Respiratory muscular strength in children with mucopolysacaridosis: comparison with predictive equations.

BACKGROUND: Mucopolysaccharidoses (MPS) are rare metabolic diseases that impair respiratory function leading to respiratory failure. This study aimed to compare maximal inspiratory and expiratory pressures (MIP and MEP) obtained in children with MPS and compare with predicted values from previous studies involving healthy children. METHODS: This is a cross-sectional study, in which the chest deformity was evaluated; MIP, MEP through digital manometer, and lung function through spirometry. MIP and MEP were compared with five different predict equations and with a control group of healthy children. Agreement between respiratory muscle weakness regarding absolute values of MIP and MEP in relation to predictive values by the equations included in the study were assessed by Kappa coefficient. RESULTS: MPS group was composed of 22 subjects. 45.5% had pectus carinatum, 36.4% pectus excavatum, and presented lower MIP (37.14±36.23 cmH2O) and MEP (60.09±22.3 cmH2O) compared with control group (22 healthy subjects) (MIP: 91.45±35.60; MEP: 95.73±22.38). Only the MEP equations proposed by Tomalak et al. were close to those found in our MPS children (P=0.09). In the MPS group it was observed a weak agreement between inspiratory weakness through absolute and predicted values in only two equations: Tomalak et al. and Domenèch-Clar et al. (for both: k=0.35, P value =0.03); and for MEP a moderate agreement was found using all predictive equations. CONCLUSIONS: In MPS children MRP data should not be normalized using the reference equations for healthy ones, is more coherent to longitudinally follow absolute pressures and lung volumes in this group.

Psychobehavioral factors and family functioning in mucopolysaccharidosis: preliminary studies.

Introduction: Mucopolysaccharidoses (MPS) constitute a group of progressive and multisystemic inherited metabolic diseases that profoundly affect both the mental health of patients and the wellbeing of their families. This study aims to evaluate the impact of MPS on family functioning and related factors. Methods and results: Twenty-five patients with MPS, including types I (n = 4), II (n = 11), IIIB (n = 2), IVA (n = 3), and VI (n = 5), and their families participated in this study. The mean patient age was 13 years [standard deviation (SD): 7.7 years]. Behavioral and emotional problems were noted in 9.1% of all patients. While the type of MPS did not directly influence mental problems, the presence of neuronal involvement did (p = 0.006). Patients with MPS III exhibited difficulties primarily in emotional areas, conduct, hyperactivity, and peer problems. Importantly, both patients with MPS II and those with MPS III experienced a significant impact on communication [mean scores for communication domain: MPS II, 35.6 (SD: 24.3); MPS III, 35.0 (SD: 22.6)]; poorer communication was directly linked to worse adaptive behavior (p = 0.012), and worse adaptive behavior was associated with lower quality of life (p = 0.001). Quality of life and caregiver burden among family members did not significantly differ across MPS types; however, higher caregiver burden was negatively associated with quality of life (p = 0.002). Concerning family functioning, the most impacted domains included independence, intellectual/cultural orientation, activity/recreation, and expressiveness. Domain scores did not vary based on MPS type, treatment, or neurological involvement. Quality-of-life scores were positively associated with the cultural/intellectual domain score. Conclusion: The impacts of quality of life and family extend beyond clinical characteristics and MPS type, strongly influenced by patient cognition and communication, as well as type of family functioning, especially those with greater cultural/intellectual skills of their family members. A multidisciplinary approach addressing the broader needs of individuals with MPS becomes essential. Techniques aimed at improving communication, including prompt interventions such as speech therapy and augmentative and alternative communication strategies, can contribute to overall family functioning improvement.

Capsular and retinaculum thickening in type II mucopolysaccharidosis: a novel MRI finding.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, resulting in an accumulation of unprocessed or partly degraded GAGs in different tissues, including bones and joints. Notably, skeletal and joint abnormalities may be the first complaint that prompts patients to seek medical attention, especially in the milder forms of the disease. To our knowledge, there are no prior imaging reports that have documented capsuloligamentous thickening in patients with MPS on MRI. In this study, we present four cases of patients with clinically and genetically confirmed diagnosis of type II MPS, encompassing seven MRI examination of different joints, including cervical spine, hip, wrist, knee, and shoulder. All of the patients were male, aged between 14 and 35 years, and exhibited varying degrees of joint stiffness in the clinical examination and carpal tunnel syndrome in cases of the wrist joint was affected. None of the patients had a history of surgical procedures on the affected joint, other metabolic or deposit diseases, or sports activity practice. The MRI revealed significant capsuloligamentous and retinaculum thickening, up to eight times greater than the normal capsular thickness reported in the literature.

Salivary Metabolites in Patients with Mucopolysaccharidosis

ABSTRACT Objective: To identify the salivary metabolites profile of Mucopolysaccharidosis (MPS) types I, II, IV, and VI patients. Material and Methods: The participants were asked to refrain from eating and drinking for one hour before sampling, performed between 7:30 and 9:00 a.m. Samples were centrifuged at 10.000 × g for 60 min at 4°C, and the supernatants (500µl) were stored at −80°C until NMR analysis. The salivary proton nuclear magnetic resonance (1H-NMR) spectra were acquired in a 500 MHz spectrometer, and TOCSY experiments were used to confirm and assign metabolites. Data were analyzed descriptively. Results: Differences in salivary metabolites were found among MPS types and the control, such as lactate, propionate, alanine, and N-acetyl sugar. Understanding these metabolite changes may contribute to precision medicine and early detection of mucopolysaccharidosis and its monitoring. Conclusion: The composition of low molecular weight salivary metabolites of mucopolysaccharidosis subjects may present specific features compared to healthy controls.

Untargeted LC-HRMS metabolomics reveals candidate biomarkers for mucopolysaccharidoses.

BACKGROUND: Mucopolysaccharidoses (MPSs) are inherited genetic diseases caused by an absence or deficiency of lysosomal enzymes responsible for catabolizing glycosaminoglycans (GAGs). Undiagnosed patients, or those without adequate treatment in early life, can be severely and irreversibly affected by the disease. In this study, we applied liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics to identify potential biomarkers for MPS disorders to better understand how MPS may affect the metabolome of patients. METHODS: Urine samples from 37 MPS patients (types I, II, III, IV, and VI; untreated and treated with enzyme replacement therapy (ERT)) and 38 controls were analyzed by LC-HRMS. Data were processed by an untargeted metabolomics workflow and submitted to multivariate statistical analyses to reveal significant differences between the MPS and control groups. RESULTS: A total of 12 increased metabolites common to all MPS types were identified. Dipeptides, amino acids and derivatives were increased in the MPS group compared to controls. N-acetylgalactosamines 4- or 6-sulfate, important constituents of GAGs, were also elevated in MPS patients, most prominently in those with MPS VI. Notably, treated patients exhibited lower levels of the aforementioned acylaminosugars than untreated patients in all MPS types. CONCLUSIONS: Untargeted metabolomics has enabled the detection of metabolites that could improve our understanding of MPS physiopathology. These potential biomarkers can be utilized in screening methods to support diagnosis and ERT monitoring.

Awake airway endoscopy in mucopolysaccharidosis: a case report.

Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.

Facial and Cephalometric Features of Individuals With Mucopolysaccharidosis: A Cross-Sectional Study.

OBJECTIVE: The aim was to assess craniofacial features through facial anthropometric and lateral cephalometry measurements of individuals with mucopolysaccharidosis (MPS) and compare them with individuals without MPS. DESIGN: Cross-sectional study. PATIENTS: A total of 14 individuals with MPS and 28 non-MPS age- and sex-matched were enrolled in this study. METHODS: A clinical facial analysis to evaluate the soft tissues and cephalometric analysis that comprised linear and angular measurements were performed. The calculation of the method error suggested no systematic errors (p > .05). Random errors for linear and angular measurements were low (less than 0.5° and 1.6 mm). Chi-square test and independent t-test were performed. RESULTS: Most individuals with MPS were dolichofacial, presented altered facial proportions with an increased anterior lower facial height (ALFH) and lip incompetence (all p < .05), when compared with non-MPS individuals. Six angular measurements (1s.Na, 1s.NB, FMA, IMPA, AFI, and Po.Or_Go.Me; all p < .05) were significantly increased among individuals with MPS, and two (1s.1i and Ba.N-Ptm.Gn, all p < .05) were significantly decreased among them. Four linear measurements were significantly increased among individuals with MPS (1s-NA, 1i-NB, S-UL, and S-LL; all p < .05) and five (PogN-Perp, Co-A, Co-Gn, Nfa-Nfp, and overbite; all p < .05) were significantly decreased among them. CONCLUSION: In summary, most individuals with MPS were dolichofacial with increased ALFH. Proclined upper and lower incisors, reduced nasopharyngeal space, and reduced overbite was also noted.

Perfil odontológico de pacientes brasileiros com doenças genéticas raras de envolvimento esquelético / Dental profile of brazilian patients with skeletal rare genetic disorders

Segundo a Organização Mundial de Saúde, uma doença é considerada rara quando acomete cerca de 65 pessoas a cada 100 mil indivíduos. No Brasil existem cerca de 13 milhões de pessoas diagnosticadas com alguma doença rara. O presente estudo objetivou comparar o perfil odontológico de pacientes brasileiros com doenças genéticas raras de envolvimento esquelético com brasileiros normotípicos. O estudo foi realizado a partir de um banco de dados cujas informações foram coletadas em 2019. Foi desenvolvido um estudo transversal, com uma amostra de conveniência (amostragem do tipo snowball) de 105 indivíduos com doenças genéticas raras ([MPS (n=27) / OI (n=78)], na faixa etária de dois a 54 anos e os pais/responsáveis, e 105 indivíduos sem doenças genéticas raras. A amostra foi selecionada em ambulatórios médicos de serviços especializados/referência em doenças raras, de cinco estados brasileiros (Ceará, Espírito Santo, Minas Gerais, Rio de Janeiro e São Paulo). Os pais/responsáveis responderam um questionário sobre aspectos individuais (sexo, idade, cor da pele e renda familiar) e perfil odontológico dos participantes. O perfil odontológico foi identificado a partir de questões relacionadas à história odontológica do participante [experiência odontológica, dor dentária (últimos 12 meses), tempo e motivo da última consulta odontológica, uso do SUS para assistência odontológica, satisfação sobre a assistência recebida na última consulta odontológica, dificuldades para o filho receber assistência odontológica] e presença/ausência de problemas dentários. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Federal de Minas Gerais, (CAAE 01480212.4.0000.5149 [MPS] / CAAE 54755516.4.0000.5149 [OI]. Foram realizadas as análises univariada, bivariada e multivariada [Regressão logística binária não-ajustada e ajustada (Odds Ratio, método Conditional Backward, IC 95%)]. A média de idade dos indivíduos com doença rara foi de 14,1 anos (±12,2) e mediana 9,5 anos. A maioria era do sexo feminino (53,8%), cor da pele não branca (56,7%) e renda familiar superior a um salário mínimo (82,4%). Entre os indivíduos com doenças raras, 78 tinham OI (37,1%) e 27 com MPS (12,9%). A maior parte era do estado de Minas Gerais (46,7%). Pacientes que já utilizaram os serviços odontológicos do SUS apresentaram uma chance 2,24 maior de pertencer ao grupo de pacientes com doenças raras (OR= 2,24; IC 95%: 1,07- 4,89). Os participantes com histórico de dificuldades para receber tratamento odontológico apresentaram 14,86 vezes maior chance de serem pacientes com doenças raras (OR=14,86; IC 95%: 5,96-27,03). E, os participantes diagnosticados com algum problema bucal apresentaram 10,38 vezes mais chances de pertencerem ao grupo com doenças raras (OR=10,38; IC 95%: 1,95-35,17). Pacientes com doenças raras apresentaram maior histórico de dificuldade em conseguir acesso a tratamento odontológico e de fazer uso do sistema público de saúde/SUS e foram diagnosticados com mais problemas dentários comparados aos indivíduos normotípicos.

According to the World Health Organization, a disease is considered rare when it affects about 65 people per 100,000 individuals. Brazil has about 13 million people affected by rare diseases. The aim of the present study was to compare the dental profile of Brazilian patients with skeletal rare genetic disorders and normotypical Brazilian patients. The study was carried out from a database with information collected in 2019. A cross-sectional study was carried out with 105 individuals with rare genetic diseases ([MPS (n=27) / OI (n=78)], with two to 54 years old and their parents/guardians. 105 normotypical individuals were also recruited for the study (Snowball sampling). The sample was selected in outpatient clinics that are reference in the care of rare diseases, in five Brazilian states (Ceará, Espírito Santo, Minas Gerais, Rio de Janeiro and São Paulo). Parents/guardians answered a questionnaire about individual aspects of their child (gender, age, skin color and level of education of parents/guardians).The dental profile was identified from questions related to dental history [(patient's dental experience, presence of dental pain (last 12 months), when was the last dental visit and the reason for it, use of Unified Health System (SUS) dental care services, satisfaction with the care received at the last dental appointment, difficulties for the child to receive dental treatment)] and presence/absence of dental problems. The study received approval from the Research Ethics Committee of Federal University of Minas Gerais (CAAE 01480212.4.0000.5149 [MPS] / CAAE 54755516.4.0000.5149 [OI]. A descriptive analysis and non-adjusted and adjusted binary logistic regression models was performed (Odds Ratio, Conditional Backward method, 95%CI). The results showed that the average age of individuals with a rare disease was 14.1 years (±12.2) and median age of 9.5 years. Most of them were female (53.8%), non-white skin color (56.7%) and with a family income higher than one minimum wage (82.4%). Among individuals with rare diseases, 78 (37.1) were with OI and 27 (12.9) with MPS. Most of the sample were from Minas Gerais state, Brazil, [98(46.7)]. Participants who had already used SUS dental care services had a 2.24 times higher chance of belonging to the group with rare diseases (OR= 2.24;95% CI: 1.07-4.89). Patients with a history of difficulties to receive dental treatment were 14.86 times more likely to belong to the group with rare diseases (OR=14.86; 95% CI: 5.96- 27.03). Patients diagnosed with 1 or more dental problems were 10.38 times more likely to belong to the group with rare diseases (OR=10.38; 95% CI: 1.95-35.17). Individuals with rare diseases have a greater history of difficulty in accessing dental treatment, use the public health system/SUS, and were diagnosed with more dental problems compared to normotypical Brazilian patients.

Análise do perfil facial e da má oclusão de crianças e adolescentes com doenças genéticas raras que afetam o desenvolvimento esquelético / Analysis of malocclusion and facial profile of children and adolescents with rare genetic diseases that affect skeletal development

As doenças raras são definidas pelo Ministério da Saúde do Brasil como aquelas que afetam até 65 pessoas por 100.000 pessoas. No Brasil, estima-se que existam entre 13 a15 milhões de pessoas afetadas aproximadamente. Dentro desse grupo de enfermidades raras estão aquelas de etiologia genética cujo desenvolvimento esquelético é afetado; como as mucopolissacaridoses (MPS) e a osteogênese imperfeita (OI); as quais estão associadas à diversas alterações orofaciais. O objetivo deste estudo foi comparar a prevalência de má oclusão e o perfil facial de crianças e adolescentes com doenças genéticas raras que afetam o desenvolvimento esquelético com crianças e adolescentes normotípicos. Foi realizado um estudo observacional transversal com 152 crianças e adolescentes, sendo 76 com doenças genéticas raras ([MPS (n=19) / OI (n=57)], e 76 sem doença genética rara; na faixa etária de dois a 19 anos e os pais/responsáveis. Os grupos foram pareados por idade e sexo. As crianças/adolescentes com doenças raras foram recrutadas em ambulatórios médicos de serviços de referência em doenças genéticas raras, de cinco estados brasileiros (Ceará, Espírito Santo, Minas Gerais, Rio de Janeiro e São Paulo). O grupo sem doença rara foi recrutado em outros ambulatórios dos mesmos hospitais. Foi realizado o exame bucal das crianças/adolescentes (presença de má oclusão) e a análise subjetiva do perfil facial (simetria facial, proporção facial, altura facial anteroinferior, perfil facial, convexidade facial, ângulo nasolabial, selamento labial, linha mento-pescoço). Os pais/responsáveis responderam um questionário sobre questões individuais, sociodemográficas, comportamentais e história médica e odontológica do filho. O Directed Acyclic Graph (DAG) foi utilizado para identificar possíveis variáveis de confusão. O estudo foi aprovado pelo Comitê de Ética em Pesquisa (CEP) da Universidade Federal de Minas Gerais (CAAE 01480212.4.0000.5149 [MPS] e CAAE 54755516.4.0000.5149 [OI]). Foi realizada a análise univariada da frequencia de alterações faciais e de má oclusão em ambos os grupos. A média de idade das crianças/adolescentes foi de 8,9 anos (±4,6). Não houve variáveis de confusão para a associação entre doenças raras e questões oclusais. Quando comparada ao grupo sem doença rara, verificou-se que a amostra de participantes com doenças raras foi identificada com maior prevalência de má oclusão (apinhamento, giroversão, alterações de overjet/overbite, mordida cruzada e/ou aberta e má oclusão de classe III). O grupo com doenças raras apresentou maior tendência com percentual maior de alterações faciais (dolicofacial, perfil convexo/côncavo, proporção/altura facial inadequadas, ângulo nasolabial aberto/fechado, ausência de selamento labial, interposição de língua e linha queixo-pescoço inadequada) do que o grupo de comparação. Pôde-se concluir que as crianças e adolescentes com doenças genéticas raras que afetam o desenvolvimento esquelético apresentaram prevalência maior de má oclusão e de alterações faciais, quando comparados às crianças/adolescentes sem doenças raras.

Rare diseases are defined as those that affect up to 65 people per 100,000 people. In Brazil, it is estimated that there are between 13 and 15 million people with rare diseases. In this group of diseases are those of genetic etiology that affect skeletal development; such as Mucopolysaccharidoses (MPS) and Osteogenesis Imperfecta (OI). They are two diseases associated with several orofacial alterations. The aim of this study was to compare the prevalence of malocclusion and the facial profile of children and adolescents with rare genetic diseases that affect skeletal development with normotypical children and adolescents. A cross-sectional observational study was carried out with 152 children and adolescents, 76 with rare genetic diseases ([MPS (n=19) / OI (n=57)], and 76 without rare genetic diseases; aged between two and 19 years and parents/guardians. The groups were matched by age and gender. Children/adolescents with rare diseases were recruited from outpatient clinics of specialized or reference services in rare genetic diseases, in five Brazilian states (Ceará, Espírito Santo, Minas Gerais, Rio de Janeiro and São Paulo). The group without a rare disease was recruited from other clinics in the same hospitals. A clinical examination of the malocclusion of the children/adolescents and an analysis of the facial profile were performed (facial symmetry, facial proportion, anteroinferior facial height, facial profile, facial convexity, nasolabial angle, lip sealing, chin-neck line). Parents/guardians answered a questionnaire about individual, sociodemographic, behavioral questions and the child's medical and dental history. The Directed Acyclic Graph (DAG) was used to identify possible confounding variables. The study was approved by the Research Ethics Committee (CEP) of the Federal University of Minas Gerais (CAAE 01480212.4.0000.5149 [MPS] / CAAE 54755516.4.0000.5149 [OI]). Univariate analysis of the frequency of facial alterations and malocclusion was performed in both groups. The average age of children/adolescents was 8.9 years (± 4.6). There were no confusion variables for the association between rare diseases and occlusal issues. When compared to the group without a rare disease, it was found that the sample of participants with rare diseases was identified with a higher prevalence of malocclusion (dental crowding, rotation, overjet/overbite changes, crossbite and/or open bite). The group with rare diseases was also diagnosed with a higher percentage of facial alterations (dolichofacial, convex/concave profile, inadequate facial proportion/height, open/closed nasolabial angle, absence of lip seal, tongue interposition and inadequate chin-neck line) when compared to the normotypic group. It could be concluded that children and adolescents with rare genetic diseases that affect skeletal development had a higher prevalence of malocclusion and facial alterations, when compared to children/adolescents without rare diseases.

Awake airway endoscopy in mucopolysaccharidosis: a case report

Abstract Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.

Gene editing strategies to treat lysosomal disorders: The example of mucopolysaccharidoses.

Lysosomal storage disorders are a group of progressive multisystemic hereditary diseases with a combined incidence of 1:4,800. Here we review the clinical and molecular characteristics of these diseases, with a special focus on Mucopolysaccharidoses, caused primarily by the lysosomal storage of glycosaminoglycans. Different gene editing techniques can be used to ameliorate their symptoms, using both viral and nonviral delivery methods. Whereas these are still being tested in animal models, early results of phase I/II clinical trials of gene therapy show how this technology may impact the future treatment of these diseases. Hurdles related to specific hard-to-reach organs, such as the central nervous system, heart, joints, and the eye must be tackled. Finally, the regulatory framework necessary to advance into clinical practice is also discussed.

Delivery and assessment of a CRISPR/nCas9-based genome editing system on in vitro models of mucopolysaccharidoses IVA assisted by magnetite-based nanoparticles.

Mucopolysaccharidosis IV A (MPS IVA) is a lysosomal disorder caused by mutations in the GALNS gene. Consequently, the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate accumulate in the lysosomal lumen. Although enzyme replacement therapy has shown essential advantages for the patients, several challenges remain to overcome, such as the limited impact on the bone lesion and recovery of oxidative profile. Recently, we validated a CRISPR/nCas9-based gene therapy with promising results in an in vitro MPS IVA model. In this study, we have expanded the use of this CRISPR/nCas9 system to several MPS IVA fibroblasts carrying different GALNS mutations. Considering the latent need to develop more safety vectors for gene therapy, we co-delivered the CRISPR/nCas9 system with a novel non-viral vector based on magnetoliposomes (MLPs). We found that the CRISPR/nCas9 treatment led to an increase in enzyme activity between 5 and 88% of wild-type levels, as well as a reduction in GAGs accumulation, lysosomal mass, and mitochondrial-dependent oxidative stress, in a mutation-dependent manner. Noteworthy, MLPs allowed to obtain similar results to those observed with the conventional transfection agent lipofectamine. Overall, these results confirmed the potential of CRISPR/nCas9 as a genome editing tool for treating MPS IVA. We also demonstrated the potential use of MLPs as a novel delivery system for CRISPR/nCas9-based therapies.

Analysis of salivary parameters of mucopolysaccharidosis individuals.

Mucopolysaccharidosis (MPS) is a heterogeneous group of rare, chronic, progressive and systemic inherited disorders resulting from deficiency or lack of lysosomal enzymes responsible for the degradation of glycosaminoglycans. Products of nitrosative stress have been previously detected in blood and urine samples of patients with MPS. However, it is unclear whether they are present in the saliva of MPS patients and also if they correlate with salivary parameters such as flow and pH. This study compared the salivary levels of NOX (NO2- + NO3-), nitrite (NO2-), protein (albumin), erythrocyte and leukocyte numbers, as well as the salivary flow rate and pH values of samples obtained from 10 MPS patients and 10 healthy subjects. MPS patients exhibited higher salivary levels of NOX and NO2- when compared to healthy subjects (p < 0.05). Albumin was only detected in six saliva samples of MPS patients and, erythrocytes and leukocytes were detected in 60% and 40% of the MPS patients, respectively. In addition, salivary flow rate and pH averages were statistically lower in this group when compared to healthy samples (p < 0.05). Overall, the data indicates that the salivary levels of NO products can be used in combination with other heath indicators to monitor MPS disorders.

Mucopolysaccharidoses: Cellular Consequences of Glycosaminoglycans Accumulation and Potential Targets.

Mucopolysaccharidoses (MPSs) constitute a heterogeneous group of lysosomal storage disorders characterized by the lysosomal accumulation of glycosaminoglycans (GAGs). Although lysosomal dysfunction is mainly affected, several cellular organelles such as mitochondria, endoplasmic reticulum, Golgi apparatus, and their related process are also impaired, leading to the activation of pathophysiological cascades. While supplying missing enzymes is the mainstream for the treatment of MPS, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), or gene therapy (GT), the use of modulators available to restore affected organelles for recovering cell homeostasis may be a simultaneous approach. This review summarizes the current knowledge about the cellular consequences of the lysosomal GAGs accumulation and discusses the use of potential modulators that can reestablish normal cell function beyond ERT-, HSCT-, or GT-based alternatives.

Functioning profiles of individuals with Mucopolysaccharidosis according to the International Classification of Functioning.

BACKGROUND: The classification of health problems of persons with Mucopolysaccharidosis (MPS) based on the International Classification of Functioning, Disability and Health (ICF) may contribute to better understanding the disease impacts. The ICF is a useful tool to describe disabilities and functioning, especially in diseases with multisystemic involvement. AIM: To identify and classify the health needs of persons with non-neuronopathic MPS according to the ICF. DESIGN: A cross-sectional study. SETTING: Department of Physical Therapy (Federal University, Brazil). POPULATION: Persons with non-neuronopathic MPS. METHODS: Semi-structured interviews covering all components of the ICF were conducted to know the patients' perspectives of their health problems (patient-reported outcomes). The speeches were transcribed verbatim and analyzed by researchers to identifying meaningful concepts. Then, the concept units were linked to ICF components and the magnitude of the problem to ICF qualifiers. Data are shown by descriptive statistics and separated into two groups: children and adolescents, and adults. RESULTS: A total of 60 different ICF categories were used to classify participants' functioning. A total of 28 and 51 categories was necessary to classify the health problems of children and adults, respectively. Additionally, 16 categories related to contextual factors were used, of which eight and 12 were identified as facilitators by children, adolescents, and adults, respectively. The main problems were related to supportive functioning of arms or legs (b7603), pain in the body part (b2801), respiratory functions (b440), and voice functions (b310). Limitations in the activity and participation component were related to walking (d450), fine hand use (d440), washing oneself (d510), and dressing (d540). Recreation and leisure (d920) was restricted to approximately half of the studied population. CONCLUSIONS: People with MPS face impairments of body structures and functions, activity limitations and restrictions to participation. Environmental factors may be act as facilitators of these problems. CLINICAL REHABILITATION IMPACT: The ICF is a useful tool to classify the health problems of people with non-neuropathic MPS. The planning of rehabilitation programs needs to covers all components of functioning to provide a biopsychosocial model of care. The ICF categories may direct health professionals to more effective targets.

Mucopolysaccharidosis patients have reduced functional capacity.

INTRODUCTION: Mucopolysaccharidoses (MPSs) are a group of rare diseases caused by an intralysosomal accumulation of glycosaminoglycans, resulting in a multisystemic clinical condition characterized by variable degrees of physical-functional impairment. OBJECTIVE: To evaluate the functional capacity (FC) of MPS patients and compare with a healthy control group. METHODS: This is a cross-sectional study of 6- to 39-year-old patients followed at a medical reference center and compared with their control peers, matched by age and sex. FC was assessed using the Sit-to-Stand Test (SST) and Incremental Shuttle Walk Test (ISWT). Heart rate (HR) and Borg rating of perceived exertion were measured before and after ISWT. HR recovery (HRR) was defined as the HR at the end of the test minus the HR in the second minute after ISWT. RESULTS: Nineteen (19) MPS patients, 69% with type II MPS and mean age 17 ± 11 years were evaluated. Every patient was under enzyme replacement therapy. The time to perform the SST was longer in the MPS group (10.6 ± 2.5 s vs. 6.7 ± 1.2 s; p < .01). The MPS group achieved lower values of distance covered on the ISWT (407.6 ± 329.8 m vs. 1131.9 ± 183.3 m; p < .01), with a significantly higher Borg (6 [5-8] vs. 2 [1-4]; p = .02). The MPS group's HRR was slower than the controls (32.9 ± 20.2 beats per minute [bpm] vs. 69.1 ± 25.9 bpm; p < .001). DISCUSSION: We observed a pronounced reduction in the MPS group's FC compared to their healthy peers and a worse HRR after completing the test.

Functional results after carpal tunnel release in mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidosis consists of a group of diseases caused by the deficiency of lysosomal enzymes, which may lead to the compression of the median nerve in the carpal tunnel due to the accumulation of glycosaminoglycan, resulting in the hand disability. The study purpose is to present functional results of carpal tunnel release in mucopolysaccharidosis patients. Patients were selected from an enzyme replacement group in the Department of Pediatric Neurology. The legal guardians of the patients were informed about the likely functional change of the hands induced by compression of the median nerve. Clinical evaluation was performed in those patients who received their legal guardians' consent to participate and was included inspection, assessment of functional level, wrinkle test and the digital pinch function to manipulate small and large objects. Ultrasound and electromyography were performed to confirm the clinical median nerve compression. Bilateral extended opening technique was performed to access the carpal tunnel and analyze the anatomic findings of the median nerve and the flexed tendons of the fingers. After the surgical release of the carpal tunnel, the clinical evaluation was repeated. Subjective observations of the legal guardians were also considered. RESULTS: Seven patients underwent bilateral surgical opening of the carpal tunnel; six boys, mean age of 9.5 (5 to 13), five of them presenting Type II mucopolysaccharidosis, 1 Type I and 1 Type VI. The average follow-up was 12 months (10-13 months). The functional results observed included the improvement in the handling of small and large objects in all children who underwent decompression of the median nerve. The comparison between the pre-operative and post-operative functional levels revealed that 2 patients evolved from Level II to IV, 3 from Level III to IV, 1 from Level IV to V and 1 patient remained in Level III. Tenosynovitis around the flexor tendons and severe compression of the median nerve in the fourteen carpal tunnels were observed during the surgical procedure. In 6 wrists, partial tenosynovitis was performed. CONCLUSIONS: Despite the improvement in the overall function of the children' hands, we cannot conclude that only surgery was responsible for the benefit. Better designed studies are required.

[Respiratory aspects and pulmonary physiotherapy in the child with mucopolysaccharidosis]. / Aspectos respiratorios y de fisioterapia pulmonar en el niño con mucopolisacaridosis.

La mucopolisacaridosis es un grupo heterogéneo de enfermedades que se caracterizan por la acumulación lisosomal de sustancias intermedias del metabolismo de los mucopolisacáridos o glucosaminoglucanos. El trastorno respiratorio que caracteriza a los pacientes con mucopolisacaridosis es la enfermedad pulmonar restrictiva crónica, por lo que la rehabilitación pulmonar, cuyo objetivo es mejorar los síntomas respiratorios, y la fisioterapia respiratoria, mejorarán la ventilación pulmonar y la biomecánica respiratoria deteriorada. Es necesario el seguimiento por el neumólogo infantil, quien cuantificará la función pulmonar y vigilará los síntomas de obstrucción nocturna y de restricción pulmonar con ayuda de estudios como la espirometría, la pletismografía y la prueba de la caminata de 6 minutos, por mencionar algunas. También es muy importante realizar un programa individualizado de técnicas de fisioterapia respiratoria y de ejercicios. Todo lo anterior, con el objetivo de evaluar la función pulmonar como un marcador de respuesta al uso de cualquiera de las terapias indicadas en la mucopolisacaridosis.Mucopolysaccharidosis is a heterogeneous group of diseases characterized by the lysosomal accumulation of intermediates in the metabolism of mucopolysaccharides or glycosaminoglycans. The respiratory disorder that characterizes patients with mucopolysaccharidosis is the chronic restrictive lung disease. Therefore, pulmonary rehabilitation aimed at improving respiratory symptoms and respiratory physiotherapy will improve pulmonary ventilation and impaired respiratory biomechanics in patients with mucopolysaccharidosis. Follow-up by the pediatric pulmonologist is necessary to quantify lung function and monitor the symptoms of nocturnal obstruction and pulmonary restriction with the help of studies such as spirometry, plethysmography and the 6-minute walk test, among others. It is also very important to perform an individualized program of respiratory physiotherapy techniques and exercises. Overall, all of these steps are followed for evaluating lung function as a marker of response to the use of any of the therapies indicated in mucopolysaccharidosis.

Genome editing in mucopolysaccharidoses and mucolipidoses.

Mucopolysaccharidoses (MPS) and mucolipidoses (ML) are disorders that alter lysosome function. While MPS are caused by mutation in enzymes that degrade glycosaminoglycans, the ML are disorders characterized by reduced function in the phosphotransferase enzyme. Multiple clinical features are associated with these diseases and the exact mechanisms that could explain such different clinical manifestations in patients are still unknown. Furthermore, there are no curative treatment for any of MPS and ML conditions so far. Gene editing holds promise as a tool for the creation of cell and animal models to help explain disease pathogenesis, as well as a platform for gene therapy. In this chapter, we discuss the main studies involving genome editing for MPS and the prospect applications for ML.