Explore the vast range of titles available.

Expansions of short tandem repeats (STRs) cause many rare diseases. Expansion detection is challenging with short-read DNA sequencing data since supporting reads are often mapped incorrectly. Detection is particularly difficult for “novel” STRs, which include new motifs at known loci or STRs absent from the reference genome. We developed STRling to efficiently count k-mers to recover informative reads and call expansions at known and novel STR loci. STRling is sensitive to known STR disease loci, has a low false discovery rate, and resolves novel STR expansions to base-pair position accuracy. It is fast, scalable, open-source, and available at: github.com/quinlan-lab/STRling .

Key Points Inherited neurodegenerative diseases are associated with a wide range of ocular abnormalities, which can cause substantial disability Ophthalmic findings can aid the genetic diagnosis of some neurodegenerative conditions; this diagnosis might, in turn, direct the clinician towards careful examination of the visual systems to provide useful adjunctive information In some patients, ophthalmic manifestations are the earliest symptoms of inherited neurodegenerative disease An increasing body of evidence indicates that ophthalmic findings can act as surrogate markers of disease progression in patients with inherited neurodegenerative conditions Optical coherence tomography is emerging as a useful tool for quantifying retinal and optic nerve findings in patients with neurodegenerative disease The role of mitochondrial dysfunction in inherited neurodegenerative disease has been well established, and ophthalmic involvement is a common manifestation of this dysfunction Ophthalmic findings are common features of neurodegenerative disorders, and have emerged as potentially useful biomarkers of disease progression in several conditions. Kersten et al . describe the various afferent visual system and other ophthalmic features of inherited neurodegenerative disorders, focusing on the expanding role of optical coherence tomography in diagnostic imaging of the retina and optic nerve head. They also discuss the ophthalmic manifestations and treatment implications of mitochondrial dysfunction—a feature of many inherited neurodegenerative diseases. Ophthalmic findings are common features of neurodegenerative disorders and, in addition to being clinically important, have emerged as potentially useful biomarkers of disease progression in several conditions. Clinically, these visual system abnormalities can be a clue to diagnosis, as well as being a prominent cause of disability in affected patients. In this Review, we describe the various afferent visual system and other ophthalmic features of inherited neurodegenerative disorders, including the muscular dystrophies, Friedreich ataxia, the spinocerebellar ataxias, hereditary spastic paraplegia, Charcot–Marie–Tooth disease, and other conditions. We focus on the expanding role of optical coherence tomography in diagnostic imaging of the retina and optic nerve head, and the possible use of ophthalmic findings as biomarkers of disease severity in hereditary neurodegenerative disorders. In addition, we discuss the ophthalmic manifestations and treatment implications of mitochondrial dysfunction, which is a feature of many inherited neurodegenerative diseases.

BackgroundNovel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages.MethodsFrataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function.ResultsBoth cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function.Discussion and conclusionAlthough isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.

Previous reports of ocular abnormalities in Huntington’s disease (HD) have detailed eye movement disorders. The objective of this case–control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p  = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration ( R 2  = −0.51, p  = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration ( R 2  = −0.71, p  = 0.002), and motor scores ( R 2  = −0.56, p  = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber’s hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials. The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated. The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well. Clinicaltrials.gov NCT03981575.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials. The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated. The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well.

aims: To describe the clinical features and outcomes of patients with myelopathy and neuropathy due to recreationally inhaled nitrous oxide. methods: We identified patients presenting with nitrous oxide-associated myelopathy from an electronic database of all discharges in a large tertiary hospital between 2016 and 2023. Demographics, clinical features and the results of investigations were recorded. The primary outcome was modified Rankin Scale score (mRS) at least 3 months after hospital discharge where available. results: There were 12 patients identified, six women, mean (SD) age 27.5 (5.1) years, range 19–47 years. The most common symptoms were numbness, weakness and mental state changes. Four patients used large amounts of inhaled nitrous oxide and also took over-the-counter vitamin B12 supplements. The median (range) hospital length of stay was 8.5 (2–56) days. Functional independence at last assessment (median [range] of 3 [1–34] months after discharge) was achieved in nine of the patients, with three requiring ongoing support for activities of daily living (mRS ≥3). conclusion: Nitrous oxide abuse and its neurological complications are an important public health issue. Clinicians should be aware that some patients who use large amounts of nitrous oxide may self-supplement vitamin B12.

Patients with congestive myelopathy due to spinal dural arteriovenous fistula (SDAVF) typically present with progressive sensory and motor disturbance in association with sphincter dysfunction. Spinal MRI usually shows longitudinally extensive T2 signal change. Here, we report four patients with progressive myelopathy due to SDAVF who also presented with findings on cerebrospinal fluid (CSF) examination suggestive of an inflammatory aetiology. Such CSF findings in SDAVF are important to recognise, to avoid the erroneous diagnosis of an inflammatory myelitis and inappropriate treatment with immunosuppression. SDAVF can be difficult to detect and may require repeated investigation, with formal angiography as the gold standard.

Background/ObjectivesTo describe the clinical features and outcomes of patients with myelopathy and neuropathy due to recreationally inhaled nitrous oxide.MethodsWe identified patients presenting with nitrous oxide associated myelopathy from an electronic database of all discharges in a large tertiary hospital between 2016 and 2023. Demographic, clinical features and the results of investigations were recorded. The primary outcome was modified Rankin Scale score (mRS) at least three months after hospital discharge where available.ResultsThere were 12 patients identified; six women, mean (SD) age 27.5 (5.1) years, range 19–47 years. The most common symptoms were numbness, weakness and mental state changes. Four patients used large amounts of inhaled nitrous oxide and also took over-the-counter vitamin B12 supplements. The median (range) hospital length of stay was 8.5 (2–56) days. Functional independence at last assessment (median [range] of 3 [1–34] months after discharge) was achieved in nine of the patients with three requiring ongoing support for activities of daily living (mRS ³3).Conclusion/DiscussionNitrous oxide abuse and its neurological complications are an important public health issue. Functional impairment secondary to nitrous oxide myelopathy can take many months to recover. Clinicians should be aware that some patients who use large amounts of nitrous oxide may self-supplement vitamin B12.