegenerative symptoms, age at regression of acquired skills and loss of functional abilities, feeding, cognitive failure through the disease, orthopaedic complications, death
Details of previously conducted enzyme assays and mutation analysis
Mahon et al.
(2014) [76]
UK MPS IIIA (4)
MPS IIIB (4)
Prospective study over 7 days of eight children with MPS III and eight age-matched typically developing controls Actigraphy
Salivary melatonin concentrations
Sleep questionnaire and daily sleep diary
Cross et al.
2014
[108]
UK MPS III (20)
ID (24)
Assessment of behaviour and adaptive skills. Questionnaire packs sent out to families and completed at a single time point. Behaviour: LDCMS, ECBI, Aberrant Behaviour Checklist, SBRS
Adaptive skills: VABS-II
Buhrman et al. (2014)
[60]
USA MPS IIIA (46) Retrospectively collected data using a standardised protocol of assessments conducted at a single visit by an MDT (neurodevelopmental pediatricians, speech and language pathologists, developmental specialists, psychologists, audiologists, physical therapists) Age at diagnosis and initial symptoms,
Audiology assessments
Cognitive function, adaptive behaviour, expressive and receptive language, motor development (neuropsychological instruments not specified)
Behavioural symptoms
Somatic symptoms
Growth parameters (height, weight, BMI, head circumference)
Survival
Mumford et al.
(2015)
[77]
UK MPS IIIA (4)
MPS IIIB (4)
Prospective study of children with MPS III and age-matched typically developing controls over 7–10 days Actigraphy
Shapiro et al.
(2016)
[58]
USA MPS IIIA (25) Longitudinal data collected prospectively over a 2 year follow up period with evaluations at baseline, 6 months, 12 months and 2 years Cognitive assessments (KABC-II or BSID-III), reported as age equivalent scores and DQs
Adaptive behaviour (VABS-II), age equivalent scores and DQs
Disability (FPSS four-point scoring system)
Sleep Habits Questionnaire
Volumetric MRI of brain (cortical grey matter volume, white matter volume, ventricular volume)
Volumetric MRI liver and spleen
Total uGAG by DMB assay
CSF biomarkers (HS by LC-MS/MS; T-tau, p-tau by immunoassay)
Truxal et al.
(2016)
[57]
USA MPS IIIA (15)
MPS IIIB (10)
Longitudinal data collected prospectively over a 1 year follow up period with evaluations at baseline, 6 months and 12 months Medical history, physical examinations conducted by a physician trained in neurology or genetics
Cognitive assessments (Leiter-3 or Leiter-R, reported as age-normed standard scores; later amended to Mullen Scales of Early Learning reported as age equivalent scores)
Adaptive behaviour (Achenbach Child Behaviour Checklist, reported as age and gender-normed T-scores; or Adaptive Behaviour System, but removed in favour of VABS-II, reported as age-normed composite standard scores)
Pediatric Evaluation of Disability Inventory (PEDI), timed motor function tests (timed 10 min walk, 6MWT, timed ascent/descent of 4 stairs)
MRI volumetric measurements of liver and spleen MR/MR spectroscopy of brain (no longitudinal volumetric studies of brain regions)
Echocardiography
SGSH or NAGLU enzyme activity in CSF
SGSH enzyme activity in leukocytes or NAGLU enzyme activity in plasma
uGAG by DMB assay
Complete blood count, coagulation studies, liver enzyme tests in blood
CSF glucose, protein and cell count
Routine urinalysis
  1. Key: FPSS four point scoring system, BMI body mass index, KABC-II Kaufman Assessment Battery for Children, Second Edition, BSID-III Bayley Scales of Infant and Toddler Development, Third Edition, DQ developmental quotient, uGAG urinary glycosaminoglycan, DMB dimethylmethylene blue, CSF cerebrospinal fluid, LC-MS/MS liquid chromatography-tandem mass spectrometry, VABS-II Vineland Adaptive Behaviour Scale, Second Edition, 6MWT 6 min walk test, ID intellectual disability, LDCMS Learning Disability Case Mix Scale, ECBI Eyberg Child Behaviour Inventory, SBRS Sanfilippo Behaviour Rating Scale