A Brazilian Rare-Disease Center's Experience with Glucosylsphingosine (lyso-Gb1) in Patients with Gaucher Disease: Exploring a Novel Correlation with IgG Levels in Plasma and a Biomarker Measurement in CSF.

Gaucher disease (GD, OMIM 230800) is one of the most common lysosomal disorders, being caused by the deficient activity of the enzyme acid ß-glucocerebrosidase (Gcase). Three clinical forms of Gaucher's disease (GD) are classified based on neurological involvement. Type 1 (GD1) is non-neuronopathic, while types 2 (GD2) and 3 (GD3) are neuronopathic forms. Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages, it undergoes deacylation to become glycosylsphingosine (lyso-Gb1), which has shown to be a useful and reliable biomarker for the diagnosis and monitoring of treated and untreated patients with GD. Multiple myeloma (MM) is one of the leading causes of cancer-related death among patients with GD and monoclonal gammopathy of undetermined significance (MGUS) is a non-neoplastic condition that can be a telltale sign of a B clonal proliferation caused by the chronic activation of B cells. This study aimed to quantify Lyso-Gb1 levels in dried blood spots (DBS) and cerebrospinal fluid (CSF) as biomarkers for Gaucher disease (GD) and discuss the association of this biomarker with other clinical parameters. This is a mixed-methods study incorporating both cross-sectional and longitudinal elements within a cohort design with a convenience-sampling strategy. Data collection took place from January 2012 to March 2023. Lyso-Gb1 extraction from DBS involved the use of a methanol-acetonitrile-water mixture, followed by incubation and centrifugation. Analysis was performed using UPLC-MS/MS with MassLynx software version 4.2 and the control group for the DBS measurements included general newborns. CSF Lyso-Gb1 was extracted using ethyl acetate, analyzed by UPLC-MS/MS with a calibration curve, and expressed in pmol/L. Lysosomal activity in CSF was assessed by measuring chitotriosidase (Cht), and other lysosomal enzyme activities were assessed as previously described in the literature. Patients with metachromatic leukodystrophy (MLD) were used as controls. Thirty-two treated patients (twenty-nine GD1 and three GD3, all on ERT except for one GD type on SRT with eliglustat) and three untreated patients (one GD1, one GD2, and one GD3) were included. When analyzing only the treated GD1 group, a significant correlation was found between lyso-Gb1 and age (rho = -0.447, p = 0.001), ChT, and IgG levels (rho = 0.73, p < 0.001; and rho = 0.36, p = 0.03, respectively). Five GD1 patients (three females, mean age 40 years) also had their CSF collected and analyzed. The average measurement of lyso-Gb1 in CSF was 94 pmol/L (range: 57.1-157.9 pmol/L) versus <6.2 pmol/L in the control group (MLD). This is the first time, to the best of our knowledge, that lyso-Gb1 has been associated with IgG levels. While this finding reflects a risk for MGUS or MM and not only chronic plasma B-cell activation, it still requires further studies. Moreover, the analysis of CSF lyso-Gb1 levels in GD1 patients was demonstrated to be significantly higher than the control group. This raises the hypothesis that CSF lyso-Gb1 may serve as a valuable indicator for neurological involvement in GD, providing insights into the potential implications for neurological manifestations in GD, including GD1. The correlation between lyso-Gb1 and ChT levels in treated GD1 patients further underscores the interconnectedness of lysosomal markers and their relevance in monitoring.

An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report.

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

Disease progression in Sanfilippo type B: Case series of Brazilian patients.

Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.

Consecutive Liver and Bone Marrow Transplantation for Erythropoietic Protoporphyria: Case Report and Literature Review.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis resulting in the accumulation of protoporphyrin, characterized by liver failure in a minority of cases. Although liver transplant (LT) is the therapeutic strategy for advanced hepatic disease, it does not correct the primary defect, which leads to recurrence in liver graft. Thus, hematopoietic stem cell transplantation (HSCT) is an approach for treating EPP. METHODS: We aim to describe the first sequential LT and HSCT for EPP performed in Latin America, besides reviewing the present-day literature. RESULTS: The patient, a 13-year-old female with a history of photosensitivity, presented with symptoms of cholestatic and hepatopulmonary syndrome and was diagnosed with EPP. Liver biopsy demonstrated cirrhosis. She was submitted to a successful LT and showed improvement of respiratory symptoms. However, she had disease recurrence on the liver graft. She underwent a myeloablative HSCT using a matched unrelated donor, conditioning with BuCy (busulfan and cyclophosphamide), and GvHD (graft vs. host disease) prophylaxis with ATG (thymoglobulin), tacrolimus and methotrexate. Neutrophil engraftment occurred on D+18. She has presented mixed chimerism, but normalization of PP levels, being 300 days after HSCT, in good state of health and normal liver function. CONCLUSIONS: Consecutive LT and HSCT for EPP is a procedure that has been described in 10 cases in the literature and, even though these patients are a highly diversified population, studies have shown favorable results. This concept of treatment should be considered in patients with established liver disease.

Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.

OBJECTIVES: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. METHODS: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. RESULTS: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. CONCLUSION: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.

Convergent molecular mechanisms underlying cognitive impairment in mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by pathogenic variants in the iduronate-2-sulfatase gene (IDS), responsible for the degradation of glycosaminoglycans (GAGs) heparan and dermatan sulfate. IDS enzyme deficiency results in the accumulation of GAGs within cells and tissues, including the central nervous system (CNS). The progressive neurological outcome in a representative number of MPSII patients (neuronopathic form) involves cognitive impairment, behavioral difficulties, and regression in developmental milestones. In an attempt to dissect part of the influence of axon guidance instability over the cognitive impairment presentation in MPS II, we used brain expression data, network propagation, and clustering algorithm to prioritize in the human interactome a disease module associated with the MPS II context. We identified new candidate genes and pathways that act in focal adhesion, integrin cell surface, laminin interactions, ECM proteoglycans, cytoskeleton, and phagosome that converge into functional mechanisms involved in early neural circuit formation defects and could indicate clues about cognitive impairment in patients with MPSII. Such molecular changes during neurodevelopment may precede the morphological and clinical evidence, emphasizing the importance of an early diagnosis and directing the development of potential drug leads. Furthermore, our data also support previous hypotheses pointing to shared pathogenic mechanisms in some neurodegenerative diseases.

Clinical trials for genetic diseases in Latin America.

Latin American geneticists have been contributing to the scientific development of Human and Medical Genetics fields since the early 1950s. In the last decades, as Medical Genetics is moving toward a new era of innovative therapies for previously untreatable conditions, the participation of Latin America in clinical trials is also increasing. This review discusses the particularities regarding funding, regulatory, and ethical aspects of conducting clinical trials for genetic diseases in Latin America, with an especial focus on Brazil, the largest country with the highest number of studies. Although there are still several barriers to overcome, the recent development of orphan drug legislation and policies for rare diseases in many Latin American countries indicates a growing opportunity for the participation of the region in international efforts for the development of new therapies for genetic diseases.

Retraction notice to Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-Dependent Manner Am J Pathol 180 (2012) 1232-1242.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article is being retracted following correspondence from the Office of Accountability and Compliance at the University of Maryland, Baltimore. An internal investigation into this manuscript by the University of Maryland, Baltimore, found evidence that there are errors with the presentation of the standard deviations and statistical significance shown in Figure 6 which are not supported by the original data, and that these inaccuracies warrant retraction to correct the scientific record. Despite extensive efforts, the journal was unable to contact Dr. Ying-hua Yang and Dr. Hua Zhou with regard to this retraction.

Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy.

Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.

Lysosomal diseases: Overview on current diagnosis and treatment.

Lysosomal diseases (LDs), also known as lysosomal storage diseases (LSDs), are a heterogeneous group of conditions caused by defects in lysosomal function. LDs may result from deficiency of lysosomal hydrolases, membrane-associated transporters or other non-enzymatic proteins. Interest in the LD field is growing each year, as more conditions are, or will soon be treatable. In this article, we review the diagnosis of LDs, from clinical suspicion and screening tests to the identification of enzyme or protein deficiencies and molecular genetic diagnosis. We also cover the treatment approaches that are currently available or in development, including hematopoietic stem cell transplantation, enzyme replacement therapy, small molecules, and gene therapy.

Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner.

Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors are expressed in tissues outside of the nervous system and represent a widespread signal transduction system that is involved in the regulation of motility and adhesion in different cell types. We believe that the plexins and semaphorins, which are strongly expressed in both axons and many carcinomas, play a role in PNI. In this study, we show that plexin-B1 is overexpressed in tissues and cell lines from neurotropic malignancies and is attracted to nerves that express its ligand, semaphorin 4D, in a Rho/Rho kinase-dependent manner. We also demonstrate that nerves are attracted to tumors through this same system of proteins, suggesting that both plexin-B1 and semaphorin 4D are important in the promotion of PNI.

Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis.

RYR1-related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.

Follow-up of pre-motor symptoms of Parkinson's disease in adult patients with Gaucher disease type 1 and analysis of their lysosomal enzyme profiles in the CSF.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Its classic motor symptoms may be preceded by non-motor symptoms (NMS). Population studies have identified GBA variants as risk factors for idiopathic PD. The increased risk of PD has also been suggested in other Lysosomal Storage Disorders (LSDs). OBJECTIVE: To assess the evolution of the prevalence of NMS compatible with PD in a cohort of South Brazilian adult patients with Gaucher Disease (GD) type 1, already evaluated 3 years ago (2018). Cerebrospinal Fluid (CSF) was collected to assess the levels of LSD enzymes (beta-hexosaminidases, beta-glucuronidase) and biomarker of macrophage activation (chitotriosidase, ChT), compared to controls (metachromatic leukodystrophy, MLD). Cognition was evaluated by the Montreal Cognitive Assessment (MoCA) questionnaire, daytime sleepiness by the Epworth Sleepiness Scale (ESS), depression by Beck´s Inventory, constipation by the Unified Multiple System Atrophy Rating Scale (UMSARS) scale, and REM sleep behavior disorder by the single-question screen. Hyposmia was assessed with Sniffin' Sticks (SST). RESULTS: Nineteen patients completed the follow-up (mean age of the sample was 44 years; range, 26-71). The patient with the highest number of NMS at the baseline (4 including the lowest SST score) was diagnosed with PD four years later. Apart from an improvement in the ESS score, no other statistical significance was found between the number of NMS between the first and second evaluation, nor between patients with one L444P variant (n = 5) and the rest of the cohort. CSF was collected in five patients (mean age of the sample was 40 years, range 30-53. A significant difference was found in the mean CSF activity levels of beta-hexosaminidases and beta-glucuronidase between GD1 and MLD patients. Mean ChT (CSF) was 62 nmol/h/mL in GD patients and 142 in MLD (n = 6) patients. CONCLUSIONS: The patient with the highest number of NMS in our 2018 cohort was the one that developed PD, corroborating with the importance of this longitudinal follow-up. CSF and plasma analysis might allow a better understanding of the neurodegenerative processes connecting PD and the lysosomal environment. Further analysis is needed to understand this relationship.

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2).

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Analysis of socio-demographic and systemic health factors and the normative conditions of oral health care in a population of the Brazilian elderly.

OBJECTIVE: To investigate the association of socio-demographic and systemic health factors according to the normative conditions of oral health care (dental caries, edentulism, periodontal disease and oral mucosal lesion) in elderly individuals. MATERIAL AND METHODS: A cross-sectional study was carried out in a group of elderly with access to community health care (n = 200). The normative conditions of oral health were then investigated according to the WHO and the SB Brazil criteria. Bivariate analyses were evaluated by the chi-square test and Fisher's exact test. An estimation of prevalence for the covariates was performed using Poisson's regression models. RESULTS: The prevalence of edentulism and oral mucosal lesions was detected in 58% and 21.5% of elderly patients, respectively. In the dentate subjects, the prevalence of dental caries and periodontal disease was 51.2% and 20.8%, respectively. Older men and individuals from lower-income groups exhibited a higher prevalence of dental caries. Elderly women, illiterate individuals, and individuals over the age of 65 years exhibited a higher prevalence of edentulism. Elderly 60-64 years old and those who are employed had a significant association with periodontal disease. CONCLUSION: Socio-demographic factors were associated with some notable oral diseases in the elderly.

Diagnosis and Emerging Treatment Strategies for Mucopolysaccharidosis VII (Sly Syndrome).

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an ultra-rare lysosomal disease caused by a deficiency of the enzyme ß-glucuronidase (GUS). The diagnosis is suspected based on a range of symptoms that are common to many other MPS types, and it is confirmed through biochemical and molecular studies. Besides supportive treatment, current and emerging treatments include enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. This review summarizes the clinical manifestations, diagnosis, and emerging treatments for MPS VII.

Genome editing in lysosomal disorders.

Lysosomal disorders are a group of heterogenous diseases caused by mutations in genes that encode for lysosomal proteins. With exception of some cases, these disorders still lack both knowledge of disease pathogenesis and specific therapies. In this sense, genome editing arises as a technique that allows both the creation of specific cell lines, animal models and gene therapy protocols for these disorders. Here we explain the main applications of genome editing for lysosomal diseases, with examples based on the literature. The ability to rewrite the genome will be of extreme importance to study and potentially treat these rare disorders.

Schizophreniform presentation and abrupt neurologic decline in a patient with late-onset mucopolysaccharidosis type IIIB.

Due to their low frequency and some atypical presentations, inborn errors of metabolism are frequently misdiagnosed or underdiagnosed, which hinders the correct management of these patients. To illustrate that, here we present a patient that, at early school age, had learning disabilities compared to her classmates, especially for writing. She completed basic education in a regular school and was transferred to a secondary school for students with special needs. At 18 years of age, she presented a first psychiatric abrupt outbreak: she spent a month screaming and without sleeping. Behavioral problems then became apparent, especially hyperactivity, destructive and chaotic behavior, anxiety, and auto-aggressivity and hetero-aggressivity. A diagnosis of schizophreniform disorder was established. Clinical genetic evaluation revealed coarse face, macroglossia, coarse thick hair, and mild hepatomegaly, and the hypothesis of mucopolysaccharidosis-III was raised. Laboratory tests indicated high levels of urinary glycosaminoglycans and almost undetectable NAGLU activity, confirming the diagnosis. Sequencing of the NAGLU gene revealed the c.1318G>C (p.Gly440Arg) and c.1834A>G (p.Ser612Gly) mutations.

Progression of Cardiovascular Manifestations in Adults and Children With Mucopolysaccharidoses With and Without Enzyme Replacement Therapy.

Background: Cardiovascular involvement is among the main features of MPS disorders and it is also a significant cause of morbidity and mortality. The range of manifestations includes cardiac valve disease, conduction abnormalities, left ventricular hypertrophy, and coronary artery disease. Here, we assessed the cardiovascular manifestations in a cohort of children and adults with MPS I, II, IV, and VI, as well as the impact of enzyme replacement therapy (ERT) on those manifestations. Methods: We performed a chart review of 53 children and 23 adults with different types of MPS that had performed echocardiograms from January 2000 until October 2018. Standardized Z scores were obtained for heart chamber sizes according to the body surface area. When available, echocardiographic measurements that were performed before ERT and at least 18 months after that date were used for the assessment of pre- and post-treatment parameters. Results: Left side valvular disease was a frequent finding, with mitral and aortic thickening being reported in most patients in all four MPS types. Left atrium dilatation was present in 26% of the patients; 25% had increased relative wall thickness; 28% had pulmonary hypertension. The cardiovascular involvement was, in general, more prevalent and more severe in adults than in children, including conduction disorders (40 vs. 16%), mitral stenosis (26 vs. 6%), aortic stenosis (13 vs. 4%), and systolic dysfunction (observed in only one adult patient). ERT promoted a significant reduction of the left ventricular hypertrophy parameters, but failed to improve valve abnormalities, pulmonary hypertension, and left atrial dilatation. Conclusions: Adult patients with MPS may develop severe cardiovascular involvement, not commonly observed in children, and clinicians should be aware of the need for careful monitoring and timely management of those potentially life-threatening complications. Our results also confirm the impact of long-term ERT on left ventricular hypertrophy and its limitations in reversing other prevalent cardiovascular manifestations.

Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series.

CONTEXT: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes. METHODS: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts. RESULTS: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated. CONCLUSIONS: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8.