What Can We Learn from the Parents of Children Affected with Mucopolysaccharidosis Type III-A in Israel?

Sanfilippo Syndrome, or mucopolysaccharidosis type III (MPS III), is a group of autosomal-recessive lysosomal storage disorders leading to tissue accumulation of heparan sulfate. MPS III is caused by deficiency in one of 4 enzymes involved in lysosomal degradation of heparan sulfate. Based on the relevant enzyme deficiency, 4 types have been recognized. MPS III constitutes a progressive neurodegenerative and systemic disorder. Parents of children diagnosed with MPS III were interviewed using a retrospective questionnaire based on the known clinical manifestations of MPS III. Eight patients from 4 unrelated families of varied ethnic origin were included. All children were diagnosed with MPS type III-A. Average age at diagnosis was 6.1 years. The most common early clinical manifestations leading to parental suspicion of illness were speech delay and coarse facial features. All children were reported to have global developmental delay, sleep disorders, recurrent infections, hyperactivity, and decreased hearing. The time from first medical inquiry until diagnosis was over 2 years on average, consistent with the delay in diagnosis described in the literature. MPS III children frequently undergo early and repeated ear, nose and throat surgeries, thus we suggest that a high index of suspicion is warranted in relevant clinical circumstances.

Music therapy and Sanfilippo syndrome: an analysis of psychological and physiological variables of three case studies

Introduction Mucopolysaccharidosis type III (MPS III) or Sanfilippo syndrome is a neurodegenerative disease caused by the accumulation of mucopolysaccharides in the body. As the symptoms are wide ranging, it is a challenge to provide a diagnosis and psychological treatment for affected children. Method The main objective of this study was to describe a form of music therapy treatment applied to three children diagnosed with MPS III. The psychological variables were evaluated by an ad hoc observation recording template, and the physiological variables were measured with a digital meter before and after each session. The perception of the parents was also considered through a semi-structured interview. Results An improvement in the psychological variables was shown in all cases. Changes in the physiological variables were also noted, although they varied according to each child. The parents report some benefit of music therapy and they share difficulty in assessing the extent of benefits of the music therapy. Discussion Findings indicate that music therapy can be a useful form of treatment with multiple benefits for children with conditions such as MPS III or similar conditions. However, further research is needed in this area and in the development of specific ways of evaluating music therapy.

Gastrointestinal Manifestations in Mucopolysaccharidosis Type III: Review of Death Certificates and the Literature

Background: Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections have been reported as frequent and as the most common cause of death, but gastrointestinal (GI) manifestations have not been acknowledged as a cause of concern. The aim of this study was to determine the incidence of GI problems as a primary cause of death and to review GI symptoms reported in published studies. Methods: Causes of death from 221 UK death certificates (1957–2020) were reviewed and the literature was searched to ascertain reported GI symptoms. Results: GI manifestations were listed in 5.9% (n = 13) of death certificates. Median (IQR) age at death was 16.7 (5.3) years. Causes of death included GI failure, GI bleed, haemorrhagic pancreatitis, perforation due to gastrostomies, paralytic ileus and emaciation. Twenty-one GI conditions were reported in 30 studies, mostly related to functional GI disorders, including diarrhoea, dysphagia, constipation, faecal incontinence, abdominal pain/distension and cachexia. Conclusions: GI manifestations may be an under-recognized but important clinical feature of MPS III. Early recognition of GI symptoms and timely interventions is an important part of the management of MPS III patients.

Electroclinical Features of Epilepsy in Mucopolysaccharidosis III: Outcome Description in a Cohort of 15 Italian Patients

Mucopolysaccharidosis III (Sanfilippo syndromes) types A–D are rare lysosomal storage disorders characterized by heparan sulfate accumulation and neurodegeneration. Patients with MPS III present with developmental stagnation and/or regression, sleep disturbance, and behavioral abnormalities usually in the first years of life. Epilepsy may occur in a proportion of patients during the disease course. However, the progression of epilepsy and EEG changes in MPS III have not been systematically investigated. We report electroclinical features in a cohort of patients with MPS III over a follow-up period ranging from 6.5 to 22 years. Participants include 15 patients (11 females; aged 7–31 years) with MPS III A (n = 7, 47%), MPS III B (n = 5, 34%), MPS III C (n = 2, 13%), and MPS III D (n = 1, 6%). At the time of this study, 8 out of 15 patients (53%) had epilepsy. Epilepsy occurred in patients with advanced disease even in the first decade of life (mean age at onset: 12.1 ± 6.7 years). However, seizure onset may also be associated with abrupt worsening of the neurobehavioral phenotype. The main epilepsy types observed were generalized (four out of eight, 50%), followed by focal (three out of eight, 37%) and combined (two out of eight, 25%) epilepsy and status epilepticus (one out of eight, 12.5%). Seizures were generally controlled by one antiepileptic drug (AED) and most patients (seven out of eight, 87%) were still on therapy after a median follow-up period of 5 years (range: 1–9 years). A total of 66 EEGs were analyzed with a median EEG follow-up duration of 7 years (range: 6 months−14 years). Slowing of the background activity occurred in 7 (46%) patients aged 4–19 years. Epileptiform EEG abnormalities were observed in 10 patients at a mean age of 9.6 ± 2.9 years. EEG epileptiform discharges were not unavoidably linked to epilepsy. Early recognition and careful monitoring of electroclinical features in MPS III is necessary for appropriate care and for the detection of disease progression.

Preconception expanded carrier screening: a focus group study with relatives of mucopolysaccharidosis type III patients and the general population

Preconception expanded carrier screening (ECS) enables prospective parents to assess their risk of having a child with an autosomal recessive disorder. Knowledge on motivations, feelings, and considerations people have towards the offer and use of ECS is limited. To enrich the public and professional discussion on ECS implementation, this study explored the perspectives towards various aspects of ECS in seven focus groups compromising first- and second-degree relatives of MPS III patients (N=9, N=4, N=5, N=5) and members of the general Dutch population (N=6, N=7, N=5). The focus groups were audio recorded and the transcripts were qualitatively analyzed to identify themes. Both relatives of MPS III patients and participants from the general population supported offering ECS, in particular for severe, childhood-onset disorders. Important barriers identified for ECS were a lack of genetic knowledge and a perceived lack of personal relevance and awareness, as well as out-of-pocket costs of testing. The majority of participants would prefer full disclosure of individual test results instead of couple-based test results. Moreover, offering people a choice for the way of reporting was proposed. All participants agreed that more efforts, for example by governmental campaigns, should be made to increase awareness on the availability, potentials, and limitations of ECS. Educating prospective parents about ECS is essential for increasing awareness and informed decision making. This study provides valuable insights that can be used by governments and public health authorities when considering implementation of preconception ECS.

Hip pathologies in mucopolysaccharidosis type III

Background Mucopolysaccharidosis type III (MPS III) comprises a group of rare lysosomal storage diseases. Although musculoskeletal symptoms are less pronounced than in other MPS subtypes, pathologies of hip and spine have been reported in MPS III patients. The purpose of this study was to describe hip pathologies and influencing parameters in MPS III patients. Methods A retrospective chart review was performed for 101 MPS III patients. Thirty-two patients met the inclusion criteria of enzymatically or genetically confirmed diagnosis and anteroposterior radiograph of the hips. Modified Ficat classification, Wiberg’s center-edge angle, and Reimer’s migration percentage were measured. Results The mean age at data assessment was 11.0 years (SD 5.7). Osteonecrosis of the femoral head was observed in 17/32 patients. No statistically significant association was found between these changes and age, sex, or MPS III subtype. Patients with a severe phenotype showed significantly higher rates of osteonecrosis (14/17) than patients with an intermediate phenotype. Hip dysplasia was present in 9/32 patients and was significantly associated with osteonecrosis of the femoral head (p = 0.04). Conclusions The present study demonstrates a high rate of hip pathologies in MPS III patients. Hip dysplasia and severe phenotype were significantly correlated with osteonecrosis of the femoral head. Therefore, radiographs of the hips are highly recommended in baseline and follow-up assessments of MPS III patients. Trial registration Retrospectively registered.

Reducing posttraumatic stress in parents of patients with a rare inherited metabolic disorder using eye movement desensitization and reprocessing therapy: a case study

Parents of children with severe inborn errors of metabolism frequently face stressful events related to the disease of their child and are consequently at high risk for developing parental posttraumatic stress disorder (PTSD). Assessment and subsequent treatment of PTSD in these parents is however not common in clinical practice. PTSD can be effectively treated by Eye Movement Desensitization and Reprocessing (EMDR), however no studies have been conducted yet regarding the effect of EMDR for parental PTSD. EMDR is generally offered in multiple weekly sessions which may preclude participation of parents as they are generally overburdened by the ongoing and often intensive care for their child. Therefore, we offered time-limited EMDR with a maximum of four sessions over two subsequent days to two parents of mucopolysaccharidosis type III (MPS III) patients to explore its potential effects. Both qualitative and quantitative outcomes were used to evaluate treatment effects. Both parents felt more resilient and competent to face future difficulties related to the disease of their child, and no adverse effects were reported. Quantitative outcomes showed a clinically significant decrease in post traumatic stress symptoms and comorbid psychological distress from pre- to post treatment, and these beneficial effects were maintained at follow-up. In conclusion, time-limited EMDR may be a highly relevant treatment for traumatized parents of children with MPS III, and probably also for parents of children with other rare progressive disorders. Further research is needed to validate the efficacy of EMDR in this specific population.

Aortic Root Dilatation in Taiwanese Patients with Mucopolysaccharidoses and the Long-Term Effects of Enzyme Replacement Therapy

Background: Cardiovascular abnormalities have been observed in patients with mucopolysaccharidosis (MPS) of any type, with the most documented abnormalities being valvular regurgitation and stenosis and cardiac hypertrophy. Only a few studies have focused on aortic root dilatation and the long-term effects of enzyme replacement therapy (ERT) in these patients. Methods: We reviewed echocardiograms of 125 Taiwanese MPS patients (age range, 0.1 to 19.1 years; 11 with MPS I, 49 with MPS II, 25 with MPS III, 29 with MPS IVA, and 11 with MPS VI). The aortic root diameter was measured at the sinus of Valsalva. Results: Aortic root dilatation (z score >2) was observed in 47% of the MPS patients, including 66% of MPS IV, 51% of MPS II, 45% of MPS VI, 28% of MPS III, and 27% of MPS I patients. The mean aortic root diameter z score was 2.14 (n = 125). The patients with MPS IV had the most severe aortic root dilatation with a mean aortic root diameter z score of 3.03, followed by MPS II (2.12), MPS VI (2.06), MPS III (1.68), and MPS I (1.03). The aortic root diameter z score was positively correlated with increasing age (n = 125, p < 0.01). For the patients with MPS II, III, and IV, aortic root diameter z score was also positively correlated with increasing age (p < 0.01). For 16 patients who had received ERT and had follow-up echocardiographic data (range 2.0–16.2 years), the mean aortic root diameter z score change was −0.46 compared to baseline (baseline 2.49 versus follow-up 2.03, p = 0.490). Conclusions: Aortic root dilatation was common in the patients with all types of MPS, with the most severe aortic root dilatation observed in those with MPS IV. The severity of aortic root dilatation worsened with increasing age, reinforcing the concept of the progressive nature of this disease. ERT for MPS appears to stabilize the progression of aortic root dilatation.

Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients

ObjectivesSanfilippo syndrome (Mucopolysaccharidosis III, MPS III) is a rare autosomal recessive hereditary disease, which is caused by lysosomal enzyme deficiency. This study was operated to investigate clinical and molecular characteristics of patients with MPS III, which will improve the diagnosis and treatment of MPS III.MethodThirty four patients with MPS III were assessed using clinical evaluation, questionnaire, and scoring system.ResultsAmong the 34 patients, 14 had MPS IIIA, 19 had MPS III B, and one had MPS III C. Speech delay (100%) and intellectual disability (100%) were the most prevalent clinical manifestations in this cohort, followed by hyperactivity (94.12%), hirsutism (91.18%), enlarged head circumference (73.52%), repeated diarrhea (67.64%), sparse teeth (67.64%), and Mongolian spots (64.71%). There were two clinical manifestations that were significantly different between IIIA and IIIB: Hepatosplenomegaly and serrated teeth. The most common initial symptoms at diagnosis were speech delay (52.94%), hyperactivity (35.29%), and mental retardation (29.41%). Genetic analysis of 25 patients was conducted, which identified 12 novel mutations.ConclusionWhen language retardation, mental retardation, and rough facial features occurred, MPS III should be considered. At same time, more examination should be operated, such as examination of changes in cranial magnetic resonance imaging of cerebral cortex atrophy. Hepatosplenomegaly and serrated teeth could be used clinically to preliminarily distinguish IIIA from IIIB.

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease—Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36—MPS I, 15—MPS II, 25—MPS III, 26—MPS IV, and 14—MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography—tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied.