Natural history of Sanfilippo syndrome in Spain

Abstract

BackgroundMucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is caused by a deficiency in one of the four enzymes involved in the lysosomal degradation of heparan sulphate. Four MPS III types have been recognized, characterized by a large phenotypic heterogeneity. This is the first Spanish study describing the natural history of Sanfilippo patients (MPSIIIA, MPSIIIB and MPSIIIC), representing an essential step for understanding patient prognosis and for the establishment and application of future therapies.MethodsThis retrospective study aimed to establish the natural history of MPS III in Spain based on an extensive chronological data survey involving physicians and parents of 55 Spanish MPSIII patients. In addition to clinical description we report biochemical and molecular analysis already performed in the majority of cases.ResultsThe most frequent subtype was MPS IIIA (62%). Symptoms before diagnosis were speech delay in 85%, followed by coarse facial features in 78%, and hyperactivity in 65% of cases at a mean age of 3 years old. The median age at clinical and biochemical diagnosis for each MPS III subtype were as follows: IIIA 4.4 years (1.2 – 16 years), IIIB 3.1 years (1–29 years), and IIIC 6.3 years (3.4-22 years).45% of patients developed epilepsy at a median age of 8.7 (2.5 – 37) years old.Age of death for MPS IIIA patients was 15 years (11.5 – 26 years).Molecular analysis of our cohort reveals, as alluded to above, a great allelic heterogeneity in the three subtypes without clear genotype-phenotype correlations in most cases.ConclusionMPS IIIA is the most frequent subtype in Spanish Sanfilippo patients. Diagnosing physicians should consider Sanfilippo syndrome in children with non-specific speech delay, behavioural abnormalities, and/or mild dysmorphic features. We stress the importance of establishing early diagnosis procedures as soon as possible so as to be able to determine future short-term enzymatic or gene therapy treatments that can change the prognosis of the disease.

Mucopolysaccharidosis III in Taiwan: Natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21‐year period

“…Accurate knowledge of the natural course of the disease will help assess disease progression and therapeutic effects, as well as evaluate clinical and biomarker endpoints for clinical trials. The natural course and clinical manifestations of this disorder have been reported by several study groups in Caucasian populations (Buhrman et al, ; Delgadillo et al, ; Héron et al, ; Jansen et al, ; Malm & Månsson, ; Meyer et al, ; Ruijter et al, ; Truxal et al, ; Valstar et al, ; Velasco et al, ). Our results indicate that Taiwanese patients with MPS III manifest a broad spectrum of disease phenotypes from mild to severe, indicating the clinical heterogeneity of the disease.…”

“…There are several reports describing the natural course of MPS III in Caucasian populations (Buhrman, Thakkar, Poe, & Escolar, ; Delgadillo, O'Callaghan, Gort, Coll, & Pineda, ; Héron et al, ; Jansen et al, ; Malm & Månsson, ; Meyer et al, ; Ruijter et al, ; Truxal et al, ; Valstar et al, ; Velasco, Sanchez, Martin, & Umaña, ). However, information regarding the natural history of this disorder in Asian patients is limited.…”

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

“…early language, loss of walking, cognitive delay, abnormal behaviours, school levelEnzyme activity in leukocytes or fibroblastsDNA sequencingGrant et al(2013)[81]UKParents (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, ECBIParental 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]SpainMPS IIIA (34)MPS IIIB (11)MPS IIIC (10)Retrospectively collected data using a questionnaire answered by physicians and parentsQuestionnaire: 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, deathDetails of previously conducted enzyme assays and mutation analysisMahon et al(2014) [76]UKMPS IIIA (4)MPS IIIB (4)Prospective study over 7 days of eight children with MPS III and eight age-matched typically developing controlsActigraphySalivary melatonin concentrationsSleep questionnaire and daily sleep diaryCross et al2014[108]UKMPS 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, SBRSAdaptive skills: VABS-IIBuhrman et al (2014)[60]USAMPS 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 assessmentsCognitive function, adaptive behaviour, expressive and receptive language, motor development (neuropsychological instruments not specified)Behavioural symptomsSomatic symptomsGrowth parameters (height, weight, BMI, head circumference)SurvivalMumford et al(2015)[77]UKMPS IIIA (4)MPS IIIB (4)Prospective study of children with MPS III and age-matched typically developing controls over 7–10 daysActigraphyShapiro et al(2016)[58]USAMPS IIIA (25)Longitudinal data collected prospectively over a 2 year follow up period with evaluations at baseline, 6 months, 12 months and 2 yearsCognitive assessments (KABC-II or BSID-III), reported as age equivalent scores and DQsAdaptive behaviour (VABS-II), age equivalent...…”

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

“…The patients in this study carried 14 different mutations in the SGSH gene, which included all but 1 previously reported as pathogenic 11, 22, 23, 24. The c.820A>G (p.N274D) mutation found in Patient 53 (see Table 2) was not previously reported but was predicted to be pathogenic by SIFT, Mutation Taster, and Polyphen‐2 prediction software.…”