Among the approximately 7000 existing rare diseases , mucopolysaccharidoses (MPS) are a group of disorders that lie within a heterogeneous group of diseases caused by deficiencies in the lysosomal enzymes, which are necessary to break down mucopolysaccharides, also known as glycosaminoglycans (GAGs). Due to the impaired function of lysosomal enzymes, GAGs accumulate in cells, blood and connective tissue. GAGs are macromolecules that provide structural support to the extracellular matrix and are an important part of cellular regulation and communication processes. Their accumulation results in permanent progressive cell damage that affects many aspects, such as an individual’s physical abilities, mental development and organ function. It is estimated that the collective occurrence of all forms of MPS in newborns ranges from 1 in 10,000 to 1 in 25,000 in Europe [2, 3].
The MPS group is classified into several subgroups, namely: (1) MPS I or Hurler syndrome; (2) MPS II or Hunter syndrome; (3) MPS III or Sanfilippo syndrome (A, B, C and D variants); (4) MPS IV or Morquio syndrome (variants A and B); (5) MPS VI or Marotaux-Lamy; (6); and (7) MPS IX or Natowicz syndrome [4, 5].
MPS III or Sanfilippo syndrome is the most common mucopolysaccharidosis, with an incidence of 0.28–4.1 cases per 100,000 births. The disease is inherited in an autosomal recessive manner and is mainly characterised by severe degeneration of the central nervous system [6, 7]. It was first described in 1963 by paediatrician Sylvestre Sanfilippo, who studied a case of eight children with intellectual disability and elevated urinary excretion of a single GAG, heparan sulphate .
The four subtypes of MPS III (A, B, C and D) are classified according to four different enzymatic deficiencies in the heparan sulphate degradation pathway, which are caused by mutations in different genes. The most common subtype is MPS IIIA or IIIB, although this varies between geographical areas [9,10,11].
MPS IIIA is the best-studied subtype due to its greater frequency, earlier presentation of symptoms and rapid rate of progression [9, 12, 13]. It has recently been suggested that the behavioural phenotype of this subtype has characteristics similar to those described in Klüver-Bucy Syndrome . The progressive loss of language and deficient social interactions characteristic of type A also resemble those that occur in autism spectrum disorders (ASDs) . Patients with MPS IIIB show greater clinical heterogeneity, with either rapid or slow progressors reported even among siblings . While MPS IIIC is less common and MPS IIID is the rarest, both are frequently attenuated forms and few studies are found in this regard .
The majority of individuals with MPS III present with a rapidly progressing form of the disease, with the neurological alteration dominating clinically. This is described as being progressive and falls into three stages that start after a period of apparently normal development. In the initial phase, which begins at 1 to 4 years of age, there is a developmental delay, especially in speech and language. The second phase begins at age 3 to 5 years and is characterised by a slowly progressive cognitive deterioration and behavioural alterations, such as impulsivity, hyperactivity, anxiety, sleep disturbances and autistic behaviours. In the third phase, from 10 years old onwards, there is serious dementia and progressive deterioration of the motor function, producing a complete loss of the ability to walk and to swallow. They also have feeding difficulties, seizures, and many patients also develop epilepsy and movement disorders. This loss of abilities often leads to death at the end of the second, or the beginning of the third decade of life [9, 10, 17,18,19,20,21].
Extra-neurological manifestations include recurrent diarrhoea, repeated otorhinolaryngological infections, visual and hearing impairment, coarse facial features, hirsutism, hepatomegaly, dental alterations, cardiac conditions, hernias, upper respiratory infections and musculoskeletal disorders such as osteonecrosis of the femoral head, dysplasia and hip pain, and spine abnormalities such as scoliosis and kyphosis [21,22,23].
Children with MPS III can easily be misdiagnosed with other pathologies like pervasive developmental disorder, or attention deficit hyperactivity disorder (ADHD) and can be subjected to more invasive tests, dietary restrictions, inappropriate medication or even unproven alternative therapies that are ultimately unnecessary or even harmful . Children with Sanfilippo usually meet criteria for an autism diagnosis, being in risk of having an incomplete diagnosis because the doctor may fail to do a timely and thorough medical workup in order to find the underlying Sanfilippo syndrome. Early diagnosis is essential, since any delay involves a greater burden for family members, in addition to the hardship associated with the disease itself, and all the care tasks to be performed by parents, coupled with the impact this has on their lives [24, 25].
Despite the therapeutic advances, there is currently no cure for this disease, so early diagnosis will help to provide a suitable treatment. Multidisciplinary support treatment is important for this disease because it focuses on ensuring the best possible quality of life and relief from symptoms. This type of treatment covers both physical and psychological aspects. This often involves multiple possible treatments or therapies, such as pharmacological, nutritional support or psychological interventions. Due to the palliative need of these children, since there are currently no treatments to cure the disease, it is very important to consider non-pharmacological alternative therapies, such as music therapy, to improve their quality of life [2, 21].
Music therapy can be used to support patients in different areas, such as prevention, individualized education, rehabilitation, mental health and medical care. This intervention can be targeted at a diverse population since it can be applied both to individuals of all chronological and mental ages, and to individuals with some form of disability or impairment, either physical or mental. There is a need to define the particular effects of music therapy that may help individuals with a range of conditions to improve their well-being, develop creativity, improve learning and interpersonal relationships, manage stress, approach childbirth, and even for pain management and self-fulfilment [26, 27].
While music therapy holds many benefits for treating many diseases, there are no studies on how this intervention can be applied to rare diseases. The theoretical framework and basis used here is the use of music therapy in children with ASD since children with Sanfilippo also develop symptoms of autism. Other disorders that share characteristic symptoms of MPS III, such as ADHD or dementia, have also been examined for the therapeutic use of music therapy. In ADHD, music therapy positively impacts hyperactivity, impulsivity and attention span, while in dementia it has shown benefits in cognitive performance [28,29,30]. This study considers those physical, cognitive, communicational and emotional aspects on which music therapy can have an effect from a neuroscientific perspective .
Calleja-Bautista et al.  carried out a review of the literature on music therapy applied to people with ASD in order to analyse its degree of effectiveness. They found that statistically significant improvements had been obtained in 11 out of 18 studies. In the rest, either no statistically significant results had been obtained, or limitations had been found regarding the follow-up evaluations. In the same line, another researcher studied the effects of music therapy in 24 children with ASD and evaluated verbal, non-verbal and social communication by comparing a music therapy group with another group receiving standard treatment. Two blinded evaluators collected the data before and after the interventions and found statistically significant differences in non-verbal communication among participants who had been diagnosed with autism . García  conducted a study on music therapy with a 6-year-old boy diagnosed with autism who presented with highly aggressive behaviour within his social environment and total loss of verbal language. Music therapy was used for three months and improvements were shown, as the child began to establish social relationships, control aggressive reactions, and perform simple orders, to which he responded quickly.
An important aspect of music therapy research applied to children with disabilities is the difficulty in collecting data since measuring variables in children with cognitive deficits or an overall developmental delay is a complex process. Therefore, it is essential to have other sources of information such as caregivers’ perception and report. Parents’ views are often considered to assess the influence that music therapy has on their children and family [35,36,37,38].
Otherwise, some researches on the use of music therapy are based on physiological data to study if that intervention promotes relaxation or reduces anxiety, stress, pain or cardiovascular problems. Regardless of whether there were changes in the results of these studies, or whether they were significant or not, these physiological indicators, especially heart rate and blood pressure are often used [39,40,41,42,43]. Music therapy was also intended to achieve changes in physiological variables since emotional excitement originates in the autonomic nervous system. Heart rate and blood pressure are commonly used biomarkers that indicate the degree of autonomous activation, which varies due to the influence and interaction between sympathetic activity (involved in stress and activity) and parasympathetic activity (responsible for rest and digestion). The level of excitement is crucial for directing and adjusting emotions and behaviours to be able to adapt. Further, it may be an indicator of changes in stress and anxiety [44, 45].
In sum, scientific literature describes Sanfilippo syndrome as a pathology in which, in addition to physical symptoms, there is a deficit in verbal communication, presence of hyperactivity, impulsiveness, anxiety, sleep disorders and cognitive impairment. Given the lack of adapted assessment and intervention models, it is crucial to develop evidence-based protocols to improve the quality of life of children with this type of pathology, as well as that of their families. On the other hand, music therapy is presented as an appropriate intervention model for this particular pathology due to its clinical profile, although there are hardly any studies that go into detail on the effects of its application [28,29,30,31,32,33,34].
In response to these shortcomings, this study aims to describe a music therapy programme applied to children with MPS III (types A and B) and to analyse the psychological and physiological variables related to the symptoms of the disease through quantitative and qualitative observational analysis. This descriptive approach aims to explore this situation to include the music therapy as an intervention and expand the scope of research on rare diseases. This seeks to further the current understanding of the possible benefits of music therapy in children suffering from Sanfilippo.
This paper will answer the following research questions:
Are clinical changes in physical, communication, social, emotional and cognitive variables identified after music therapy sessions?
Are there qualitative and quantitative changes in physiological measures (diastolic blood pressure, systolic blood pressure and heart rate) after music therapy sessions?
Do primary caregivers identify an effect in their child after music therapy sessions?