Development of a Clinical Algorithm for the Early Diagnosis of Mucopolysaccharidosis III

Maria Escolar Jessica Bradshaw Valerie Tharp Byers Roberto Giugliani Lynn Golightly Charles Marques Lourenço Kimberly McDonald Nicole Muschol Imogen Newsom-Davis Cara O’Neill Holly L. Peay Jennifer Siedman Martha L. Solano Tessa Wirt Tim Wood Lonnie Zwaigenbaum About the authors

Abstract

Mucopolysaccharidosis III (MPS III) is a rare inherited metabolic disease primarily affecting the central nervous system, leading to developmental and/or speech regression. Early diagnosis of the disease is important to introduce appropriate management measures and to optimize therapeutic outcomes. The diagnosis of MPS III is often significantly delayed due to the rarity of the disease, the more attenuated somatic presentation compared to other MPS types, and the symptom overlap with other developmental disorders. To shorten the time to diagnosis, a list of eight early signs and symptoms was identified through an expert system approach by a global, multidisciplinary working group of 13 specialists with expertise in various aspects of MPS and developmental disorders and three parents of MPS III patients. Coarse facial features and persistent hirsutism or prominent, thick eyebrows were identified as the most important MPS III early signs. The list of eight early MPS III signs and symptoms is the first step towards the development of a clinical algorithm aiming to identify neonates and infants with MPS III before the onset of neurocognitive damage, ultimately shortening the diagnostic journey of MPS III patients.

Keywords:
Mucopolysaccharidosis III; Sanfilippo syndrome; signs; symptoms; diagnostic algorithm

Background

Mucopolysaccharidoses (MPSs) are a group of rare, autosomal recessive lysosomal storage disorders. Each MPS type is characterized by the absence or deficiency of a lysosomal enzyme involved in the catabolic pathway of glycosaminoglycans (GAGs), resulting in multi-organ accumulation of different GAGs and subsequent cellular damage 11. Andrade F, Aldámiz-Echevarría L, Llarena M and Couce ML. Sanfilippo syndrome: Overall review. Pediatr Int. 2015; 57(3):331-338. doi:10.1111/ped.12636
https://doi.org/10.1111/ped.12636...

2. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
-33. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(Suppl 5): v4-v12.doi:10.1093/rheumatology/ker394
https://doi.org/10.1093/rheumatology/ker...
. MPS IV and VI manifest as purely somatic diseases with normal cognitive development 33. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(Suppl 5): v4-v12.doi:10.1093/rheumatology/ker394
https://doi.org/10.1093/rheumatology/ker...
. The somatic manifestations in MPS IV and VI are similar to those seen in MPS I, II, and VII. However, the severe forms of the latter MPS types have both somatic and cognitive involvement 33. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(Suppl 5): v4-v12.doi:10.1093/rheumatology/ker394
https://doi.org/10.1093/rheumatology/ker...
. Somatic features are relatively mild in MPS III or Sanfilippo syndrome, which is mainly characterized by cognitive and neurological impairment due to accumulation of the GAG heparan sulfate 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
,44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189
https://doi.org/10.1186/1750-1172-8-189...
. MPS III comprises four different subtypes: MPS IIIA, B, C, and D, which are the result from a deficiency in N-sulfoglucosamine sulfohydrolase, alpha-N-acetylglucosaminidase, heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase, respectively 11. Andrade F, Aldámiz-Echevarría L, Llarena M and Couce ML. Sanfilippo syndrome: Overall review. Pediatr Int. 2015; 57(3):331-338. doi:10.1111/ped.12636
https://doi.org/10.1111/ped.12636...
. MPS III is one of the most common types of MPS with an estimated incidence ranging from 0.17 to 2.35 per 100,000 births for all four subtypes, with subtypes A and B being more frequently diagnosed than types C and D 55. Zelei T, Csetneki K, Voko Z and Siffel C. Epidemiology of Sanfilippo syndrome: results of a systematic literature review. Orphanet J Rare Dis. 2018; 13(1):53. doi:10.1186/s13023-018-0796-4
https://doi.org/10.1186/s13023-018-0796-...
. Heparan sulfate mainly accumulates in the central nervous system, leading to early-onset neurodevelopmental and/or speech delay after an initial period of normal development 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
. Natural history studies have demonstrated that the first phase generally presents as a delay in speech and cognitive development occurring between the ages of 1 and 3 years for rapidly progressing phenotypes and around the age of 4 years for more slowly progressing phenotypes 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
,44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189
https://doi.org/10.1186/1750-1172-8-189...
. In rapidly progressing phenotypes, this first phase is immediately followed by a period of progressive neurocognitive decline, emergence of behavioral difficulties, and sleep disturbances. In slowly progressing phenotypes, especially in MPS IIIC and MPS IIID, the initial mild cognitive impairment may remain stable until the teenage years or even adulthood 66. Valstar MJ, Marchal JP, Grootenhuis M, Colland V and Wijburg FA. Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J Rare Dis. 2011;6: 43. doi: 10.1186/1750-1172-6-43
https://doi.org/10.1186/1750-1172-6-43...

7. Bax MCO and Colville GA. Behaviour in muco-polysaccharide disorders. Arch Dis Child. 1995;73(1): 77-81. doi: 10.1136/adc.73.1.77
https://doi.org/10.1136/adc.73.1.77...
-88. Fraser J, Gason AA, Wraith JE and Delatycki MB. Sleep disturbance in Sanfilippo syndrome: a parental questionnaire study. Arch Dis Child. 2005;90(12): 1239-1242. doi:10.1136/adc.2004.065482
https://doi.org/10.1136/adc.2004.065482...
. Somatic features such as coarse facial features, hepatomegaly, and umbilical hernia might appear throughout the disease course but are usually less pronounced than in other types of MPS 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
,44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189
https://doi.org/10.1186/1750-1172-8-189...
. During the third and final phase of the disease, motor function begins to decline and patients eventually progress to a vegetative state. MPS III patients have a poor prognosis, with life expectancy varying between the second and third decade of life 99. Lavery C, Hendriksz CJ and Jones SA. Mortality in patients with Sanfilippo syndrome. Orphanet J Rare Dis. 2017;12: 168. doi:10.1186/s13023-017-0717-y
https://doi.org/10.1186/s13023-017-0717-...
. However, life expectancy can range between the fourth and fifth decade for the slowly progressing phenotype in MPS IIIB 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
. Currently, no specific treatment option for MPS III exists, but several therapeutics are in clinical development 1010. Aoyagi-Scharber M, Crippen-Harmon D, Lawrence R, et al. Clearance of heparan sulfate and attenuation of CNS pathology by intracerebroventricular BMN 250 in Sanfilippo type B mice. Mol Ther Methods Clin Dev. 2017; 6:43-53. doi: 10.1016/j.omtm.2017.05.009
https://doi.org/10.1016/j.omtm.2017.05.0...
,1111. Gilkes JA, Bloom MD and Heldermon CD. Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10. Gene Ther. 2016;23(3):263-271. doi: 10.1038/gt.2015.111
https://doi.org/10.1038/gt.2015.111...
. These therapeutics are expected to result in optimal patient outcomes when initiated before neurological damage has occurred. This is supported by findings in MPS I, where hematopoietic stem cell transplantation can preserve cognitive development when performed before the onset of severe developmental deterioration 1212. Souillet G, Guffon N, Maire I, et al. Outcome of 27 patients with Hurler’s syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31(12): 1105-1117. doi:10.1038/sj.bmt.1704105
https://doi.org/10.1038/sj.bmt.1704105...
,1313. Poe MD, Chagnon SL and Escolar ML. Early treatment is associated with improved cognition in Hurler syndrome. Ann Neurol. 2014;76(5):747-753. doi:10.1002/ana.24246
https://doi.org/10.1002/ana.24246...
. Hence, it is becoming increasingly important to identify patients with MPS III as early as possible.

Diagnostic Delay of MPS III

Despite the importance of early diagnosis, diagnostic delays of more than 2 years are not uncommon in the MPS III population 44. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis. 2013; 8:189. doi:10.1186/1750-1172-8-189
https://doi.org/10.1186/1750-1172-8-189...
,1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
https://doi.org/10.1007/s10545-013-9661-...

15. Kuiper GA, Meijer OLM, Langereis EJ and Wijburg FA. Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications. Orphanet J Rare Dis. 2018;13:2. doi:10.1186/s13023-017-0733-y
https://doi.org/10.1186/s13023-017-0733-...
-1616. Vieira T, Schwartz I, Muñoz V, et al. Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis? Am J Med Genet A. 2008;146A(13):1741-1747. doi:10.1002/ajmg.a.32320
https://doi.org/10.1002/ajmg.a.32320...
. Studies, mainly including MPS IIIA patients, have shown that in 40.0% to 67.7% of children, initial symptoms appear before the age of 12 months. Common initial signs were sleep disturbances, behavioral abnormalities, speech delay, dysmorphology, and hearing loss 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
https://doi.org/10.1007/s10545-013-9661-...
,1717. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007;120(5):e1255-e1261. doi:10.1542/peds.2007-0282
https://doi.org/10.1542/peds.2007-0282...
. Nevertheless, recent data from a study conducted in The Netherlands demonstrated that the median age at diagnosis remains 62 months (range 20-522 months). The diagnostic age was dependent on the disease phenotype, with rapidly progressing patients being diagnosed at a significantly younger age (mean age 54 months) than slowly progressing patients (mean age 71 months). In addition, the diagnostic delay, defined as the time between the first medical specialist visit and final diagnosis of MPS III, has not changed over the last 30 years (1988-2017). Although rapidly progressing patients were diagnosed earlier than slowly progressing patients, the median diagnostic delay was 33 months for both phenotypes 1515. Kuiper GA, Meijer OLM, Langereis EJ and Wijburg FA. Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications. Orphanet J Rare Dis. 2018;13:2. doi:10.1186/s13023-017-0733-y
https://doi.org/10.1186/s13023-017-0733-...
. The diagnostic delay may be due to poor disease awareness caused by the rarity of the disease, the absence or mild presentation of somatic symptoms, and the symptoms of the neurological progression (e.g., speech delay and behavioral problems) being similar to commonly seen developmental problems in the general population 1515. Kuiper GA, Meijer OLM, Langereis EJ and Wijburg FA. Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications. Orphanet J Rare Dis. 2018;13:2. doi:10.1186/s13023-017-0733-y
https://doi.org/10.1186/s13023-017-0733-...
. Furthermore, MPS III is not included in newborn screening programs and is often misdiagnosed as other developmental disorders such as idiopathic developmental delay, attention deficit hyperactivity disorder (ADHD), or autism spectrum disorder 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
,1818. Wolfenden C, Wittkowski A, Jones SA, Rust S and Hare DJ. Autism spectrum disorder symptomatology in children with mucopolysaccharide disease type III. Br J Learn Disabil. 2019;47:5-11. doi:10.1111/bld.12248
https://doi.org/10.1111/bld.12248...
,1919. Shapiro E, King K, Ahmed A, et al. The neurobehavioral phenotype in mucopolysaccharidosis type IIIB: an exploratory study. Mol Genet Metab Rep. 2016;6:41-47. doi:10.1016/j.ymgmr.2016.01.003
https://doi.org/10.1016/j.ymgmr.2016.01....
.

Besides primary care physicians and pediatricians, metabolic geneticists, orthopedic surgeons, ear-nose-throat specialists, audiologists, pediatric neurologists, and developmental specialists may be involved in the diagnostic journey of MPS III patients 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
. Although campaigns and initiatives to create more disease awareness among physicians and parents have been launched, reducing the diagnostic delay of MPS III remains a major challenge 2020. Cure Sanfilippo Foundation. https://curesff.org/
https://curesff.org/...
,2121. Sanfilippo Children’s Foundation. https://www.sanfilippo.org.au/
https://www.sanfilippo.org.au/...
.

Workshop Objective and Approach

Here, we present the findings from a workshop held in December 2018 attended by an international multidisciplinary group of 13 specialists and three parents of MPS III patients. The group of specialists consisted of four specialists with extensive expertise in MPS, including three experts in (neurodevelopmental) pediatrics and one expert in clinical genetics and neurogenetics, two geneticists/lab directors, and seven specialists with expertise in clinical psychology, autism, speech pathology, clinical audiology, pediatric neurology, developmental pediatrics, and social sciences/bioethics. A panel discussion with the latter group of specialists aimed to identify signs and symptoms that could distinguish MPS III from other developmental disorders. In addition, the importance of including early parental concerns in the clinical setting was discussed. Following the discussions, an expert system approach 2222. Escolar ML, Poe MD, Martin HR and Kurtzberg J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics. 2006;118:e879-889. doi:10.1542/peds.2006-0747
https://doi.org/10.1542/peds.2006-0747...
was applied to select the most important early signs and symptoms that should be tested in an MPS III early diagnosis algorithm aiming at reducing the average diagnostic age of MPS III patients to less than 2 years. For this purpose, the medical history, developmental milestones, and diagnostic pathways of different MPS III clinical cases were scored by the experts and parents on a 5-point scale according to the degree of suspicion for MPS III. The most important early signs and symptoms that should drive further testing for MPS III were defined by consensus generation and ranked according to importance based on the scoring of the clinical cases and clinical experience. Afterwards, the identified early signs and symptoms were supported by existing literature, if available.

Workshop Outcome

Inclusion of Parental Concerns Into the Development of an MPS III Diagnostic Algorithm

To accelerate diagnosis of MPS III, it is crucial to identify early concerns raised by parents and to establish which hurdles they might have in communicating these effectively to a healthcare provider. There is evidence that parental concerns about their child’s development are predictive of later developmental deficits in more than 80% of the cases 2323. Lurio JG, Peay HL and Mathews KD. Recognition and management of motor delay and muscle weakness in children. Am Fam Physician. 2015; 91(1): 38-44. https://www.aafp.org/afp/2015/0101/p38.html
https://www.aafp.org/afp/2015/0101/p38.h...
. Studies in the autism field have demonstrated that parents often express concerns before receiving a diagnosis, emphasizing the need for healthcare providers to seriously elicit parental concerns 2424. Richards M, Mossey J and Robins DL. Parents’ concerns as they relate to their child’s development and later diagnosis of autism spectrum disorder. J Dev Behav Pediatr. 2016;37(7):532-540. doi:10.1097/dbp.0000000000000339
https://doi.org/10.1097/dbp.000000000000...
,2525. Guinchat V, Chamak B, Bonniau B, et al. Very early signs of autism reported by parents include many concerns not specific to autism criteria. Res Autism Spectr Disord. 2012;6: 89-601. doi:10.1016/j.rasd.2011.10.005
https://doi.org/10.1016/j.rasd.2011.10.0...
.

A major challenge with parental concerns is that they are often diffuse and difficult for healthcare providers to pursue. An example of an initial concern of parents of children diagnosed with MPS III was “he has a lot of thick hair”, which in hindsight might have been related to hirsutism. How inclusion of parental concerns in the diagnostic pathway can be promoted is illustrated in the field of muscle weakness disorders, including Duchenne and Becker, congenital muscular dystrophies, and spinal muscular atrophy 2626. National Task Force for Early Identification of Childhood Neuromuscular Disorders. Child Muscle Weakness. https://www.childmuscleweakness.org/
https://www.childmuscleweakness.org/...
. To prompt early diagnosis of these diseases, pre-diagnostic experiences of parents presenting their earliest concerns to their healthcare providers are described on a website, ChildMuscleWeakness.org 2626. National Task Force for Early Identification of Childhood Neuromuscular Disorders. Child Muscle Weakness. https://www.childmuscleweakness.org/
https://www.childmuscleweakness.org/...
. Reliable patient websites can be extremely helpful for parents as an initial source of information and can facilitate early diagnosis by including the parental voice.

Another challenge with parent-reported data is retrospective bias due to incorrect recall of signs and symptoms. Electronic medical records may also not adequately document early signs and symptoms reported by parents, and therefore do not always allow a robust assessment of the early developmental trajectory. In addition, parents might not be willing to seek a diagnosis and may downplay initial (unspecific) signs because they are unable to cope with their child’s symptoms, particularly early in the disease course. Education of parents, caregivers, and physicians on early signs and symptoms of MPS III can help to distinguish “normal” from “clinically significant” parental concerns.

Furthermore, experience with the ChildMuscleWeakness.org program revealed that the broadest reasonable range of possible disorders should be included under a parent-reported assessment due to overlap of early signs with other conditions, the rarity of each diagnosis, and the increased ability to capture primary care provider attention with education about a related set of disorders with a much higher prevalence. More specifically, differential diagnosis of MPS III should be part of the diagnostic algorithms of other developmental disorders such as ADHD, hearing loss, and autism spectrum disorder. By implementing MPS III signs and symptoms into the differential diagnosis of other developmental disorders, providers are more likely to consider MPS III in their differential diagnoses.

Early MPS III Signs and Symptoms Before the Onset of Developmental Delay

In line with the goal of diagnosing neonates and infants before the onset of neurological damage, Table 1 summarizes a list of early signs and symptoms, identified during the workshop, that might become apparent before the age of 1 year. These signs and symptoms are believed to warrant referral in a timely manner and to shorten the diagnostic trajectory of MPS III patients.

Table 1.
Early signs and symptoms of MPS III patients identified by the experts and parents through the expert system approach. The experts’ observations were supported by existing medical literature, if available.

Some of these early signs and symptoms, such as diarrhea, are rather nonspecific and do not facilitate differential diagnosis, while other symptoms such as coarse facial features, persistent hirsutism and synophrys, accelerated growth during the 1st year of life, and macrocephaly are more characteristic of MPS III 11. Andrade F, Aldámiz-Echevarría L, Llarena M and Couce ML. Sanfilippo syndrome: Overall review. Pediatr Int. 2015; 57(3):331-338. doi:10.1111/ped.12636
https://doi.org/10.1111/ped.12636...
,1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
https://doi.org/10.1007/s10545-013-9661-...
,2727. Muschol NM, Pape D, Kossow K, et al. Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III). Orphanet J Rare Dis. 2019;14:93. doi:10.1186/s13023-019-1065-x
https://doi.org/10.1186/s13023-019-1065-...
. Part of the signs and symptoms that were identified, including behavioral problems, speech regression, coarse facial features, gastro-intestinal problems, mouthing, sensorineural hearing loss, hip dysplasia, and sleep disturbances, might only occur after the age of 1 year, especially in patients with a more slowly progressing disease.

Behavioral problems and speech regression often resemble ADHD-like behaviors or autism respectively, resulting in delayed diagnosis of MPS III due to misdiagnosis, which can be even more delayed when symptomatic treatment initially provides some relief of these symptoms 22. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013;102(5):462-470. doi:10.1111/apa.12169
https://doi.org/10.1111/apa.12169...
,2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007
https://doi.org/10.1016/j.jpeds.2014.01....
. However, subtle behavioral differences supporting the differential diagnosis do exist and the autistic-like symptoms of MPS III patients differ from those seen in children with autism spectrum disorder in several ways. One subtle difference that might distinguish MPS III from autism spectrum disorder is the initial period of normal development followed by the acquisition of autism symptoms during first 3 to 4 years of life in patients with MPS III 2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007
https://doi.org/10.1016/j.jpeds.2014.01....
. This regression has also been reported in 16% to 50% of patients with autism spectrum disorder but appears to occur earlier, between the first and second birthday 2929. Ozonoff D, Heung K, Byrd R, et al. The onset of autism: patterns of symptom emergence in the first years of life. Autism Res. 2008;1(6):320-328. doi:10.1002/aur.53
https://doi.org/10.1002/aur.53...
. Furthermore, MPS III children might preserve functional play skills while the play behavior of children with autism spectrum disorder can be more limited or non-functional and characterized by repetitive and restricted patterns. In addition, unlike many children with autism spectrum disorder, MPS III patients might initially develop robust joint attention skills, enjoy engaging in social interaction without anxiety, and easily adjust to changes in routine. The increase in anxiety seen in children with MPS III coincides with the speech regression and the inability to communicate and express themselves, which can lead to frustration and aggressive behavior. Although autistic-like behaviors do exist in some MPS III children, the most common and typical restrictive and repetitive behavior present in children with MPS III is mouthing or oral fixation. The absence of other restrictive and repetitive behaviors might differentiate MPS III from autism spectrum disorder 2828. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007
https://doi.org/10.1016/j.jpeds.2014.01....
. Early presentation of macrocephaly in children with MPS III, sometimes as early as birth, might further distinguish both disorders 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
https://doi.org/10.1007/s10545-013-9661-...
. Another MPS III-specific, albeit later sign, is the regression of speech, which usually precedes the deterioration of motor function 1717. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007;120(5):e1255-e1261. doi:10.1542/peds.2007-0282
https://doi.org/10.1542/peds.2007-0282...
. The trajectory of speech regression appears to be specific for MPS III and is characterized by a gradual loss of language. In addition, hearing loss is often observed early on in MPS III while being absent in autism spectrum disorder 1414. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis. 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
https://doi.org/10.1007/s10545-013-9661-...
.

As most signs and symptoms summarized in Table 1 are not exclusively presenting before the age of 1 year, consensus was reached on a final list of eight early presenting signs and symptoms in neonates and infants dependent on the likelihood that the particular signs or symptoms are MPS III-specific (Table 2). Each sign or symptom was attributed a score ranging from 1 to 3. A score of 1 corresponds to a rather unspecific sign while a score of 3 is considered to be highly characteristic of MPS III. Coarse facial features and persistent hirsutism or prominent thick eyebrows, which have previously been reported as MPS III-specific signs, should prompt referral to a metabolic physician and/or developmental specialist. Presence of both facial coarsening and prominent thick eyebrows before the age of 2 is illustrated in Figure 1, showing the progression of MPS III patients in comparison with their unaffected siblings. Breathing problems within the first week of life, frontal bossing and macrocephaly (i.e. head circumference above the 99th percentile), and an increased need for nursing were classified as having only some specificity for MPS III. Lastly, colic-like episodes and gastrointestinal discomfort, umbilical or inguinal hernia, and upper respiratory congestion are considered to be prevalent among neonates and infants. Screening for this combination of unspecific and specific signs and symptoms is anticipated to raise suspicion for MPS III as early as possible and to shorten the diagnostic journey of MPS III patients.

Table 2.
Final list of early MPS III signs and symptoms

Figure 1.
Early facial coarsening and presence of synophrys in MPS IIIB patients. (A) Left: progression of an MPS IIIB patient (upper panel) in comparison with her unaffected sibling (lower panel) at comparable ages. Right: comparison of the MPS IIIB patient (left) with her unaffected sibling (right) at different ages. (B & C) Progression of two MPS IIIB patients (upper panels) in comparison with their age-matched unaffected siblings (lower panels).

Early Diagnosis Algorithm - Future Perspectives and Barriers to Overcome

In order to validate the observations, the incidence of the early signs and symptoms summarized in Table 2 will be retrospectively and prospectively reviewed in clinical cases of MPS III, cases of developmental delay, and healthy controls. Some of the signs and symptoms might be eliminated when they fail to distinguish neonates and infants with MPS III from the healthy control group. Other signs and symptoms might be up-/down-rated when they are found to be more/less prevalent in young MPS III patients than initially anticipated. The ultimate goal is to develop an easy-to-use early diagnostic algorithm to be used mainly by primary care physicians and pediatricians as they are most likely to be consulted first by parents. Dependent on the MPS III suspicion score, follow-up, testing, and referral to a clinical geneticist or developmental specialist is recommended. Diagnostic testing for MPS III can be performed using a variety of samples depending on the available resources. Testing can include screening methods such as analysis of urinary GAGs, enzymatic analysis in blood or cultured fibroblasts, or genetic analysis of MPS III genes. Depending on the testing ordered, results are typically available within several weeks or a month 3030. Bodamer OA, Giugliani R, Wood T. The laboratory diagnosis of mucopolysaccharidosis III (Sanfilippo syndrome): A changing landscape. Mol Genet Metab. 2014;113(1-2):34-41. doi:10.1016/j.ymgme.2014.07.013
https://doi.org/10.1016/j.ymgme.2014.07....
.

Further recommendations of the multidisciplinary group to increase disease awareness among physicians not familiar with MPS III were to increase awareness of facial dysmorphisms and MPS III-like behaviors through videos and pictures. In addition, physicians should try to elicit parental concerns about their child’s development. It is expected that interest in MPS III and possibly newborn screening will increase once treatment options are available. However, until then, an early diagnosis algorithm could already be implemented into the differential diagnosis of other neurodevelopmental or genetic disorders, such as autism spectrum disorder.

Besides challenges associated with creating disease awareness and implementation of an early diagnosis algorithm, shortening referral times in healthcare will be a major hurdle for improving early diagnosis of MPS III. Waiting times between the first medical visit and an appointment with a metabolic geneticist or neurodevelopmental specialist can be as long as 18 months as recently determined in a cohort of Dutch MPS III patients 1515. Kuiper GA, Meijer OLM, Langereis EJ and Wijburg FA. Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications. Orphanet J Rare Dis. 2018;13:2. doi:10.1186/s13023-017-0733-y
https://doi.org/10.1186/s13023-017-0733-...
. Therefore, primary care physicians and pediatricians should consider an accelerated referral after profound suspicion of MPS III based on the early diagnosis algorithm. Ultimately, newborn screening will be needed to diagnose MPS III before symptoms, but until this is available, early diagnosis is necessary for optimal outcomes of novel therapies.

Conclusion

MPS III is a rare inherited metabolic disease with poor prognostic outcomes due to severe neurological deficits and the absence of curative treatment options. Although new treatment options for the disease are being developed, neurocognitive deterioration will likely only be prevented if treatment is initiated before the onset of developmental delay. The consensus list of early signs and symptoms presented here is a crucial step towards the development of an early diagnosis algorithm for patients with MPS III. This list was developed based on current evidence and experiences from a multidisciplinary group of MPS experts and MPS III parents. These observations can be retrospectively and prospectively validated with more in-depth analysis of the early development of MPS III patients. An early diagnostic algorithm developed based on these early signs and symptoms is expected to eventually shorten the diagnostic journey of MPS III patients until newborn screening is available for this disorder.

Abbreviations

ABR: auditory brainstem response; ADHD: attention deficit hyperactivity disorder; ENT: ear-nose-throat; GAGs: glycosaminoglycans; MPS: mucopolysaccharidosis.

Acknowledgements

The authors are grateful to Ismar Healthcare NV who provided medical writing assistance, which was funded by BioMarin Pharmaceutical Inc.

References

  • 1. Andrade F, Aldámiz-Echevarría L, Llarena M and Couce ML. Sanfilippo syndrome: Overall review. Pediatr Int 2015; 57(3):331-338. doi:10.1111/ped.12636
    » https://doi.org/10.1111/ped.12636
  • 2. Wijburg FA, Wegrzyn G, Burton BK and Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr 2013;102(5):462-470. doi:10.1111/apa.12169
    » https://doi.org/10.1111/apa.12169
  • 3. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 2011;50(Suppl 5): v4-v12.doi:10.1093/rheumatology/ker394
    » https://doi.org/10.1093/rheumatology/ker394
  • 4. Delgadillo V, O’Callaghan MDM, Gort L, Coll MJ and Pineda M. Natural history of Sanfilippo syndrome in Spain. Orphanet J Rare Dis 2013; 8:189. doi:10.1186/1750-1172-8-189
    » https://doi.org/10.1186/1750-1172-8-189
  • 5. Zelei T, Csetneki K, Voko Z and Siffel C. Epidemiology of Sanfilippo syndrome: results of a systematic literature review. Orphanet J Rare Dis 2018; 13(1):53. doi:10.1186/s13023-018-0796-4
    » https://doi.org/10.1186/s13023-018-0796-4
  • 6. Valstar MJ, Marchal JP, Grootenhuis M, Colland V and Wijburg FA. Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J Rare Dis 2011;6: 43. doi: 10.1186/1750-1172-6-43
    » https://doi.org/10.1186/1750-1172-6-43
  • 7. Bax MCO and Colville GA. Behaviour in muco-polysaccharide disorders. Arch Dis Child 1995;73(1): 77-81. doi: 10.1136/adc.73.1.77
    » https://doi.org/10.1136/adc.73.1.77
  • 8. Fraser J, Gason AA, Wraith JE and Delatycki MB. Sleep disturbance in Sanfilippo syndrome: a parental questionnaire study. Arch Dis Child 2005;90(12): 1239-1242. doi:10.1136/adc.2004.065482
    » https://doi.org/10.1136/adc.2004.065482
  • 9. Lavery C, Hendriksz CJ and Jones SA. Mortality in patients with Sanfilippo syndrome. Orphanet J Rare Dis 2017;12: 168. doi:10.1186/s13023-017-0717-y
    » https://doi.org/10.1186/s13023-017-0717-y
  • 10. Aoyagi-Scharber M, Crippen-Harmon D, Lawrence R, et al. Clearance of heparan sulfate and attenuation of CNS pathology by intracerebroventricular BMN 250 in Sanfilippo type B mice. Mol Ther Methods Clin Dev 2017; 6:43-53. doi: 10.1016/j.omtm.2017.05.009
    » https://doi.org/10.1016/j.omtm.2017.05.009
  • 11. Gilkes JA, Bloom MD and Heldermon CD. Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10. Gene Ther 2016;23(3):263-271. doi: 10.1038/gt.2015.111
    » https://doi.org/10.1038/gt.2015.111
  • 12. Souillet G, Guffon N, Maire I, et al. Outcome of 27 patients with Hurler’s syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant 2003;31(12): 1105-1117. doi:10.1038/sj.bmt.1704105
    » https://doi.org/10.1038/sj.bmt.1704105
  • 13. Poe MD, Chagnon SL and Escolar ML. Early treatment is associated with improved cognition in Hurler syndrome. Ann Neurol 2014;76(5):747-753. doi:10.1002/ana.24246
    » https://doi.org/10.1002/ana.24246
  • 14. Buhrman D, Thakkar K, Poe M and Escolar ML. Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis 2014;37(3):431-437. doi:10.1007/s10545-013-9661-8
    » https://doi.org/10.1007/s10545-013-9661-8
  • 15. Kuiper GA, Meijer OLM, Langereis EJ and Wijburg FA. Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications. Orphanet J Rare Dis 2018;13:2. doi:10.1186/s13023-017-0733-y
    » https://doi.org/10.1186/s13023-017-0733-y
  • 16. Vieira T, Schwartz I, Muñoz V, et al. Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis? Am J Med Genet A 2008;146A(13):1741-1747. doi:10.1002/ajmg.a.32320
    » https://doi.org/10.1002/ajmg.a.32320
  • 17. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 2007;120(5):e1255-e1261. doi:10.1542/peds.2007-0282
    » https://doi.org/10.1542/peds.2007-0282
  • 18. Wolfenden C, Wittkowski A, Jones SA, Rust S and Hare DJ. Autism spectrum disorder symptomatology in children with mucopolysaccharide disease type III. Br J Learn Disabil 2019;47:5-11. doi:10.1111/bld.12248
    » https://doi.org/10.1111/bld.12248
  • 19. Shapiro E, King K, Ahmed A, et al. The neurobehavioral phenotype in mucopolysaccharidosis type IIIB: an exploratory study. Mol Genet Metab Rep 2016;6:41-47. doi:10.1016/j.ymgmr.2016.01.003
    » https://doi.org/10.1016/j.ymgmr.2016.01.003
  • 20. Cure Sanfilippo Foundation. https://curesff.org/
    » https://curesff.org/
  • 21. Sanfilippo Children’s Foundation. https://www.sanfilippo.org.au/
    » https://www.sanfilippo.org.au/
  • 22. Escolar ML, Poe MD, Martin HR and Kurtzberg J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics 2006;118:e879-889. doi:10.1542/peds.2006-0747
    » https://doi.org/10.1542/peds.2006-0747
  • 23. Lurio JG, Peay HL and Mathews KD. Recognition and management of motor delay and muscle weakness in children. Am Fam Physician 2015; 91(1): 38-44. https://www.aafp.org/afp/2015/0101/p38.html
    » https://www.aafp.org/afp/2015/0101/p38.html
  • 24. Richards M, Mossey J and Robins DL. Parents’ concerns as they relate to their child’s development and later diagnosis of autism spectrum disorder. J Dev Behav Pediatr 2016;37(7):532-540. doi:10.1097/dbp.0000000000000339
    » https://doi.org/10.1097/dbp.0000000000000339
  • 25. Guinchat V, Chamak B, Bonniau B, et al. Very early signs of autism reported by parents include many concerns not specific to autism criteria. Res Autism Spectr Disord 2012;6: 89-601. doi:10.1016/j.rasd.2011.10.005
    » https://doi.org/10.1016/j.rasd.2011.10.005
  • 26. National Task Force for Early Identification of Childhood Neuromuscular Disorders. Child Muscle Weakness. https://www.childmuscleweakness.org/
    » https://www.childmuscleweakness.org/
  • 27. Muschol NM, Pape D, Kossow K, et al. Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III). Orphanet J Rare Dis 2019;14:93. doi:10.1186/s13023-019-1065-x
    » https://doi.org/10.1186/s13023-019-1065-x
  • 28. Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB and Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr 2014;164(5):1147-1151.e1. doi:10.1016/j.jpeds.2014.01.007
    » https://doi.org/10.1016/j.jpeds.2014.01.007
  • 29. Ozonoff D, Heung K, Byrd R, et al. The onset of autism: patterns of symptom emergence in the first years of life. Autism Res 2008;1(6):320-328. doi:10.1002/aur.53
    » https://doi.org/10.1002/aur.53
  • 30. Bodamer OA, Giugliani R, Wood T. The laboratory diagnosis of mucopolysaccharidosis III (Sanfilippo syndrome): A changing landscape. Mol Genet Metab 2014;113(1-2):34-41. doi:10.1016/j.ymgme.2014.07.013
    » https://doi.org/10.1016/j.ymgme.2014.07.013
  • 31. Zanetti D, Vezzani M, Di Berardino F, et al. Characterization of hearing loss in children with mucopolysaccharidosis. An Excursus into Hearing Loss. London, UK: IntechOpen; 2018.
  • 32. Oussoren E, Mathijssen IMJ, Wagenmakers M, et al. Craniosynostosis affects the majority of mucopolysaccharidosis patients and can contribute to increased intracranial pressure. J Inherit Metab Dis 2018;41(6):1247-1258. doi:10.1007/s10545-018-0212-1
    » https://doi.org/10.1007/s10545-018-0212-1
  • 33. Yodoshi T and Hurt TL. Avoiding diagnostic delay for mucopolysaccharidosis IIIB: do not overlook common clues such as wheezing and otitis media. BMJ Case Rep 2018;2018:bcr-2018-224412. doi:10.1136/bcr-2018-224412
    » https://doi.org/10.1136/bcr-2018-224412
  • 34. Roberts AL, Howarth GS, Liaw WC, et al. Gastrointestinal pathology in a mouse model of mucopolysaccharidosis type IIIA. J Cell Physiol 2009;219(2):259-64. doi:10.1002/jcp.21682
    » https://doi.org/10.1002/jcp.21682
  • 35. Bowling K, Hart N, Cox P and Srinivas G. Management of paediatric hernia. BMJ 2017;359:j4484. doi:10.1136/bmj.j4484
    » https://doi.org/10.1136/bmj.j4484
  • 36. Lin HY, Chuang CK, Lee CL, et al. Mucopolysaccharidosis III in Taiwan: natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21-year period. Am J Med Genet A 2018;176(9): 1799-1809. doi:10.1002/ajmg.a.40351
    » https://doi.org/10.1002/ajmg.a.40351
  • 37. de Ruijter J, Broere L, Mulder MF, et al. Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). J Inherit Metab Dis 2014;37(3):447-454. doi:10.1007/s10545-013-9658-3
    » https://doi.org/10.1007/s10545-013-9658-3
  • 38. Akhtar N and Gernsbacher MA. Joint attention and vocabulary development: a critical look. Lang Linguist Compass 2007;1(3):195-207. doi:10.1111/j.1749-818X.2007.00014.x
    » https://doi.org/10.1111/j.1749-818X.2007.00014.x
  • 39. White KK, Karol LA, White DR and Hale S. Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III). J Pediatr Orthop 2011;31(5):594-598. doi:10.1097/bpo.0b013e31821f5ee9
    » https://doi.org/10.1097/bpo.0b013e31821f5ee9
  • 40. de Ruijter J, Maas M, Janssen A and Wijburg FA. High prevalence of femoral head necrosis in Mucopolysaccharidosis type III (Sanfilippo disease): a national, observational, cross-sectional study. Mol Genet Metab 2013;109(1):49-53. doi:10.1016/j.ymgme.2013.03.004
    » https://doi.org/10.1016/j.ymgme.2013.03.004

  • Funding

    This work was supported by BioMarin Pharmaceutical Inc. and Allievex.
  • Ethics and Consent

    Consent was obtained to publish the patients’ pictures.

Publication Dates

  • Publication in this collection
    15 June 2020
  • Date of issue
    2020

History

  • Received
    27 Feb 2020
  • Reviewed
    23 Apr 2020
  • Accepted
    28 Apr 2020
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br