Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Assessment of small fiber neuropathy in patients carrying the non-classical Fabry variant p.D313Y.

INTRODUCTION: The pathophysiological significance of the Fabry-related, non-classical variant p.D313Y still remains to be solved. This study assesses the involvement of the peripheral nervous system with respect to small fiber neuropathy and neuropathic pain in female patients carrying p.D313Y. METHODS: This study examined nine females carrying the Fabry-related p.D313Y variant by obtaining skin punch biopsies above the right lateral malleolus. Intraepidermal nerve fiber density was determined for each patient and compared to reference values matched for the patient's decade of life and sex. Moreover, each patient was characterized by a detailed neurological examination and by pain assessment via questionnaire. RESULTS: Compared to sex-matched lower fifth percentile reference values per decade, intraepidermal nerve fiber density was decreased in seven out of nine patients. Four patients reported acral paresthesias and neuropathic pain with an average visual analogue scale score of 7 out of 10 points. Two patients experienced acute pain crises. Six out of seven patients diagnosed with small fiber neuropathy had a their medical history of hypo- and/or hyperhidrosis. DISCUSSION: The diagnosis of small fiber neuropathy was made in seven out of nine females carrying the non-classical variant p.D313Y. Moreover, neuropathic pain and symptoms indicative of autonomic nervous system dysfunction seem to be common findings that may be of clinical significance and may warrant therapeutic intervention.

CNS Manifestations in Mucolipidosis Type II-A Retrospective Analysis of Longitudinal Data on Neurocognitive Development and Neuroimaging in Eleven Patients.

Mucolipidosis type II (MLII), an ultra-rare lysosomal storage disorder, manifests as a fatal multi-systemic disease. Mental inhibition and progressive neurodegeneration are commonly reported disease manifestations. Nevertheless, longitudinal data on neurocognitive testing and neuroimaging lack in current literature. This study aimed to provide details on central nervous system manifestations in MLII. All MLII patients with at least one standardized developmental assessment performed between 2005 and 2022 were included by retrospective chart review. A multiple mixed linear regression model was applied. Eleven patients with a median age of 34.0 months (range 1.6-159.6) underwent 32 neurocognitive and 28 adaptive behaviour assessments as well as 14 brain magnetic resonance imagings. The scales used were mainly BSID-III (42%) and VABS-II (47%). Neurocognitive testing (per patient: mean 2.9, standard deviation (SD) 2.0) performed over 0-52.1 months (median 12.1) revealed profound impairment with a mean developmental quotient of 36.7% (SD 20.4) at last assessment. The patients showed sustained development; on average, they gained 0.28 age-equivalent score points per month (confidence interval 0.17-0.38). Apart from common (63%) cervical spinal stenosis, neuroimaging revealed unspecific, non-progressive abnormalities (i.e., mild brain atrophy, white matter lesions). In summary, MLII is associated with profound developmental impairment, but not with neurodegeneration and neurocognitive decline.

Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis-A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients.

Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. This retrospective study includes ML patients who underwent anaesthesia in two centres between 2008 and 2022. We reviewed patients' demographics, medical history, disease manifestations, as well as procedure- and outcome-related data. A total of 12 patients (7 MLII, 2 ML intermediate, 3 MLIII) underwent 44 anaesthesia procedures (per patient: median 3, range 1-11). The median age was 3.3 years (range 0.1-19.1). At least one complication occurred in 27.3% of the anaesthesia procedures. The vast majority of complications (94%) occurred in children with MLII and ML intermediate. A predicted difficult airway was found in 100% and 80% of the MLII and ML intermediate patients, respectively. Accordingly, most complications (59%) occurred during the induction of anaesthesia. Altogether, respiratory complications were the most frequent (18%), followed by difficult airway management (14%). The risk for anaesthesia-related complications is alarmingly high in patients with ML, particularly in those with MLII and ML intermediate. Multidisciplinary risk-benefit analysis and thoughtful anaesthesia planning are crucial in these patients.

Disease Manifestations in Mucopolysaccharidoses and Their Impact on Anaesthesia-Related Complications-A Retrospective Analysis of 99 Patients.

Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and adults with MPS undergoing anaesthesia from 2002 until 2018. We retrieved the patients' demographics, medical history, clinical manifestations, and indication by each anaesthesia. Multivariable mixed-effects logistic regression was calculated for a clinical model based on preoperative predictors preselected by lasso regression and another model based on disease subtypes only. Of the 484 anaesthesia cases in 99 patients, 22.7% experienced at least one adverse event. The clinical model resulted in a better forecast performance than the subtype-model (AICc 460.4 vs. 467.7). The most relevant predictors were hepatosplenomegaly (OR 3.10, CI 1.54-6.26), immobility (OR 3.80, CI 0.98-14.73), and planned major surgery (OR 6.64, CI 2.25-19.55), while disease-specific therapies, i.e., haematopoietic stem cell transplantation (OR 0.45, CI 0.20-1.03), produced a protective effect. Anaesthetic complications can best be predicted by surrogates for advanced disease stages and protective therapeutic factors. Further model validation in different cohorts is needed.

Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

BACKGROUND: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. METHODS: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. RESULTS: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. CONCLUSIONS: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.

Hematopoietic stem cell transplantation in mucopolysaccharidosis type IIIA: A case description and comparison with a genotype-matched control group.

BACKGROUND: Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is a chronic progressive neurodegenerative storage disorder caused by a deficiency of lysosomal sulfamidase. The clinical hallmarks are sleep disturbances, behavioral abnormalities and loss of cognitive, speech and motor abilities. Affected children show developmental slowing from the second year of life, dementia occurs by the age of 5 years followed by death in the second decade of life. Only a few studies concerning HSCT in MPS IIIA have been published and do not document a clear benefit of treatment. METHODS: The present study summarizes the clinical outcome of a girl with MPS IIIA who received HSCT at the age of 2.5 years. Her clinical course was compared with the natural history of six untreated MPS IIIA patients carrying the same mutations (p.R74C and p. R245H) in the SGSH-gene. RESULTS: Eight years after successful HSCT, the patient showed a global developmental delay. However, cognitive abilities continued to develop, albeit very slowly. There was no sign of regression. She could talk in short sentences, had good motor abilities and performed basic daily living activities by herself. She did not present with sleeping problems, but behavioral abnormalities were profound. In contrast, the six untreated patients with identical mutations in the SGSH-gene showed the typical progressive course of disease with early and continuous loss of abilities. CONCLUSIONS: The present data suggest a beneficial effect of HSCT performed at an early stage of MPS IIIA on cognitive skills, motor function and quality of life.

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.

Burden of influenza among hospitalized febrile children in Ghana.

BACKGROUND: Influenza surveillance data from Africa indicate a substantial disease burden with high mortality. However, local influenza data from district hospitals with limited laboratory facilities are still scarce. OBJECTIVES: To identify the frequency and seasonal distribution of influenza among hospitalized febrile children in a rural hospital in Ghana and to describe differential diagnoses to other severe febrile infections. METHODS: Between January 2014 and April 2015, all children with a temperature of ≥38°C admitted to a district hospital in Ghana were screened for influenza A and B by RT-PCR and differentiated to subtypes A(H1N1)pdm09 and A(H3N2). Malaria microscopy and blood cultures were performed for each patient. RESULTS: A total of 1063 children with a median age of 2 years (IQR: 1-4 years) were recruited. Of those, 271 (21%) were classified as severe acute respiratory infection (SARI) and 47 (4%) were positive for influenza, namely 26 (55%) influenza B, 15 (32%) A(H1N1)pdm09, and 6 (13%) A(H3N2) cases. Influenza predominantly occurred in children aged 3-5 years and was more frequently detected in the major rainy season (OR = 2.9; 95% CI: 1.47-6.19) during the first half of the year. Two (4%) and seven (15%) influenza-positive children were co-diagnosed with an invasive bloodstream infection or malaria, respectively. CONCLUSION: Influenza contributes substantially to the burden of hospitalized febrile children in Ghana being strongly dependent on age and corresponds with the major rainy season during the first half-year.