An investigation of the middle and late behavioural phenotypes of Mucopolysaccharidosis Type-III

Mucopolysaccharidosis type-III (MPS III (Sanfilippo syndrome)) is a recessively inherited lysosomal storage disorder and is the most prevalent of the seven mucopolysaccharide (MPS) disorders, occurring 0.28–4.1 in 100,000 live births [1]. MPS disorders are caused by deficiency in enzymes responsible for the degradation of glycosaminoglycans (GAGs) and subsequent GAG accumulation in various organs causes a multi-system disease [2]. MPS III has four subtypes A to D associated with a specific enzyme deficiency. All four enzymes, heparan N-sulfatase, a-N-actylglucosaminidase, acetyl-CoA: a-glycosaminide and N-acetylglucosamine 6-sulfatase (A to D, respectively), are associated with the breakdown of heparan sulphate [3]. The most prevalent type in the UK is type A; type B is less common and types C and D rare [4].

MPS III causes severe neurological impairment and a gradual decline in functioning with a tri-phasic clinical course. The beginning phase (1–2 years) is characterised by developmental delay but normal stature and physical growth [5]. The middle phase (2–9 years) shows considerable variation and is characterised by behavioural problems and sleep disturbance. The late phase (10+ years) is associated with skill loss, reduced behaviour problems, loss of motor skills, increased spasticity, seizures and swallowing difficulties [5]. Other symptoms include recurrent diarrhoea; ear, nose and throat infections; and visual impairment [6]. Age of death varies within and between subtypes with a median of 15.2 years for type A [7] and 34 years for type C [8].

A recent survey of care professionals and families investigating non-carcinomatous life-limiting conditions identified MPS disorders as the primary priority for further research, given the complex symptom profile, difficulties in managing symptoms and distress experienced by families [9, 10]. Research into treatments is ongoing but inconclusive [11].

A recent systematic review of behaviour and development in MPS III [12] identified behaviour problems, including restlessness and hyperactivity, physical aggression, unusual affect (laughing/screaming/crying), ‘tantrums’ and orality [5, 7, 8, 13‐20], as strongly associated with the middle phase, thence declining with age and loss of functions [8]. Sleep and circadian rhythm were found to be significantly different from matched controls in two studies [5, 21]. Linguistic and motor development was ‘relatively normal’ for the 1st year with first signs and symptoms differing between subtypes, ranging from 2 years 3 months to 5 years. Age at onset of cognitive delay and rate of decline increased across types A to D respectively [13].

Research to date has been limited by inadequate measurement, control groups, statistical analyses and methodologies (e.g. case-note review). To address this, the present study used validated and syndrome-specific measures and a genetically distinct, ability-matched, control group to address the following research questions:

1: Do the frequencies of challenging behaviour differ significantly between children with MPS III and children with ID?

2: Are any types of challenging or adaptive behaviour observed significantly more frequently in children with MPS III than in children with ID?

Data for 20 children with MPS III (N = 10 aged 2–9 years; N = 10 aged 10–15 years) and 25 children with ID (N = 15 aged 2–9 years; N = 10 aged 10–15 years) were collected. In the 2–9-year age group, all children with MPS III had severe ID, and therefore, only children receiving a score indicative of severe ID were included in the control group (N = 10 remained). In the 10–15-year age group, all the children with MPS III had severe or moderate ID and children with mild ID were excluded from the comparison group (N = 7) (Table 1).

The SBRS current understanding, past understanding, orality, body movements, fearfulness, attention, self-control/compliance and mood, anger and aggression domains had good internal reliability (α > 0.7), the remaining domains having poor internal reliability (α < 0.7).

As seen in Figure 1, there was an outlier in the MPS III group with a high level of skills aged 11 years. Subsequent analyses were conducted both with and without this outlier, but the latter are only reported if these differed from those conducted with the whole dataset. Skills increased with age for the ID group (green line) but decreased with age for the MPS III group (blue line), with LDCS A score being significantly correlated with age in the MPS III group (r = 0.728, p = 0.01).

Frequency of challenging behaviour (ECBI Intensity score) and level of disability (LDCS A score) were negatively correlated in both the MPS III (r = -0.676, p = 0.008) and ID (r = -0.573, p = 0.02) groups, but this relationship was non-significant in the MPS III when the outlying case was omitted, which was most likely due to the lack of variability in the MPS group.

Figure 2 shows the relationship between the ECBI behaviour intensity score and age. For the MPS III group (blue line), the frequency of behavioural problems reduced with age, while for the ID group (green line) the frequency increases. Age and intensity score were significantly negatively correlated for children with MPS III (r = -0.639, p = 0.008), but this was non-significant when the outlier was removed.

In the 2–9-year age range, gross motor skills were the only adaptive skills that differentiated between the MPS III and ID groups. In the 10–15-year age group, the ID group showed significantly more advanced adaptive skills than the MPS III group in all areas of daily living skills, written communication and coping skills and in current understanding and current expression. Thus, level of disability increased with age in the MPS III group, while the ID group acquired new skills with age, possibly accounting for the age-related decrease in challenging behaviour in MPS III as they lose physical and cognitive skills and are less able to actually perform such behaviour. Although such behavioural problems are a feature of the middle phase of MPS III, the high frequency is not in itself phenotypic and may be associated with ID level. Middle phase children with MPS III displayed significantly more behaviours relating to hyperactivity, orality, body movements, interactions with objects and inattention than the control group, but given the poor internal consistency of the interactions with objects domain on the SBRS, this finding should be viewed with caution. Such behaviours may be part of the behavioural phenotype of the middle phase of MPS III, but this requires further investigation [36, 37]. In the late phase MPS III group, few behaviours remained problematic; possibly, parents were used to managing higher levels of challenging behaviour in the middle phase and/or because the reduction in challenging behaviour corresponded to the inevitable physical and cognitive deterioration—one parent remarked that they wished their child was still able to display challenging behaviour.

The present findings confirm previous reports of behaviours relating to orality, unusual affect and hyperactivity in the middle phase of MPS III and add that they occur significantly more frequently compared to matched controls. A novel finding was of unusual body movements being phenotypic in the middle stage of MPS III. The previously reported high rates of challenging behaviour and physical aggression in MPS III were found to be no different from matched controls in the middle phase and are probably associated with the level of ID. Interestingly, although unusual/inappropriate affect were no more frequent compared to matched controls, they were displayed by children with MPS III throughout their lives and even after other behaviours had disappeared. Unlike previous research, this study did not examine ‘temper tantrums’ as these are poorly defined and subjective in report. This study found sleep disturbance to be a common problem in MPS III but with lower prevalence than previous studies, which with a parallel of sleep in MPS III that identified that the quantity of night-time sleep in children with MPS III was not significantly different from typically developing children [23].

This study was limited by the small sample size and grouping of MPS III subtypes. It is possible that the within-group variability found in this study could be accounted for by genetic subtype. As MPS III subtypes are genetically distinct, the findings of this study can only be described as preliminary and identify areas to focus future research. A larger sample size would also show fewer outliers, as was the case in the late phase MPS III sample where there was an outlier in terms of ability, although this did not substantially affect the findings, and it is likely that this was a case of the MPS III B mild phenotype and thus indicative of the heterogeneous presentation of MPS III [15, 14].

The SBRS is a relatively under-developed measure that requires further work to improve its psychometric properties, and therefore, the data derived from the SBRS should be treated with caution.

Although this study was predicated on a biological basis for the behaviour of children with MPS III, the complex relationship between environment, biology, learning and personal factors must be considered given that social context [39], physical environment and triggers [40] and effect of personal characteristics on phenotypic behaviour [41] are demonstrably important when examining behaviour in other genetic syndromes. Examination of differences in behavioural presentation between the genetic subtypes of MPS III would also inform the understanding of the genotype-phenotype relationship in MPS III, but this may be difficult within a UK sample and might require international recruitment, possibly utilising on-line data collection.

No single questionnaire in this study captured the behavioural phenotype or was completed by parents exactly according to guidelines, and the present findings should inform further development of existing and novel questionnaire-based measures for use with this small but important population [9, 10]. Moreover, given the progressive nature of MPS III coupled with the evident phenotypic heterogeneity, future research could use more naturalistic methodologies with an emphasis on describing the progressive nature of the disorder rather than on mapping evident differences.