Development and Longitudinal Neurocognitive Functioning in Mucopolysaccharidosis type IIIC: A Case Study

doi:10.21203/rs.3.rs-5240993/v1

This case study presents a comprehensive analysis of the neurocognitive, medical, and developmental functioning of a 9-year-old girl diagnosed with mucopolysaccharidosis type IIIC (MPS IIIC). Genetic testing revealed a homozygous pathogenic variant of the HGSNAT gene (c.1872C>A), typically associated with severe neurodegeneration. However, her clinical presentation has been milder compared to the expected progression, based on her genetic profile and residual enzyme levels. This study incorporates data from various assessments, including yearly intelligence quotient (IQ) scores over the past four years, adaptive skills evaluated by parents and two teachers, neuropsychological functioning, MRI brain imaging, and extensive medical tests. The results revealed that the child maintains the majority of her cognitive skills at a stable level, except for a marked decline in working memory. The study highlights the complexity and variability in the progression of MPS IIIC, emphasizing the need for early diagnosis, regular monitoring, and a multidisciplinary approach. This case highlights the need to consider individual variability in MPS IIIC progression, even when genetic and biochemical markers suggest a more severe course.

lysosomal storage disorders

Sanfilippo disease

neurodevelopmental disorders

neurocognitive assessment

HGSNAT gene

Mucopolysaccharidosis type IIIC (MPS IIIC ), also known as Sanfilippo syndrome type C, is a rare, autosomal recessive lysosomal storage disorder, characterized predominantly by severe neurological symptoms (Neufeld and Muenzer 2001). In this diseases, the deficiency lies in the enzyme acetyl-CoA:α-glycosaminide acetyltransferase, the product of the HGSNAT gene (Ruijter et al. 2007; Valstar et al. 2008; Wijburg et al. 2013).

Children with MPS IIIC experience severe intellectual and cognitive impairments such as severe deficits in memory, attention, and language skills, which are exacerbated by the neurodegenerative nature of the disorder (Shapiro et al. 2017). First symptoms occur usually between 3 and 5 years of life and the progression of MPS IIIC can lead to a severe neurological decline (Ruijter et al. 2007). Initial symptoms may include delayed speech, increased hyperactivity, and progressive sleep disturbances. Intellectual development is significantly affected, with intelligence quotient (IQ) scores often falling below average as the disease progresses (Shapiro et al. 2017). Other symptoms, such as hyperactivity, aggression, anxiety and sleep disturbances (e.g. difficulty settling down to sleep, frequent night-time awakenings, early morning waking, reduced overall sleep quality) occur in more than 90 % of these patients (Wijburg et al. 2013), further complicating the management of the disease (Shapiro et al. 2017). This can lead to a cycle where poor sleep contributes to worsening of behavioral problems, further complicating management strategies.

Sanfilippo syndrome type C presents a significant challenge in pediatric neurology due to its gradual progression and lack of curative treatments (Valstar et al. 2008; Wijburg et al. 2013; Wiśniewska et al. 2022). The combination of clinical examination, biochemical testing, neuropsychological assessment and genetic analysis is essential for accurate diagnosis and designing of appropriate support mechanisms (Valstar et al. 2008). Here we present an MPS IIIC patient revealing relatively mild phenotype despite the presence of a genetic variant identified previously as coupled with the severe symptoms.

2.1 Developmental and medical context

The patient was born 10 March, 2015 and was diagnosed with Sanfilippo C after genetic tests at the age of 8. Urinary tests showed increased excretion of heparan sulfate (642mg/g creatinine; N 116 +/- 70) , and enzyme activity tests (residual HGSNAT enzyme activity in leukocytes below 0.1% of the norm) confirmed MPS IIIC. Physical examination showed slight facial dysmorphism, skeletal abnormalities, and normal organ volume. Brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG)and cardiac ultrasound pictures were normal. Ophthalmological exams revealed astigmatism and hyperopia.

The family history showed healthy, non-consanguineous parents. The patient was born via C-section (due to a previous procedure), with green amniotic fluid. Birth weight: 3650 g, length: 57 cm, Apgar score: 10. Inflammatory markers were low, the hyperbilirubinemia was diagnosed (the highest totally bilirubin level was 10.26 mg/dl), the newborn did not require any treatment. Early psychomotor development was within normal limits. The patient sat by 8th months, walked by 13th months, and spoke first words around age 1.

She started preschool at 2.5 years and was toilet trained. She had recurrent respiratory infections since 18 months. Adenotonsillar hypertrophy and conductive hearing loss were diagnosed, adenotonsillectomy procedure was done at age 4. At age 3, the patient began experiencing allergies. Around the same time, brittle hair was also observed.

From age 6, she experienced paroxysmal pain in the upper and lower abdomen, which resolved after vomiting. The recurring diarrhea was also reported – the girl passed stool 3-4 times a day with some undigested food remains. The ultrasound volume of the abdominal organs and results of gastroscopy and colonoscopy were normal. The urea test for the presence of Helicobacter pylori was negative. The histopathological examination has shown features of non-eosinophilic esophagitis. The 24-hour pH monitoring revealed gastroesophageal reflux disease. Her facial features (coarse face) and stiff hair were observed during hospitalization.

The Whole Genome Sequencing showed that the patient is homozygous for the HGSNAT c.1872C>A (p.Tyr624Ter) variant which is considered pathological due to the non-sense mutation. This type of mutation results in shortening of the length of the protein, thus making any residual activity of the enzyme unlikely. On the other hand, the HGSNAT gene product, heparan-□-glucosaminide-N-acetyltransferase (or acetyl-CoA:α-glycosaminide acetyltransferase), is a polypeptide consisting of 663 amino acid residues. Therefore, one might speculate that a lack of the C-terminal segment of 20 amino acids (some 3% of the polypeptide total length) might still allow for possessing a significant residual activity of the affected enzyme. However, biochemical tests indicated a severe deficiency in the activity of this enzyme in leukocytes of the described patient (0.06 nmol/mg protein/18hours, with the norm range of 40-130 nmol/mg protein/18 hours), showing that the non-sense mutation c.1872C>A caused a drastic reduction in the enzymatic activity. Therefore, either the effects of the genetic background or environmental conditions or both are perhaps responsible for this attenuated course of the disease in this patient. Since the age of 7, the patient has been suffering from recurrent headaches occurring on average once a week without vomiting.

In the clinical examination at the age of 8, the following parameters were measured: height 131 cm (70thcentile), weight 28 kg (75th centile), head circumference 52 cm (50th centile). Physical examination demonstrated slightly facial dysmorphism (coarse face), abundant hair, skeletal abnormalities: valgus feet and knees, hyperlordosis and slightly stiffnes of hand joints. The volume of internal organs in the ultrasound examination and the cardiac ultrasound were normal. Routine laboratory analysis demonstrated decreased level of vitamin D (20 ng/ml,; N: 30-50 ng/ml), the rest test results were normal.

Brain MRI showed no abnormalities. The EEG result was normal. Ophthalmological examination showed no signs of retinopathy, astigmatism. Hyperopia was diagnosed. The patient requires spectacle correction. In hearing tests, impedance audiometry and otoacoustic emissions were normal.

From the age of 8, parents independently decided to supply genistein at a dose of 4.5 g per day, no adverse effects were observed.

2.2 Psychological functioning

In addition, to her physical and medical symptoms, the patient's psychological functioning has also been evaluated to provide a more comprehensive understanding of her condition.

The child was diagnosed with the intellectual disability. However, her cognitive functioning profile displayed a harmonic development of mental skills. She was very impulsive and had significant difficulty focusing on tasks. Additionally, she had difficulties in inhibiting some of her reactions. Sometimes she struggled to adapt her behavior to social norms (e.g. she may ask socially inappropriate questions due to difficulties with impulse control). She established good rapport with diagnostician and was enthusiastic.

The diagnosis of intellectual abilities was done using WISC-V (Stańczak et al. 2020) at age 6 and SB-5 (Roid et al. 2017) at ages 7, 8, 9 years. The results are reported in the Table 1.

Table 1. Results of diagnosis of intellectual abilities in the patient.

Date	09-03-2021	06-20-2022		04-13-2023		04-13-2024
Tool	WISC-V	SB-5		SB-5		SB-5
Age	6;6	7;3		8;1		9;1
	IQ	IQ	DA	IQ	DA	IQ	DA
Total	84	74 (70-80)	5;3	60 (56-66)	5;3	55 (52-62)	5;3
NV	92	78 (73-86)	5;7	63 (59-72)	5;3	59 (55-69)	5;3
V	81	73 (70-80)	5;3	61 (57-71)	4;11	57 (54-67)	5;3
FR		76 (71-89)	5;7	67 (63-82)	5;3	70 (66-84)	5;8
K		83 (77-93)	5;3	71 (67-83)	4;11	71 (67-83)	5;3
QR		79 (74-91)	5;8	71 (67-83)	5;8	57 (54-71)	5;3
VS		64 (61-79)	4;7	64 (61-79)	5;3	64 (61-79)	5;7
WM		87 (80-98)	7;0	57 (55-73)	4;7	50 (49-67)	4;6

Adaptive skills were measured with Adaptive Behavior Assessment System, 3rd edition (ABAS-3) (Otrębski et al. 2019) at age 9 in the home environment (from the perspective of both parents) and the school environment (from the perspective of two teachers). Detailed scores are presented in the supplementary materials. The girl obtained scores of 85 and 83, respectively, when the questionnaires were filled out by her mother and father. However, when they were filled out by teachers the scores of adaptive behaviors were 59 and 71.

2.3 Neuropsychological Diagnosis

Experimental diagnostic tests were conducted with the child using the Neuropsychological Child Diagnosis toolkit (Borkowska et al. 2018). A qualitative assessment of the performed tests are presented in Table 2.

Table 2. Summary of the data obtained in the neuropsychological assessment of the patient.

Neuropsychological domains		Results/ observations
Praxis	Oral praxis	The girl planned and executed correctly the non-habitual motor movements involved in speech production after demonstration and on command. Speech was slightly slurred.
	Postural praxis	Difficulties arose in the area of movement planning and the physical positioning of the palms in non-standard positions (even if she arranged the fingers with her other hand).
	Dynamic praxis	Executed the subsequent elements correctly but not smoothly, with pauses and extra hand movements before completing the correct gesture.
Somesthesis	Touch discrimination	Difficulties with detecting soft materials with the left hand. Correct identification of rough materials and distinction between warm and cold (with both hands).
	Tactile localization	The localization of stimuli from the body occurring on both the right and left sides (on the shoulders and cheeks) occurred without disturbances.
	Tactile discrimination	Distances of 3, 5, and 7 cm proceeded without disturbances for the right hand and with erroneous differentiation of the stimuli at the smallest distance (3 cm) on the left hand
	Proprioception	Difficulties in this area (also with the dominant hand) were observed, and challenges in completing the task were also due to difficulties with response inhibition and sustaining attention.
Auditory processing		No differences detected in the sound of softened syllables (“sa-sia”) or those differing by similarly sounding letters (“f-w”) correctly located the source of the sound on both right and left sides, as well as the sound presented bilaterally
Visuospatial working memory		Difficulties with maintenance of the pattern during execution, she maintained the pattern for 3-5 seconds of reproduction than errors occurred

It is worth mentioning that the child completed all subtests impulsively. The execution time was relatively short, but many errors occurred, including omissions and perseverations (characteristic of children with hyperactivity). After a short engagement in every task (about 30-40 seconds), the girl lose attention, and report fatigue

The results In this case study we presented a medical, molecular, and neuropsychological data of the 9 years old girl with MPS IIIC, one of the less common subtype of MPS III (Węgrzyn et al. 2010). A case of a patient with the same type of mutation HGSNAT c.1872C>A (p.Tyr624Ter), to the best of our knowledge, was never reported before. The presence of this severe mutation in a homozygous state and very low residual enzyme activity are surprising in the light a relatively mild phenotype of the patient.

The occurrence of first symptoms are commonly reported between the age 3 and 5 (Wijburg et al. 2013), meanwhile in the investigated patient, the first symptom was headache reported at the age of 6.

During the neuropsychological assessment, typical impulsive behaviors, hyperactivity, and difficulties with maintaining attention (Węgrzyn et al. 2010) were observed; however, they were not severe enough to require stopping the examination. The results in the field of praxis suggested that she could met some challenges in adapting her motor actions to novel tasks, which is critical for effective communication and interaction. The lack of fluidity in her movements may reflect difficulties with coordinating complex behaviors, which can impact her ability to engage in activities requiring fine and gross motor skills. Challenges in body awareness and spatial orientation were also noted. The discrepancy between right and left hand may suggests a potential lateralization of sensory processing deficits. The limitations in short-term visual memory capacity can affect her ability to follow multi-step instructions or engage in tasks requiring sustained attention. Difficulties with auditory processing are consistent with the child's previous challenges in this area, as well as with reports of auditory issues in children with MPS III (Shapiro et al. 2017). However, the profile of neurocognitive functioning is mild compared to other reported cases of MPS III (Ruijter et al. 2007).

The IQ score calculated for a specific age decreased (from 84 at the age 6;6 to 55 at the age 9;1). However, an analysis of the raw scores shows that in most of the measured areas, the patient has not lost the skills she had acquired. An analysis using raw scores showed the girl's developmental age (DA) remained stable, except for working memory, which decreased significantly between the ages of 7 and 8 (from 7;0 to 4;11). The decline of cognitive functioning in children with MPS III is not uniform across all patients; some may retain certain cognitive abilities longer than others and some of them reach a developmental plateau at certain age (Nijmeijer et al. 2019). Deficits in working memory have previously been reported in children with MPS III (Valstar et al. 2011). It is also worth noting that this aspect of cognitive functioning is characteristic of children with ADHD and other attention-related deficits (Wiśniewska et al. 2022). Additionally, the baseline result (measured at age 6) indicates a broadly understood intellectual norm (intelligence lower than average). At the age of 6 and at this level of enzymes usually an intellectual disability has been reported (Shapiro et al. 2017).

Furthermore, managing the cognitive and behavioral symptoms of MPS IIIC is challenging due to the complexity and variability of the disease. Behavioral issues often lead to initial misdiagnoses of conditions like autism or ADHD, complicating the clinical picture (Wiśniewska et al. 2022). The progressive nature of cognitive decline necessitates regular monitoring and a comprehensive approach to care that includes neurocognitive assessments and supportive therapies to address the wide range of symptoms exhibited by these children (Valstar et al. 2011).

The cognitive difficulties are mirrored by neuroimaging findings that show cerebral and cerebellar atrophy, ventriculomegaly, and changes in the volumes of specific brain regions such as the amygdala and hippocampus. These structural changes correlate with the cognitive and behavioral symptoms observed in these children (Heon-Roberts et al. 2020). However, the patient’s brain MRI showed no abnormalities.

Case studies highlight the variability in the progression of adaptive skills among children with MPS IIIC. For instance, a national observational study in the Netherlands indicated that children with MPS IIIC exhibit severe impairments in adaptive behaviors by age 10, often losing previously acquired skills (Ruijter et al. 2007). Furthermore, these children frequently display severe behavioral issues such as hyperactivity, aggression, and sleep disturbances, which compound the challenges in managing their adaptive skill development. The reported patient met some of these problems such as some symptoms of mild hyperactivity, attention deficits, difficulties with impulse control and relatively mild inappropriate social behaviors. However, she do not present autistic like disorders or sleep disturbances.

Parents of children with MPS often perceive their child's condition and its impacts differently than external observers such as healthcare professionals and educators. Firstly, external assessments may capture aspects of the child's experience that parents could overlook or misinterpret. However, in the case of this patient, the parents' assessments were consistent with each other, while the two teachers rated the child's adaptive skills differently (59 and 71). It is possible that the subjective perception of a child displaying hyperactivity, inattention, and frequent impulsive or socially inappropriate behaviors may influence the evaluation of their abilities (Valstar et al. 2008).

Mucopolysaccharidosis type IIIC (MPS IIIC) represents a significant challenge in paediatric neurology due to its progressive and severe neurological manifestations (Wijburg et al. 2013). The current lack of curative treatments underscores the importance of early diagnosis and comprehensive supportive care to manage symptoms and improve the quality of life. The complexity of MPS IIIC highlights the need for a multidisciplinary approach to care, integrating advancements in medical research with clinical practice to optimize outcomes for patients. Furthermore, the ongoing development of international patient registries and collaborative research networks is critical for advancing our understanding of MPS IIIC.

Funding

This work was supported by National Science Centre Poland, grant no. 2022/45/N/HS6/00992, awarded to Paulina Anikiej-Wiczenbach.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

The authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

CRediT authorship contribution statement

All authors contributed to the study conception and design. The first draft of the manuscript was written by Paulina Anikiej-Wiczenbach and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of Gdansk (no.38/2024/WNS).

Consent to participate and publish

Written informed consent was obtained from the parents, and informed consent was obtained from the child participating in the study.

Borkowska AR, Daniluk B. Neuropsychologiczna Diagnoza Dziecka. Warszawa: Pracownia Testów Psychologicznych i Pedagogicznych SEBG; 2018.
Heon-Roberts R, Nguyen ALA, Pshezhetsky AV. Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease. J Clin Med. 2020;9(2):344. https://doi.org/10.3390/jcm9020344
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2001. p. 3421-52.
Nijmeijer SCM, van den Born LI, Kievit AJA, et al. The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype. Orphanet J Rare Dis. 2019;14:249. https://doi.org/10.1186/s13023-019-1232-0
Otrębski W, Domagała-Zyśk E, Sudoł A. ABAS-3 System Oceny Zachowań Adaptacyjnych. Wyd. 3. Podręcznik polski. Warszawa: Pracownia Testów Psychologicznych Polskiego Towarzystwa Psychologicznego; 2019.
Roid GH, Sajewicz-Radtke U, Radtke BM, Lipowska M. Skala Inteligencji Stanford-Binet, Edycja Piąta. Warszawa: Pracownia Testów Psychologicznych i Pedagogicznych; 2017.
Ruijter GJG, Valstar MJ, van de Kamp JM, van der Helm RM, Durand S, van Diggelen OP, et al. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol Genet Metab. 2008;93(2):104-11. https://doi.org/10.1016/j.ymgme.2007.09.011.
Shapiro EG, Jones SA, Escolar ML. Developmental and behavioral aspects of mucopolysaccharidoses with brain manifestations—Neurological signs and symptoms. Mol Genet Metab. 2017;122:1-7. https://doi.org/10.1016/j.ymgme.2017.09.009.
Stańczak J, Matczak A, Jaworowska A, Bac I. WISC-V. Skale Inteligencji Wechslera dla Dzieci. Wydanie V. Warszawa: Pracownia Testów Psychologicznych Polskiego Towarzystwa Psychologicznego; 2020.
Valstar MJ, Marchal JP, Grootenhuis M, et al. Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J Rare Dis. 2011;6:43. https://doi.org/10.1186/1750-1172-6-43.
Valstar MJ, Ruijter GJG, van Diggelen OP, Poorthuis BJH, Wijburg FA. Sanfilippo syndrome: a mini-review. J Inherit Metab Dis. 2008;31(2):240-52. https://doi.org/10.1007/s10545-008-0838-5.
Wijburg FA, Węgrzyn G, Burton BK, Tylki-Szymańska 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):462-70. https://doi.org/10.1111/apa.12169.
Wiśniewska K, Wolski J, Gaffke L, Cyske Z, Pierzynowska K, Węgrzyn G. Misdiagnosis in mucopolysaccharidoses. J Appl Genet. 2022;63(3):475-95. https://doi.org/10.1007/s13353-022-00703-1.
Węgrzyn G, Jakóbkiewicz-Banecka J, Narajczyk M, Wiśniewski A, Piotrowska E, Gabig-Cimińska M, et al. Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different? Med Hypotheses. 2010;75(6):605-9. https://doi.org/10.1016/j.mehy.2010.07.044.

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Development and Longitudinal Neurocognitive Functioning in Mucopolysaccharidosis type IIIC: A Case Study

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Abstract

Introduction

Case Report

Discussion

Declarations

References

Supplementary Materials

Status:

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