Canavan disease (CD) is a severe neurodegenerative disorder caused by aspartoacylase (ASPA) deficiency, leading to N-acetyl-L-aspartic acid (NAA) accumulation and spongy degeneration. While several therapeutic candidates improve outcomes in CD mouse models when delivered before symptom onset, there remains a need for treatments targeting established disease pathology. Here, we demonstrate that transplantation with human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) expressing a functional ASPA gene (ASPA iNPCs) can rescue disease manifestations in symptomatic CD (Nur7) mice. When administered at postnatal day 21 (P21), ASPA iNPCs successfully engrafted, differentiated into neural lineage cells, and restored ASPA activity as revealed by reduced NAA level. Transplanted mice showed a significant reduction in brain and cerebrospinal fluid (CSF) NAA levels, decreased vacuolation across multiple brain regions, improved myelination, and enhanced motor function 6-month post-transplantation. Our findings demonstrate that ASPA iNPC transplantation can effectively reverse established CD pathology, suggesting therapeutic potential for treating symptomatic patients.

Legionella is a common cause of community-acquired pneumonia and can affect multiple organ systems. An association with rhabdomyolysis and acute kidney injury (AKI) have been noted for several decades, but population-based studies are limited and could aid in better understanding the prevalence, associated risk factors, and clinical significance of this complication. We performed a retrospective manual review of the electronic health record on 323 patients with legionellosis identified on the basis of urinary antigen or culture in a large, urban hospital system. Demographic and clinical data were extracted by four physician reviewers. Rhabdomyolysis was assessed on the basis of creatine kinase (CK) values ≥1,000 IU/L or suggestive urinalysis findings. AKI was classified according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Patients were excluded for missing data or potential alternative causes of rhabdomyolysis. Data were analyzed using appropriate parametric and non-parametric statistical tests and multivariate logistic regression analysis. A total of 210 patients were included in the analysis. Fifty patients (23.8%) had evidence of rhabdomyolysis, 20% of whom had severe rhabdomyolysis (CK ≥15,000 IU/L). Rhabdomyolysis was associated with male sex, black race, and age <65. Common comorbidities were not associated with rhabdomyolysis. Rhabdomyolysis was associated with AKI, including for mild cases (CK 1000-5000 IU/L), with longer hospital length of stay, and with higher likelihood of intensive care unit admission, but not with overall mortality, which was 5.1% in the patient cohort. Rhabdomyolysis is a common feature of legionellosis, is associated with AKI, and may be a marker of more severe disease.

Canavan disease (CD) is a rare autosomal recessive leukodystrophy caused by biallelic pathogenic variants in the ASPA gene. CD is characterized by developmental delay, macrocephaly, and abnormal muscle tone. The biochemical diagnosis is confirmed by increased N-acetylaspartic acid levels. The phenotypic presentation varies, with 85-90% of individuals exhibiting the severe, typical form, while 10-15% present with a milder, atypical form. Here we report on five patients with a clinical and biochemically proven diagnosis in whom a second pathogenic variant had not yet been identified. Targeted long-read sequencing of the entire ASPA gene revealed an SVA_E retrotransposable element located in intron 4 that had been missed by standard short-read-based diagnostic procedures. Haplotype analysis of all patients showed linkage of the SVA_E element with a noncoding variant in intron 1. Functional characterization of the SVA_E element suggests that transcripts of the affected allele are prone to highly efficient mRNA degradation processes. These findings enhance the precision of genetic diagnostics and enable improved guidance for families as well as facilitating potential access to targeted therapies.

Crohn's disease (CD) is a chronic, immune-mediated inflammatory bowel disease (IBD), presenting with symptoms of abdominal pain and bleeding from the gastrointestinal tract. There is no known cure. In vitro-expanded 'thymus-derived' regulatory T cells (tTreg) have shown promise in preclinical models of IBD, leading to interest in their use as a potential therapy in CD. We present a study protocol for a first-in-human study of Tregs for IBD using ex vivo Treg expansion. This study will explore the preliminary safety and tolerability of a single dose of Treg immunotherapy and will inform the design of a subsequent larger trial. Four patients will be recruited from gastroenterology clinics at Guy's and St Thomas' NHS Foundation Trust. Eligible participants are those who are at least 18 years old, have a diagnosis of active moderate to severe CD and have failed to respond to or tolerate at least two prior lines of standard medication. Participants receive a single dose of autologous ex vivo-expanded Tregs and will be followed up to week 21 to collect safety and exploratory efficacy data. Additional safety monitoring will occur at 1 and 2 years post-dose. The primary endpoint is defined as the occurrence of dose-limiting toxicity occurring within 5 weeks post-infusion. The study protocol and related documents have been approved by a NHS Research Ethics Committee, the Health Research Authority and the Medicines and Healthcare products Regulatory Agency for Clinical Trial Authorisation. It is intended that the results of the trial will be presented at international conferences and will be submitted for publication in a peer-reviewed scientific journal. NCT03185000.

The aim of this position statement is to provide recommendations aimed at Canadian reproductive care clinicians and genetics professionals regarding the use of reproductive carrier screening for autosomal recessive and X-linked recessive conditions. A multidisciplinary expert group was assembled to review the existing literature on reproductive carrier screening for autosomal recessive and X-linked recessive conditions and make recommendations relevant to the Canadian context. The statement was circulated for comment to the membership of the Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC), and multiple family physician reviewers. Feedback from these groups was incorporated, and the final position statement was approved by the CCMG Board of Directors on 5 December 2024 and the CAGC Board of Directors on 14 April 2025. Routinely offered pan-ethnic reproductive carrier screening via a provincial or territorial programme is recommended for a limited panel of relatively common and severe childhood onset genetic conditions, based on Canadian experience with ethnicity-based testing: cystic fibrosis, fragile X syndrome, spinal muscular atrophy, haemoglobinopathies and founder mutations for Tay-Sachs disease, Canavan disease and familial dysautonomia. Provincial/territorial programmes must be developed to provide oversight, ensure appropriate resourcing and manage education and roll-out. Maintaining regional ethnicity-based screening programmes is also recommended, where relevant. Publicly funded population-level expanded carrier screening is not recommended at this time.