Sanfilippo syndrome: taking away the guesswork

FREQUENT ear infections, enlarged adenoids and/or tonsils, a mild speech or developmental delay – you could certainly be forgiven for not hearing alarm bells ringing when observing these symptoms in a toddler.

Pair them with a history of an abdominal or inguinal hernia, possibly an enlarged liver and/or spleen, a larger head size and emerging behavioural issues – are the red flags waving yet?

As the child gets a bit older more signs emerge or become more obvious – sleep issues, hyperactivity, autistic behaviours, maybe some mildly coarse facial features such as full lips and prominent eyebrows, and hair that has become thicker.

The first health professional this child sees might be a GP, paediatrician, speech pathologist, occupational or behavioural therapist or an ear, nose and throat specialist. Viewed in isolation, these signs and symptoms can be shelved away under more common diagnoses, including quite frequently a diagnosis such as attention deficit/hyperactivity disorder (ADHD) and autism.

Most families will tell a similar tale of their odyssey towards a diagnosis of Sanfilippo syndrome (mucopolysaccharidosis type III), taking years for their concerns to be investigated and the puzzle pieces solved. Diagnosing rare conditions like Sanfilippo presents a challenge for health professionals who may go through their entire career without meeting an individual with this condition.

As genetic causes of autism are rapidly being discovered and behavioural symptoms overlapping with ADHD can be seen in numerous paediatric neurological diseases, this serves to highlight the need to consider a medical work-up across the scope of neurodevelopmental and behavioural symptoms.

It is also worth noting that while Sanfilippo syndrome is rare, affecting approximately one in 76 000 live births, it is just one of more than 70 conditions that can cause a type of childhood dementia, with similar gradual emergence of signs and symptoms. One in 2800 children are born with a childhood dementia disorder – that is collectively more common than other well known disorders such as cystic fibrosis.

Regardless of its rarity, the devastating nature of the diagnosis and its impact on quality of life for the child and the whole family is enormous. Sanfilippo syndrome is a progressive and fatal condition with neurodegeneration being a dominant feature. There are no approved therapies that can reverse or halt its progression. This means that early diagnosis, supportive and well informed health care providers, and best practice clinical care are vital to optimise the journey for the child and family. However, many are simply told that there is nothing that can be done, to go home and love their children. Clinical care and management are often pieced together and the subject of guesswork.

Fortunately, the guesswork for providing this care has now been removed. We, together with our international colleagues, have recently published the first global consensus clinical guidelines for Sanfilippo syndrome.

A collaboration between Cure Sanfilippo Foundation (United States) and Sanfilippo Children’s Foundation (Australia) initiated and led this project together with an international clinician steering committee. The guidelines were established through a multistage process to arrive at consensus recommendations, with input from more than 100 clinicians around the world with a range of specialist expertise, who have experience in the care of individuals with Sanfilippo syndrome. The two foundations worked to ensure the patient perspective was incorporated.

The impact of this lysosomal storage disorder on the brain presents some of the earliest and most rapidly progressive features of this condition. As the disease progresses, children experience severe hyperactivity, impulsive behaviour, lack of fear (of danger), disordered sleep, loss of speech and motor skills, cognitive decline (dementia), seizures and loss of mobility     . The heart, gastrointestinal system, bones and joints, lungs, eyes and hearing are also affected. The average life expectancy is 15–23 years depending on the subtype, although some individuals show an attenuated disease course and may live well into their third, fourth or even fifth decade.

As with any complex, multisystem condition, a multidisciplinary approach to management is vital. Helping families to assemble such a team around them and facilitating communication between members of the health care team can greatly help to ease the stress for families. Implementing regular monitoring as recommended in the guidelines will identify emerging issues before they become critical or impinge on quality of life.

The consensus guidelines set out the best practice strategies for Sanfilippo syndrome-specific care, management and monitoring of disease-related changes to optimise development, health and quality of life for the individual and their family. Topics addressed in the guidelines include:

• symptoms that should raise suspicion for the diagnosis of Sanfilippo syndrome;
• methods of establishing the diagnosis;
• evaluating, monitoring and managing neurological, gastrointestinal, airway, musculoskeletal and the many other complications that develop;
• special focus on the evaluation of unexplained pain and distress – a significant source of concern and stress for families;
• rehabilitative therapies (eg, speech, occupational therapy, behavioural therapy, physiotherapy); and
• supports for families.

Families note that their greatest unmet needs are around management of pain, distress, hyperactivity, impulsivity, sleep, communication, mobility, feeding and nutrition. More research is needed to enable really effective management of these symptoms, but supports and therapies are available.

Despite the progressive and fatal nature of this condition, optimising education and development and managing behavioural and other symptoms are crucial to enable the child to gain and maintain skills and independent function for as long as possible. The COVID-19 pandemic has highlighted the negative impact that disruptions to educational and rehabilitative support can have for children with progressive neurological disorders who are unlikely to be able to “catch up” and return to their previous developmental trajectory.

Currently, optimising existing care and symptomatic support, as described in the recently published care guidelines, is the only option available for individuals with Sanfilippo syndrome. However, a small number of patients have been provided an opportunity to try experimental treatment strategies in ongoing clinical trials. Examples are gene therapy clinical trials for Sanfilippo type A (here, here and here) and enzyme replacement therapy for Sanfilippo type B.

It is increasingly clear from the interim data emerging from these trials that early treatment is vital. When initiated beyond the age of 2 or 3 years in severe forms of the disease, current investigational treatments appear to have limited impact on cognitive outcome measures. With Sanfilippo syndrome      not yet included in the newborn bloodspot screening schedule, primarily due to the lack of an approved therapy, this highlights the need for vigilance among health care providers for the earliest signs and symptoms. Without a family history or older sibling, the majority of children are not diagnosed until they are between 4 and 6 years of age. This is much too late to access available clinical trials and is frequently too late to allow for informed family planning for subsequent children.

These clinical guidelines can help all health practitioners to recognise the signs and symptoms, expedite a diagnosis, and from there coordinate the best care for children with Sanfilippo syndrome and their families. Then they really can go home and love their children and better enjoy their precious time together.

Dr Lisa Melton is Head of Research at the Sanfilippo Children’s Foundation, Australia. She has a PhD in neuroscience.

Dr Nicholas Smith is a Paediatric Neurologist at the Women’s and Children Hospital Network, Adelaide with a conjoint academic appointment with the University of Adelaide, School of Medicine.

Dr Cara O’Neill is a Paediatrician and the Chief Science Officer and Co-founder of Cure Sanfilippo Foundation, USA. She is also mother to Eliza who has Sanfilippo syndrome.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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