Diagnostic tests for Niemann-Pick disease type C (NP-C): A critical review

Niemann-Pick disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the wide range in age of onset of NP-C and clinical presentation of the disease, combined with the complexity of the cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations, notably with unidentified mutations and the classification of new variants. This review is intended to increase awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress, definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical markers do not provide a clear answer. Expertise and reference laboratories thus remain essential, and further work is still required to fulfill unmet needs

A Case Report of Sandhoff Disease

Sandhoff disease is a rare and severe lysosomal storage disorder representing 7% of GM2 gangliosidoses. Bilateral thalamic involvement has been suggested as a diagnostic marker of Sandhoff disease. A case of an 18-month-old infant admitted for psychomotor regression and drug resistant myoclonic epilepsy is presented. Cerebral CT scan showed bilateral and symmetrical thalamic hyperdensity. MRI revealed that the thalamus was hyperintense on T1-weighted images and hypointense on T2-weighted images with a hypersignal T2 of the white matter. Enzymatic assays objectified a deficiency of both hexosaminidases A and B confirming the diagnosis of Sandhoff disease

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed

Diagnosing mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey

peer reviewedMany countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS. © 2021 The Author

Clinical significance of soluble interleukin-2 receptor measurement in patients with idiopathic retroperitoneal fibrosis

Background Idiopathic retroperitoneal fibrosis (iRPF) is a rare chronic fibro-inflammatory disorder of unknown etiology. Activated T-helper cells, which shed soluble interleukin-2 receptor (sIL-2R) into the circulation, may play a pathogenetic role. Hence, measuring sIL-2R may be of value in monitoring disease activity and treatment response in iRPF patients. Methods We performed a prospective inception cohort study of 82 patients with untreated (re)active iRPF stratified by elevated (> 623 U/mL) or normal sIL-2R level at baseline and compared disease characteristics among these groups. Baseline and changes in sIL-2R levels following treatment with tamoxifen (TMX) or prednisone (PDN) were analyzed and related to treatment response. Results Median sIL-2R level was 668 U/mL (IQR 502.8-827.5); 48 patients (59%) had elevated baseline sIL-2R levels. Patients with elevated sIL-2R presented with higher CRP (P = 0.049) and serum creatinine (sCr) levels (P < 0.001) and more often had hydroureteronephrosis (P = 0.01). There was an age and sex adjusted linear association between baseline sIL-2R and both CRP (P = 0.02) and sCr (P < 0.001). Baseline and serial levels of sIL-2R were predictive and concordant, respectively, with clinical response in patients treated with PDN. ROC curve analyses of sIL-2R on a continuous scale and PDN treatment success showed an AUC of 0.84. A serum sIL-2R cut-off value for PDN treatment success of <= 703 U/mL was found with a sensitivity of 100% and specificity of 72%. Conclusion Serial measurement of sIL-2R may be of value in monitoring disease activity and PDN treatment response in iRPF patients.Personalised Therapeutic