Citations

Significance RBM28 is a human protein essential for proper assembly of the large ribosomal subunit, crucially enabling synthesis of all cellular proteins. Defects in RBM28 cause rare ribosomopathies: alopecia, neurological defects, and endocrinopathy (ANE) syndrome. We investigated an ANE syndrome patient with a clinical presentation consistent with the definition of ANE syndrome but possessing differing genetic variants and molecular pathology. We find one inherited allele is null, clarifying that ANE syndrome is not caused by RBM28 haploinsufficiency, while the other inherited allele retains enough function to enable survival but preclude proper development. Our results define an underlying pathology of ANE syndrome, further delineating an emerging class of assembly factor ribosomopathies and underscoring the importance of nucleolar processes in human health.

AbstractBackgroundMucopolysaccharidoses (MPS) is a group of hereditary multisystemic lysosomal disorders. Most neuroimaging studies in MPS have focused on the supratentorial compartment and craniocervical junction abnormalities, and data regarding posterior fossa findings are scarce in the literature. Thus, our purpose is to describe posterior fossa findings on magnetic resonance imaging (MRI) of MPS patients.MethodsWe reviewed routine MRI scans of MPS patients being followed up at our institution (types I, II, III, IV, and VI), focusing on posterior fossa structures.ResultsForty‐seven MPS patients were included. MRI‐visible perivascular spaces were commonly found in the midbrain and adjacent to the dentate nuclei (85% and 55% of patients, respectively). White‐matter lesion was not identified in most cases. Its most frequent localizations were in the pons and cerebellum (34% and 30% of patients, respectively). Enlargement of cerebrospinal fluid (CSF) spaces in the posterior fossa was present in 55% of individuals and was more frequent in neuronopathic patients (73% vs 40%; P = .02). Cerebellar volume was classified as normal, apparent macrocerebellum, atrophic, and hypoplastic in 38%, 38%, 21%, and 3% of patients, respectively. A depression of the posterior fossa floor in the midline sagittal plane was found in 22 patients (47%), which was statistical significantly associated with enlargement of CSF spaces (P = .02) and with apparent macrocerebellum (P = .03).ConclusionThe present study compiled the main posterior fossa findings in MPS patients. Classically described in the supratentorial compartment, MRI‐visible perivascular spaces, white matter lesions, and enlarged perivascular spaces were also found in the posterior fossa. However, atrophy, which commonly affects cerebral hemispheres, was not the most frequent cerebellar morphology found in our study. Moreover, potential findings for future research were described.

Abstract 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.

Abstract Background GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. Methods Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. Results A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. Conclusion Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans.

Background:Mucopolysaccharidosis type II (Hunter syndrome, or MPS II) is an X-linked lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which leads to the accumulation of glycosaminoglycans (GAGs) in a variety of tissues, resulting in a multisystemic disease that can also impair the central nervous system (CNS).Objective:This review focuses on providing the latest information and expert opinion about the therapies available and under development for MPS II.Methods:We have comprehensively revised the latest studies about hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT - intravenous, intrathecal, intracerebroventricular, and intravenous with fusion proteins), small molecules, gene therapy/genome editing, and supportive management.Results and Discussion:Intravenous ERT is a well-established specific therapy, which ameliorates the somatic features but not the CNS manifestations. Intrathecal or intracerebroventricular ERT and intravenous ERT with fusion proteins, presently under development, seem to be able to reduce the levels of GAGs in the CNS and have the potential of reducing the impact of the neurological burden of the disease. Gene therapy and/or genome editing have shown promising results in preclinical studies, bringing hope for a “one-time therapy” soon. Results with HSCT in MPS II are controversial, and small molecules could potentially address some disease manifestations. In addition to the specific therapeutic options, supportive care plays a major role in the management of these patients.Conclusion:At this time, the treatment of individuals with MPS II is mainly based on intravenous ERT, whereas HSCT can be a potential alternative in specific cases. In the coming years, several new therapy options that target the neurological phenotype of MPS II should be available.

Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM.

Abstract Background Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. Objectives To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. Methods Twenty‐seven families were screened for germline variants in eight XP‐related genes. Results All patients ( N = 32) were diagnosed with bi‐allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251‐1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2 / XPD , DDB2 / XPE and ERCC5 / XPG variants were found in a few patients. Aside from melanoma and non‐melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. Conclusions We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP‐related genes, unexpected non‐skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.