To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional ...outcomes for patients with HSP.
We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65).
A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were
(SPG4, 48%),
(SPG3A, 16%),
(8%),
(7%), and
(SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset (
= 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04-548.24,
< 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes (
= 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI (
= 0.014).
The most important predictors of disability in our HSP cohort were
mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.
Abstract Background Mutations in the fukutin-related protein gene account for a broad spectrum of phenotypes ranging from severe congenital muscular dystrophies to a much milder limb-girdle muscular ...dystrophy 2I. The involvement of the eyes is variable, with most patients having normal eye examination. Objectives We describe eye and brain abnormalities in a 16 month-old-boy with Walker-Warburg syndrome phenotype resulting from a novel fukutin-related protein gene mutation in exon 4 and compare these with other reported patients with fukutin-related protein gene mutation. Methodology All patients with reported fukutin-related protein gene mutations who had eye involvement were included. Their clinical features, brain magnetic resonance imaging, and eye findings were compared with our patient. Conclusions Patients with fukutin-related protein gene mutation tend to have no or mild eye involvement (generally strabismus), with very few cases reported of moderate to severe eye involvement. Our patient with a novel mutation c.558dupC(p.Ala187fs) represents one of the most severe phenotypes described in regard to eye involvement.
Beckwith–Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for ...appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15 %) have been attributed mainly to mutations in the growth suppressor gene
CDKN1C,
but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification. Molecular alterations were detected in 167 patients, where 103 (62 %) showed loss of methylation at IC2, 23 (14 %) had gain of methylation at IC1, and 41 (25 %) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9 %) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counseling.
The transforaminal lumbar interbody fusion (TLIF) has seen significant evolution since its early inception, reflecting advancements in surgical techniques, patient safety, and outcomes. Originally ...described as an improvement over the posterior lumbar interbody fusion (PLIF), the TLIF began as an open surgical procedure, that notably reduced the need for the extensive neural retractation that hindered the PLIF. In line with the broader practice of surgery, trending toward minimally invasive access, the TLIF was followed by the development of the minimally invasive TLIF (MIS-TLIF), a technique that further decreased tissue trauma and postoperative complications. Subsequent advancements, including Trans-Kambin's Triangle TLIF (percLIF) and transfacet LIF, have continued to refine surgical access, minimize surgical footprint, and reduce the risk of injury to the patient. The latest evolution, as we will describe it, the patient-specific TLIF, is a culmination of the aforementioned adaptations and incorporates advanced imaging and segmentation technologies into perioperative planning, allowing surgeons to tailor approaches based on individual patient anatomy and pathology. These developments signify a shift towards more precise methods in spine surgery. The ongoing evolution of the TLIF technique illustrates the dynamic nature of surgery and emphasizes the need for continued adaptation and refinement.
The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in ...clinical genetic diagnostics, including the application of whole‐exome sequencing and next‐generation sequencing‐based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq‐based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of right ventricular free wall myocardium and life-threatening ventricular ...arrhythmias. A missense mutation, c.1073C>T (p.S358L) in the transmembrane protein 43 (
TMEM43
) gene, has been genetically identified to cause ARVC type 5 in a founder population from Newfoundland. It is unclear whether this mutation occurs in other populations outside of this founder population or if other variants of
TMEM43
are associated with ARVC disease. We sought to identify non-Newfoundland individuals with
TMEM43
variants among patient samples sent for genetic assessment for possible ARVC. Of 195 unrelated individuals with suspected ARVC, mutation of desmosomal proteins was seen in 28 and the p.S358L TMEM43 mutation in six. We identified a de novo p.S358L mutation in a non-Newfoundland patient and five separate rare
TMEM43
(four novel) sequence variants in non-Newfoundland patients, each occurring in an evolutionarily conserved amino acid.
TMEM43
mutations occur outside of the founder population of the island of Newfoundland where it was originally described.
TMEM43
sequencing should be incorporated into clinical genetic testing for ARVC patients.
Abstract
Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It ...requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI’s ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.
Graphical Abstract
Graphical Abstract
PDF
