Studies on cartilage and bone disease in Mucopolysaccharidoses and Mucolipidoses

Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystem involvement. In MPS, deficiencies of glycosaminoglycans (GAGs) degrading enzymes lead to intralysosomal GAG storage. In the MLs, defective trafficking of lysosomal enzymes to the lysosome, leads to accumulation of a combination of GAGs and several other complex molecules. GAGs are degraded by enzymes, in part extracellularly and in part intracellularly in the lysosomes after uptake through endocytosis. Intralysosomal storage in MPS and ML patients gives rise to loss of cellular function by disturbed autophagy, polyubiquitination, mitochondrial dysfunction, inflammation, apoptosis, and loss of lysosomal membrane integrity, followed by tissue damage and organ dysfunction. These events eventually determine the clinical symptoms observed in the patients. Skeletal abnormalities are common in MPS and ML patients and originate from intralysosomal storage in cells of the cartilage, bones and ligaments. A major problem of these tissues is that they are difficult to treat as vascularization is poor and cell renewal (division) is slow. The existing therapies for these diseases are unable to fully correct or prevent the abnormalities occurring in bones and cartilage. To enable development of new therapies it is crucial to understand the processes involved in abnormal cartilage and bone development as observed in MPS and ML and relate them to normal skeletal development. The aim of this thesis is to create a better understanding of the etiology and pathophysiology of cartilage and bone development in patients with mucopolysaccharidosis and mucolipidosis, the clinical course and therapeutic challenges of skeletal disease in these disorders

Pathway to diagnosis and burden of illness in mucopolysaccharidosis type VII- A European caregiver survey

Background: Mucopolysaccharidosis type VII (Sly disease, MPS VII), is an ultra-rare, multi-symptom disease with variable clinical presentations which can present challenges with diagnosis, management and care. We believe this survey is the first to explore the patient experience through direct questioning of the caregivers of 13 individuals with MPS VII. Methods: This European survey, using a specifically designed questionnaire, was conducted in order to describe the pathway to diagnosis and the burden of illness of MPS VII. Information on early symptoms, clinicians seen, and current symptoms was collected. Questions on the caregivers' ability to work and the use and availability of health, social and educational support were included. Results: Caregivers of 13 patients from Germany, Spain, The Netherlands and Turkey responded to the survey. Five patients with non-immune hydrops fetalis (NIHF) were diagnosed with MPS VII at a mean age of 1.9 years (median 0.3 years, range 0.2 to 6 years). Those without NIHF (n = 7) were diagnosed at a mean age of 6.1 years (median 6.0 years, range 1.9 to 14 years). The symptoms most likely to raise a suspicion of MPS VII, excluding NIHF, did not appear until a median age of at least three years. Over one half of patients required assistance with daily living and mobility. Reduction of the working hours of caregivers was often necessary (46.2% reduced hours, 30.8% stopped working). Patients attended frequent medical appointments (12.7/year), over 80% had surgery and 30% had been hospitalised for respiratory issues. While support for learning and behavioural needs was generally available, support for mobility was not available to 50% of patients. Half of the respondents (6/12) said they were not offered genetic counselling. Conclusions: For children that do not present with NIHF, diagnosis can take several years as early symptoms can be non-specific and mistaken for other conditions. Increased awareness of the early signs of disease and more information for parents/caregivers at diagnosis are needed. MPS VII poses significant burden to patients, caregivers, healthcare, social and educational services. Access to information and support varies across Europe and the availability of genetic counselling is limited in some countries

Orofacial abnormalities in mucopolysaccharidosis and mucolipidosis type II and III:A systematic review

Mucopolysaccharidoses (MPSs) and mucolipidosis II and III (ML II and III) often manifest with orofacial (progressive) abnormalities, which may have a major impact on quality of life. However, because these patients have multiple somatic health issues, orofacial problems are easily overlooked in clinical practice and available literature on this topic solely consists of case reports, small case series, and small cohort studies. The aim of this systematic review was to gain more insight in the nature and extent of orofacial abnormalities in MPS, ML II, and III. A systematic review of all previously published articles addressing orofacial abnormalities in MPS, ML II, and III was performed. Both clinical studies and case reports were included. Outcome was the described orofacial abnormalities, subdivided into abnormalities of the face, maxilla, mandible, soft tissues, teeth, and occlusion. The search resulted in 57 articles, describing orofacial features in 340 patients. Orofacial abnormalities were present in all subtypes of MPS, ML II, and III, and consisted of thickened lips, a hypoplastic midface, a high‐arched palate, hypoplastic condyles, coronoid hyperplasia, macroglossia, gingival hyperplasia, thick dental follicles, dentigerous cysts, misshapen teeth, enamel defects, and open bite. Orofacial abnormalities are present in all subtypes of MPS, ML II, and III. As orofacial abnormalities may cause complaints, evaluation of orofacial health should be part of routine clinical care

Hip Morphology in Mucolipidosis Type II

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included. A total of 16 patients were followed over a mean of 3.5 years (range 0.2–10.7 years). Typical age-dependent radiographic signs identified were femoral cloaking (7/16), rickets/hyperparathyroidism-like changes (6/16) and constrictions of the supra-acetabular part of the os ilium (16/16) and the femoral neck (7/16). The course of acetabular and migration indexes (AI, MI) significantly increased in female patients. However, in the overall group, there was no relevant progression of acetabular dysplasia with a mean AI of 23.0 (range 5◦–41◦ ) and 23.7◦ (range 5◦–40◦ ) at the first and last assessments, respectively. Better knowledge on hip morphology in MLII could lead to earlier diagnosis, improved clinical management and enables assessment of effects of upcoming therapies on the skeletal system

Mucopolysaccharidosis: Cardiologic features and effects of enzyme-replacement therapy in 24 children with MPS I, II and VI

We determined the cardiologic features of children with MPS I, II and VI, and evaluated the effect of enzyme-replacement therapy (ERT) on cardiac disease. Twenty-four children aged 1-18 years with MPS I, II or VI were prospectively evaluated with echocardiogram and electrocardiogram from the start of enzyme-replacement therapy up to 6 years of treatment. At start of therapy, 66% had abnormal cardiac geometric features. Left-ventricular mass index (LVMI) was increased in half of the patients, due mainly to concentric hypertrophy in MPS I and II and to eccentric hypertrophy in MPS VI. Regurgitation was most severe in a subgroup of young MPS VI patients ( 2. LVMI Z-scores decreased significantly in patients with MPS I and MPS II (p = 0.04 and p = 0.032). Despite ERT, valve regurgitation increased in 60% of the patients. We conclude that all our MPS patients have cardiac abnormalities. The most severe cardiac disease was observed in a subgroup of young MPS VI patients. While ERT had an effect on LVMI and IVSd, it apparently had little or none on valve regurgitation

Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities

BACKGROUND: Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, beh

Intrafamilial oocyte donation in classic galactosemia: ethical and societal aspects

Classic galactosemia is a rare inherited disorder of galactose metabolism. Primary ovarian insufficiency (POI) with subfertility affects > 80% of female patients and is an important concern for patients and their parents. Healthcare providers are often consulted for subfertility treatment possibilities. An option brought up by the families is intrafamilial oocyte donation (mother-to-daughter or sister-to-sister). In addition to POI, galactosemia patients can also present varying cognitive and neurological impairments, which may not be fully clear at the time when mother-to-daughter oocyte donation is considered. Ethical and societal aspects arise when exploring this option. This study aimed to provide guidance in aspects to consider based on the views of different groups involved in the oocyte donation process. A qualitative study using in-depth semi-structured interviews with > 50 participants (patients, family members, and healthcare providers) was conducted. From these interviews, themes of concern emerged, which are illustrated and reviewed: (1) family relations, (2) medical impact, (3) patients’ cognitive level, (4) agreements to be made in advance and organization of counseling, (5) disclosure to the child, and (6) need for follow-up. We conclude that discussing and carrying out intrafamilial oocyte donation in galactosemia patients requires carefully addressing these themes. This study adds value to the already existing recommendations on intrafamilial oocyte donation in general, since it highlights important additional aspects from the perspectives of patients and their families

The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes

Background: The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes. Methods: Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients. The association between the galactose index (GI) defined as the ratio of the measured metabolites [U13C]Gal-1-P/ [13C6]UDP-galactose, and both intellectual and neurological outcome and galactose-1-phosphate (Gal-1-P) levels was investigated. Results: GMP was performed in fibroblasts of 28 patients and 3 control subjects. The GI of the classical phenotype patients (n = 22) was significantly higher than the GI of four variant patients detected by newborn screening (NBS) (p = .002), two homozygous p.Ser135Leu patients (p = .022) and three controls (p = .006). In the classical phenotype patients, 13/18 (72%) had a poor intellectual outcome (IQ < 85) and 6/12 (50%) had a movement disorder. All the NBS detected variant patients (n = 4) had a normal intellectual outcome (IQ ≥ 85) and none of them has a movement disorder. In the classical phenotype patients, there was no significant difference in GI between patients with a poor and normal clinical outcome. The NBS detected variant patients had significantly lower GI levels and thus higher residual galactose metabolism than patients with classical phenotypes. There was a clear correlation between Gal-1-P levels in erythrocytes and the GI (p = .001). Conclusions: The GI was able to distinguish CG patients with varying geno- and phenotypes and correlated with Gal-1-P. The data of the NBS detected variant patients demonstrated that a higher residual galactose metabolism may result in a more favourable clinical outcome. Further research is needed to enable individual prognostication and treatment in all CG patients

Using out-of-batch reference populations to improve untargeted metabolomics for screening inborn errors of metabolism

Untargeted metabolomics is an emerging technology in the laboratory diagnosis of inborn errors of metabolism (IEM). Analysis of a large number of reference samples is crucial for correcting variations in metabolite concentrations that result from factors, such as diet, age, and gender in order to judge whether metabolite levels are abnormal. However, a large number of reference samples requires the use of out-of-batch samples, which is hampered by the semi-quantitati