Introduction

The mucopolysaccharide (MPS) disorders are a group of lysosomal storage disorders in which specific enzymes responsible for the catabolism of glycosaminoglycans (GAGs) are deficient (Lakhotia et al 2004). The deficiency results in accumulation of GAGs in the cells, blood and connective tissue of the body and brain; a period of normal development is usually followed by physical and/or cognitive decline and premature death (Udwin and Dennis 1995). Seven distinct types of MPS disorder have been identified, associated with different enzyme deficiencies.

MPS I includes Hurler syndrome and the less severe variants; Scheie and Hurler-Scheie syndromes. It is particularly associated with skeletal abnormalities (dysostosis multiplex) and motor and cognitive delay. Prevalence is approximately 1 in 100,000 live births although, as with all the MPS disorders, international variation exists (Brown and Trivette 1998). MPS II, Hunter syndrome, occurs in approximately 1 in 170,000 live births, almost exclusively in males and results in a wide spectrum of cognitive and physical disability (Martin et al 2008). MPS III, Sanfilippo Syndrome, is the most common MPS disorder with an estimated incidence of 1 in 24,000 live births. It has four genetically distinct subtypes A-D; each associated with a deficiency in a different enzyme responsible for the breakdown of heparan sulphate. MPS III causes fewer physical abnormalities than the other MPS disorders but is associated with behavioural disturbance (Jacob-Timm and Daniels 1998). MPS IV, Morquio syndrome, has a prevalence rate of approximately 1 in 1,000,000 live births and primary features including skeletal abnormalities and ‘near normal’ intellectual abilities (Brown and Trivette 1998). MPS VI (Maroteaux-Lamy syndrome) is characterised by relatively normal intellectual abilities, valvular heart disease, corneal clouding, dysostosis multiplex and distinctive facial features (Lakhotia et al 2004). MPS VII (Sly syndrome) and IX (Natowicz syndrome) are extremely rare and result in short stature and skeletal and joint abnormalities (Udwin and Dennis 1995).

Previous literature reviews have been conducted into the MPS disorders, however, a review of MEDLINE and Google Scholar databases found none which focused primarily on behaviour. Further, none employed systematic methodology, which aims to be replicable, thorough and unbiased (Jesson et al 2011). A book chapter reviewing research on the psychological and behavioural phenotypes of the MPS disorders was published in 1995, however this was not systematic and does not include the research published in the last 17 years (Udwin and Dennis 1995).

Rationale and review aim

A ‘behavioural phenotype’ (BP) is defined as ‘a characteristic pattern of motor, cognitive, linguistic and social abilities which is consistently associated with a biological disorder’ (Flint and Yule 1994). A description of phenotypic behaviour is beneficial to aid recognition, early diagnosis and intervention monitoring in genetic syndromes. It can help families prepare and plan the future care of their child (van Balkom 2012). The study of behavioural phenotypes contributes to the understanding of genotype-phenotype relationships and behaviour and development in typically developing children (Lloyd and Valles 2010).

This systematic review will identify the extant literature on behaviour in the mucopolysaccharide disorders, assess the quality of empirical studies and report behaviours consistently associated with each syndrome. This review aims to identify studies that demonstrate BPs in any of the syndromes.

Method

Search strategy

MEDLINE (1946-), PsycINFO (1806-) and Embase (1980-) databases were searched for relevant articles on February 1st 2012. The following search terms were used:

  • In title or abstract One of: Mucopolysaccharid*, Hunter syndrome, Hurler, Sanfilippo, Morquio, Maroteaux-Lamy, Sly syndrome, Natowicz

    And

  • In all fields One of: behaviour*, motor, linguistic, speech, cognitive, intellectual, intelligence, social

  • Limited to: Journal article, English language, Empirical study, human

Selection criteria

For inclusion studies had to be : (1) investigations of motor, linguistic, cognitive or social development or behaviour in one or all of the MPS disorders (2) empirical research (3) published in peer reviewed journals. Studies were excluded if they: (1) investigated animal behaviour, (2) had < 4 participants, (3) were intervention studies, (4) primarily investigated physical features and/or biological and genetic mechanisms.

Search results

With duplicates removed, 335 papers were identified, with 305 being subsequently excluded on the basis of their title and abstract indicating: single case studies, mouse model studies, literature reviews, physical health studies, gene and enzyme studies or intervention studies. Ten studies were then excluded after review of the whole article. Reference sections were screened for relevant articles, identifying five further papers. Therefore, 25 papers were included in the current review.

Data extraction and scoring

No tool for assessing the methodology of research into BPs currently exists. Data were extracted and scored, based on principles of best practice described in literature on BP methodology.

  1. 1.

    Control group (Flint and Yule 1994; Hodapp and Dykens 2001). Papers will score: 0 = no control group, 1 = comparisons between non-genetically distinct groups or utilise standardised assessment tools, 2 = genetically distinct control group.

  2. 2.

    Sample size. Papers will score: 0 = fewer than 15 participants, 1 = 15+, 2 = 30 + .

  3. 3.

    Recruitment (O’Brien and Yule 1995). Papers will score: 0 = participants selected by clinician(s), 1 = participants recruited either through charity or medical clinic, and 2 = multiple methods, multiple clinics or multiple charities are used for recruitment.

  4. 4.

    Syndrome diagnosis (Lloyd and Valles 2010). Papers will score: 0 = syndrome diagnosis based on self-report, 1 = diagnosis based on physical features or sibling diagnosis, 2 = diagnosis based on appropriate genetic/enzyme testing.

  5. 5.

    Methodology (Lloyd and Valles 2010; Flint and Yule 1994; Einfeld and Hall 1994). Papers will score: 0 = no validated measures are used, 1 = use validated and/or standardised assessment tools, 2 = validated and/or standardised measures are used alongside new measures, observations or other methodology.

  6. 6.

    Considerations for development (Hodapp and Dykens 2001; Karmiloff-Smith 1998). Papers will score: 0 = participants are compared ‘en mass’, 1 = the study considers age as a variable for at least one aspect of development or behaviour, 2=age is considered as a variable in relation to development and behaviour (or all areas investigated).

  7. 7.

    Appropriate statistics/ comparisons. A paper will score: 0 = data not analysed, 1 = descriptive statistics are used, 2 = appropriate comparative/correlative statistics are reported.

Papers scoring in the upper tertile of possible scores (9+) were deemed to be of reasonable methodological quality and to contribute to the understanding of behaviour in the MPS disorders (Barley et al 2011). If any of these studies utilised validated measurements, was case controlled and demonstrated a significant difference in behaviour between the syndrome group and a suitable control group then it was considered to have identified phenotypic behaviour (Dykens 1995; Einfeld and Hall 1994). Studies scoring below nine were not excluded from the review but were discussed separately from higher scoring papers.

Results

Methodology and findings (Table 1)

MPS I

Four studies investigated MPS I, two exclusively. Papers 24 and 25 included participants with MPS I and scored 10 and 11 with large sample sizes, recruitment through multiple agencies and making developmental considerations of behaviour. Weaknesses of these studies were unconfirmed diagnoses, unvalidated measures and no tests for statistically significant differences between MPS syndromes. Therefore, these studies did not identify phenotypic behaviour but contribute to our understanding of behaviour in MPS I. They found that ‘first concerns’ related to physical appearance and were raised at a mean age of 13 months (24). Behaviours reported as being present in over half the sample were sleep problems (59 %) and fearfulness (65 %) (25).

Table 1 Review of methodology and findings
Full size table

The two papers that exclusively investigated MPS I (1, 2) received scores of 4 and 5, suggesting lower quality methodology; being limited by small sample sizes (n = 10 and n = 4) and no control group (2). Recruitment methods were not specified. These studies indicate that motor skills are below average in children with MPS I and diminish with age.

MPS II

Six papers investigated MPS II and two included it. Collectively these papers investigate cognitive, behavioural, linguistic, and motor development and degeneration. All studies had sample sizes of N > 15 with seven of N ≥ 30. Six papers received methodology scores of 9 or above (5, 6, 7, 8, 24, 25). Three of these were limited by not specifying MPS II diagnosis confirmation (8, 24, 25) and four did not have a genetically distinct control group (5, 6, 7, 8). Two studies had genetically distinct contrast groups but made no statistical comparisons (24, 25). No papers utilised methodology that could demonstrate phenotypic behaviour in MPS II.

Three high scoring studies compared severe and mild phenotypes (5, 6, 7). However, while two (6, 7) defined the severe type as including cognitive impairment, one study (5) reported that 11.7 % participants with mild type had cognitive impairment, suggesting that differentiation between types was not clear. The utility of comparing severe and mild type, which are defined by presentation not genetic differentiation (Wraith et al 2008), is of limited value in the study of behavioural phenotypes, although is prognostically useful for patients. These studies found that patients with the mild form had relatively normal development while children with the severe form reached a developmental plateau and declined at 48–60 months (7). Of children with the severe form of MPS II 85–90.9 % had delayed speech of two years or more, while those with the mild form had little or no speech delay (5, 6, 7). One study identified motor impairment in 75 % of patients (5) while another found a plateau of motor development at 48 months and decline thereafter in all patients (7). Given the age of participants in each study, these two findings are not contradictory. Of children with the severe form 100 % showed behavioural disturbance compared to 0 % in the mild group (5). Concerns about the child were first raised at a mean age of 21 months and first signs were developmental and speech delay, hearing problems and atypical appearance (24); 63 % had sleep problems, 69 % could not settle, 73 % were fearful and 42 % destructive (25).

Two studies (3, 4) scored 5 and 8 respectively. One gave no information about recruitment or syndrome diagnosis and used no standardised measures (3). These studies found that behavioural problems in MPS II included over-activity (76 %), obstinacy (47 %) and aggression (42 %).

MPS III

Fifteen papers investigated and two included MPS III. Of those, three papers primarily investigated MPSIII type A, four type B and one type C. The papers spanned eight countries and 11 studies scored nine or above (13–15, 17, 19–25). Nine of these had sample sizes over 30, the largest being 274; including participants from three countries (21). These sample sizes are large for such a rare genetic disorder and suggest a good representation of the MPS III population.

Two studies, both scoring 11, utilised validated methodology and demonstrated a statistically significant difference between syndrome and genetically distinct control groups and therefore identified phenotypic behaviour (14, 15). One study utilised age and gender matched controls (14) and the other sibling controls, thus controlling for physical and social environmental factors (15). One study (N = 6 MPS IIIA) utilised electroencephalogram (EEG) and polygraphic recording (14), while the other had a large sample size (N = 141 MPSIII (mixed)) and utilised validated questionnaires (15). Both studies demonstrated that children with MPS III experience significantly more sleep problems than controls, with one identifying no circadian rhythm in children with MPS III A (14). Therefore, sleep disturbance can be said to be part of the behavioural phenotype of MPS III. Five other high quality studies identified sleep as a major problem, with prevalence rates between 78 and 96 % (13, 17, 19, 20, 25) and included difficulty settling, early waking, night waking, staying up at night, chewing bedclothes, crying, singing or laughing in the night (13). Sleep problems correlated positively with challenging behaviours in the daytime (15).

Six additional studies utilised genetically distinct comparison groups; four comparing MPSIII subtypes A-C (13, 17, 21, 22) and two comparing MPS types I-IV (24, 25). However only two made statistical comparisons between sample and control groups (13, 21); one finding no significant difference in the overall occurrence of sleep problems between MPS III subtypes and the other more early morning and night waking in MPS III type B than type A (13). This cannot be said to be part of the MPS IIIB phenotype as the study did not use validated methodology. A trend for earlier onset and faster decline was identified in type A than B and C (21). Age of onset of cognitive delay increased across types A-D respectively (21). One study compared results to findings from previous studies in an ID population (13) which is less useful, as methodology and definition of ‘sleep problems’ may be different.

High quality studies with no genetically distinct comparison group found linguistic and motor development ‘normal’ in most children for at least the first year. Mean/median age for first signs and symptoms differed between subtypes, from 2 years 3 months to 5 years, with some cases not diagnosed until their third decade and one person diagnosed aged 66 years (19, 24). Initial concerns related to language and developmental delay and sometimes behavioural problems (24). Rates of decline varied throughout the studies, although cognitive and linguistic skills consistently declined in advance of motor skills (17, 20). MPS III had higher rates of behavioural problems than the other MPS disorders (25), with prevalence rates varying across studies (69–97 %) possibly due to the age of participants and the criteria for ‘behavioural problems’ or ‘abnormal behaviour’ (20, 21). Behavioural concerns were consistent across high and low scoring papers and related to restlessness and hyperactivity (10–12, 16–20, 25), aggression (11, 15–17, 19, 25), temper tantrums (11, 18, 19, 20), unusual affect, i.e. laughing /screaming/ crying (13, 16, 18, 19, 20, 25) and orality (13, 25).

Six studies scored below nine (9, 10, 11, 12, 16, 18). These studies also identified sleep as a major problem in MPS III, with prevalence of 63 %–100 % (10, 12, 16, 18). One study found behaviour problems beginning between 5 and 7 years and declining with age (18).

MPS IV

No studies investigated MPS IV exclusively, but it was included in two high scoring studies, which found concerns were first raised at a mean age of 19 months and were primarily associated with the child’s appearance (24). Children with MPS IV had good mobility, few behavioural problems past age five, and 96 % spoke fluently (25). Some sleep problems were observed and many were incontinent before age ten.

Discussion

Two studies clearly contribute towards the understanding of the behavioural phenotypes of the MPS disorders (14, 15); demonstrating that sleep and circadian rhythms in children with MPS III are significantly different to matched controls. Sleep disturbance can therefore be considered part of the behavioural phenotype of MPS III. Several studies investigating MPS I-IV received methodology scores high enough to be considered to contribute towards the understanding of the behavioural profile of each syndrome. In MPS I and II, fearfulness and sleep problems occurred in most cases. In MPS II participants with the mild form were found to have relatively normal development and few or no behavioural problems, while those with the severe form had behavioural problems, delayed speech, delayed development and limited motor function. In MPS III sleep disturbance and frequent behavioural problems relating to; aggression, hyperactivity, orality, unusual affect and temper tantrums were identified in a number of high quality studies. Children with MPS IV had good mobility and speech and few behaviour problems but distinct physical features.

Review limitations

Search terms were selected to target all seven MPS disorders, but 15/25 solely investigated MPS III, probably due to prevalence and challenging behaviour being more problematic in MPS III. The review exclusion of studies examining physical and medical features meant that the number of papers examining MPS I, II, and IV, where these are primary features, was lower. No papers investigating MPS VI, VII or IX were found given the extreme rarity of these disorders and the review inclusion criteria of n ≥ 4. Papers were scored based on the contribution they made to the phenotypic understanding, rather than simply the quality of the paper, even though none explicitly investigated BPs. The scoring system utilised was based on the extant literature on methodology in BP research and may have further utility with further refinement.

A difficulty in describing the behavioural phenotypes of the MPS disorders is the degree of phenotypic variance. In MPS II, this has resulted in the subtypes ‘mild’ and ‘severe’, but variance is high in all the disorders (e.g. age of diagnosis in MPS III was found to range between 1 and 64 (16)), which makes it difficult to define a single phenotype and to identify statistically significant differences in future controlled studies.

Research implications

Obtaining sample sizes sufficient for inferential statistical analysis is problematic in rare disorders (Flint 1996) and a limiting factor in many of the studies in this review. Limited participants should not preclude research into rare disorders and sample sizes should be considered with regard to epidemiology of the syndrome. Further, small sample sizes often result in syndrome populations being considered as a whole, rather than divided into age groups and future research should consider age and adopt a developmental perspective (Karmiloff-Smith 1998).

Best practice in BP research involves the use of standardised measures, but phenotypic behaviours are often unusual and not measured by existing tools (Flint 1996). Future research should use existing validated tools alongside idiosyncratic measures or new measures designed and validated for specific syndrome populations. Identifying a suitable control group is problematic in BP research, especially the MPS disorders; as few other populations combine such a degree of physical and intellectual disability. Many studies in this review were uncontrolled, however, using age and cognitive functioning matched controls could identify behaviour specifically associated with the syndromes.

A limitation of the studies reviewed was the imprecise terminology such as ‘behavioural problems’, ‘playful exuberance’, ‘faddy’ and ‘temper tantrums’. Further detail about type of behaviour, frequency and intensity and the developmental and environmental context in which it occurs is necessary to map MPS behavioural phenotypes (Arron et al 2011).

Bone marrow transplants and Enzyme Replacement Therapies (ERTs) have been found to be effective for MPS I (Dumas et al 2004) and ERTs have reduced symptoms in MPS II. These treatments are widely used, thus limiting the feasibility of further natural history or BP studies in these disorders. Treatments are currently in development for both MPS III and MPS IV, but are not yet widely used, which means that conducting natural history and BP research in these two syndromes should be a priority.

Clinical implications and conclusions

Phenotypic behaviour can be mediated by the physical and social milieu (Oliver 1995; Hanley et al 2003). Therefore, once a BP is identified, clinicians should plan and evaluate early interventions for anticipated difficulties in the population. Families with a child who has MPS III may benefit from education about sleep hygiene early in their child’s life to reduce the impact of sleep disturbance on their child and family. Both melatonin and behavioural interventions have been found to improve sleep for some individuals in this population but require further research (Fraser et al 2005). Families with a child with MPS II or III may require early access to appropriate clinical services for support in managing challenging behaviour and paediatricians should consider making such referrals. Clinicians working in community services should be aware of the early signs of MPS II and III to improve early identification and diagnosis. Efficacy of behavioural interventions should be tested for these small but important populations.