Clinical phenotyping is key to differentiating RFC1-associated neuropathy from immune-mediated neuropathy.

This scientific commentary refers to 'Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies', by Nagy et al. (https://doi.org/10.1093/braincomms/fcae163).

A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity.

Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2,670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3) was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (GnomADv4 allele frequency 1.76e-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.

A deep intronic variant in MME causes autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing.

BACKGROUND: Loss-of-function variants in MME (membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant, MME c.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. MME c.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic MME variant (c.467del; p.Pro156Leufs*14) in Family 2. AIMS: We aimed to determine the pathogenicity of the MME c.1188+428A>G variant through segregation and splicing analysis. METHODS: The splicing impact of the deep intronic MME variant c.1188+428A>G was assessed using an in vitro exon-trapping assay. RESULTS: The exon-trapping assay demonstrated that the MME c.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon between MME exons 12 and 13. The incorporation of the pseudoexon into MME transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in MME exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of MME transcript leading to a pathogenic loss-of-function. INTERPRETATION: To our knowledge, this is the first report of a pathogenic deep intronic MME variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.

Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Next-Generation Sequencing and Emerging Technologies.

Genetic sequencing technologies are evolving at a rapid pace with major implications for research and clinical practice. In this review, the authors provide an updated overview of next-generation sequencing (NGS) and emerging methodologies. NGS has tremendously improved sequencing output while being more time and cost-efficient in comparison to Sanger sequencing. The authors describe short-read sequencing approaches, such as sequencing by synthesis, ion semiconductor sequencing, and nanoball sequencing. Third-generation long-read sequencing now promises to overcome many of the limitations of short-read sequencing, such as the ability to reliably resolve repeat sequences and large genomic rearrangements. By combining complementary methods with massively parallel DNA sequencing, a greater insight into the biological context of disease mechanisms is now possible. Emerging methodologies, such as advances in nanopore technology, in situ nucleic acid sequencing, and microscopy-based sequencing, will continue the rapid evolution of this area. These new technologies hold many potential applications for hematological disorders, with the promise of precision and personalized medical care in the future.

MAN-C: A masked autoencoder neural cryptography based encryption scheme for CT scan images.

Sharing medical images securely is very important towards keeping patients' data confidential. In this paper we propose MAN-C: a Masked Autoencoder Neural Cryptography based encryption scheme for sharing medical images. The proposed technique builds upon recently proposed masked autoencoders. In the original paper, the masked autoencoders are used as scalable self-supervised learners for computer vision which reconstruct portions of originally patched images. Here, the facility to obfuscate portions of input image and the ability to reconstruct original images is used an encryption-decryption scheme. In the final form, masked autoencoders are combined with neural cryptography consisting of a tree parity machine and Shamir Scheme for secret image sharing. The proposed technique MAN-C helps to recover the loss in image due to noise during secret sharing of image.•Uses recently proposed masked autoencoders, originally designed as scalable self-supervised learners for computer vision, in an encryption-decryption setup.•Combines autoencoders with neural cryptography - the advantage our proposed approach offers over existing technique is that (i) Neural cryptography is a new type of public key cryptography that is not based on number theory, requires less computing time and memory and is non-deterministic in nature, (ii) masked auto-encoders provide additional level of obfuscation through their deep learning architecture.•The proposed scheme was evaluated on dataset consisting of CT scans made public by The Cancer Imaging Archive (TCIA). The proposed method produces better RMSE values between the input the encrypted image and comparable correlation values between the input and the output image with respect to the existing techniques.

An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Two Novel Variants in PI4KA in a Family Presenting With Hereditary Spastic Paraparesis: A Case Report.

Objectives: To report novel biallelic PI4KA variants in a family presenting with pure hereditary spastic paraparesis. Methods: Two affected sisters presented with unsolved hereditary spastic paraparesis and underwent clinical and imaging assessments. This was followed by short-read next-generation sequencing. Results: Analysis of next-generation sequencing data uncovered compound heterozygous variants in PI4KA (NM_058004.4: c.[3883C>A];[5785A>C]; p.[(His1295Asn);(Thr1929Pro)]. Using ACMG guidelines, both variants were classified as likely pathogenic. Discussion: Here, next-generation sequencing revealed 2 novel compound heterozygous variants in the phosphatidylinositol 4-kinase alpha gene (PI4KA) in 2 sisters presenting with progressive pure hereditary spastic paraparesis. Pathogenic variants in PI4KA have previously been associated with a spectrum of disorders including autosomal recessive perisylvian polymicrogyria, with cerebellar hypoplasia, arthrogryposis, and pure spastic paraplegia. The cases presented in this study expand the phenotypic spectrum associated with PI4KA variants and contribute new likely pathogenic variants for testing in patients with otherwise unsolved hereditary spastic paraparesis.

Understanding monogenic Parkinson's disease at a global scale.

Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's (GP2) Monogenic Network took a different approach by targeting PD centers not yet represented in the medical literature. Here, we describe combining both efforts in a "merger project" resulting in a global monogenic PD cohort with build-up of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expression of monogenic PD. This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results.

Upper Gastrointestinal Bleeding Secondary to Sodium Polystyrene Sulfonate Use: A Rare Adverse Effect of Commonly Prescribed Treatment.

We report a case of a 62-year-old man who was brought in by emergency medical services after a fall and change in mental status. He was found to have severe hyperkalemia, acute kidney injury, and rhabdomyolysis. The hyperkalemia was treated with sodium polystyrene sulfonate (SPS). During hospitalization, he witnessed having black tarry stools along with a significant drop in hemoglobin. Endoscopic evaluation demonstrated nonbleeding large diffuse gastric ulcers with stigmata of recent bleeding, and ulcer biopsy revealed findings consistent with SPS-induced gastric ulceration. No other source of bleeding was localized, suggesting acute upper gastrointestinal bleeding due to SPS mucosal injury.

International Online Survey on the Management of Patent Ductus Arteriosus.

INTRODUCTION: There is uncertainty and lack of consensus regarding optimal management of patent ductus arteriosus (PDA). We aimed to determine current clinical practice in PDA management across a range of different regions internationally. MATERIALS AND METHODS: We surveyed PDA management practices in neonatal intensive care units using a pre-piloted web-based survey, which was distributed to perinatal societies in 31 countries. The survey was available online from March 2018 to March 2019. RESULTS: There were 812 responses. The majority of clinicians (54%) did not have institutional protocols for PDA treatment, and 42% reported variable management within their own unit. Among infants <28 weeks (or <1,000 g), most clinicians (60%) treat symptomatically. Respondents in Australasia were more likely to treat PDA pre-symptomatically (44% vs. 18% all countries [OR 4.1; 95% CI 2.6-6.5; p < 0.001]), and respondents from North America were more likely to treat symptomatic PDA (67% vs. 60% all countries [OR 2.0; 95% CI 1.5-2.6; p < 0.001]). In infants ≥28 weeks (or ≥1,000 g), most clinicians (54%) treat symptomatically. Respondents in North America were more likely to treat PDAs in this group of infants conservatively (47% vs. 38% all countries [OR 2.3; 95% CI 1.7-3.2; p < 0.001]), and respondents from Asia were more likely to treat the PDA pre-symptomatically (21% vs. 7% all countries [OR 5.5; 95% CI 3.2-9.8; p < 0.001]). DISCUSSION/CONCLUSION: There were marked international differences in clinical practice, highlighting ongoing uncertainty and a lack of consensus regarding PDA management. An international conglomeration to coordinate research that prioritises and addresses these areas of contention is indicated.

Genetic Testing of Movements Disorders: A Review of Clinical Utility.

Currently, pathogenic variants in more than 500 different genes are known to cause various movement disorders. The increasing accessibility and reducing cost of genetic testing has resulted in increasing clinical use of genetic testing for the diagnosis of movement disorders. However, the optimal use case(s) for genetic testing at a patient level remain ill-defined. Here, we review the utility of genetic testing in patients with movement disorders and also highlight current challenges and limitations that need to be considered when making decisions about genetic testing in clinical practice. Highlights: The utility of genetic testing extends across multiple clinical and non-clinical domains. Here we review different aspects of the utility of genetic testing for movement disorders and the numerous associated challenges and limitations. These factors should be weighed on a case-by-case basis when requesting genetic tests in clinical practice.

A review of safety and immunogenicity of a novel measles, mumps, rubella (MMR) vaccine.

Measles, mumps, and rubella (MMR) are highly infectious viral diseases affecting young children and have high secondary attack rates. Present MMR vaccines show consistent seroconversion rates for anti-measles and anti-rubella antibodies with variable responses for anti-mumps antibodies. Most common strains for MMR vaccines, currently available in India, are the Edmonston-Zagreb measles strain, Leningrad Zagreb (L-Z) mumps strain, and the RA 27/3 rubella strain. L-Z strain of mumps virus has been found to be associated with aseptic meningitis by different studies from different parts of the world including India. Recently, a novel freeze-dried MMR vaccine developed by Zydus Lifesciences (Zyvac MMR) contains Edmonston Zagreb measles strain, Hoshino mumps strain, and RA 27/3 rubella strain. The Hoshino strain is WHO approved and was found to induce interferon gamma production. This review article aims to provide a comprehensive appraisal of the data available on the safety and immunogenicity of the novel MMR vaccine.

Two New Families and a Literature Review of ELOVL4-Associated Spinocerebellar Ataxia Type 34.

Autosomal dominant variants in ELOVL4 cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Maltese-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next-generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C > T p.(Thr233Met). The variant was initially classified as a variant of uncertain significance; however, through segregation studies, we reclassified the variant as likely pathogenic. We next identified an individual from another family (Algerian-Maltese-Australian) with the same ELOVL4 variant with spinocerebellar ataxia but without dermatological manifestations. We subsequently performed the first dedicated literature review of ELOVL4-associated ataxia to gain further insights into genotype-phenotype relationships. We identified a total of 60 reported cases of SCA34 to date. The majority had gait ataxia (88.3%), limb ataxia (76.7%), dysarthria (63.3%), and nystagmus (58.3%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.3%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa, and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple system atrophy type C) was seen in 32.4% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.

Omega-3 fatty acid supply in pregnancy for risk reduction of preterm and early preterm birth.

This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations, and is based on a review of the available strong evidence from randomized clinical trials and a formal consensus process. We concluded the following. Women of childbearing age should obtain a supply of at least 250 mg/d of docosahexaenoic+eicosapentaenoic acid from diet or supplements, and in pregnancy an additional intake of ≥100 to 200 mg/d of docosahexaenoic acid. Pregnant women with a low docosahexaenoic acid intake and/or low docosahexaenoic acid blood levels have an increased risk of preterm birth and early preterm birth. Thus, they should receive a supply of approximately 600 to 1000 mg/d of docosahexaenoic+eicosapentaenoic acid, or docosahexaenoic acid alone, given that this dosage showed significant reduction of preterm birth and early preterm birth in randomized controlled trials. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation. Identification of women with inadequate omega-3 supply is achievable by a set of standardized questions on intake. Docosahexaenoic acid measurement from blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cutoff values is needed. Information on how to achieve an appropriate intake of docosahexaenoic acid or docosahexaenoic+eicosapentaenoic acid for women of childbearing age and pregnant women should be provided to women and their partners.