Leukodystrophies (LDs) are a group of rare, genetic disorders unified by their hallmark involvement of the cerebral white matter. They are typically characterized as progressive disorders, resulting in severe neurologic decline and premature death within months to years after onset. Managing LDs therefore requires lifelong, multidisciplinary care, a challenge compounded by their rarity and phenotypic heterogeneity, for which detailed clinical and scientific information is sometimes lacking. Research networks have proven useful in the rare disease community to unite efforts, increase awareness, and accelerate progress toward understanding and treating these often understudied conditions. Therefore, we established the Canadian Association for Research Excellence in Leukodystrophy (CARELeuko), a national network dedicated to improving LD care, research, and treatment within Canada. To better understand and address the most pressing needs for LDs in Canada, we engaged a diverse group of stakeholders including researchers, clinicians, and patient advocates to highlight and prioritize gaps in LD care and research. In this review, we discuss the key gaps identified in the Canadian LD landscape and outline strategies to address these challenges. This effort will inform the development of targeted initiatives aimed at improving outcomes for Canadian families affected by these debilitating disorders.

Lafora disease (LD) is a severe, ultra-rare childhood-onset progressive myoclonus epilepsy caused by biallelic pathogenic variants in either or and currently without cure. Body fluid-derived biomarkers have remained largely unexplored in LD. Neurofilament light chain (NfL) levels in serum (sNfL) and CSF (cNfL) reflect ongoing neurodegeneration and have been established as prognostic and therapeutic biomarkers in various neurologic disorders. In this study, we assessed the utility of NfL as a biomarker of LD in a multicenter cohort of patients with LD.

[This corrects the article DOI: 10.1212/NXG.0000000000200293.].

Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by biallelic variants, is classically characterized by spasticity, ataxia, and peripheral neuropathy. The aim of this study was to define the clinical and genetic spectrum of -related inherited peripheral neuropathies (IPNs) in Japanese patients.

Our aim was to report a novel variant of Guanine nucleotide-binding protein subunit beta-4 gene () variants and to report the clinical and molecular spectrum of the -related neuropathy based on the currently reported cases.

Neurodevelopmental disorders (NDDs) are often the results of genetic factors, whose identification and key role in their etiology may be elusive. Despite advancements in genetic testing, many cases remain unsolved. Single-nucleotide variants in a critical 18-bp region of the noncoding gene , a crucial component of the spliceosome complex, have been recently recognized as being responsible for ReNU syndrome, also known as NDD with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA). The aim of this study was to investigate the prevalence of variants within a cohort of unsolved patients exhibiting NDDs from the Telethon Undiagnosed Disease Program (TUDP).

SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by intronic expansions of pentanucleotide repeats in the gene. While various repeat motifs have been described, emerging evidence suggests that specific repeat motifs, rather than repeat length alone, can modify disease features such as seizure prevalence and penetrance.

Limb-girdle muscular dystrophy (LGMD) type R1/2A, calpain-3-related, is a rare, autosomal recessive disorder caused by pathogenic variants in the gene. LGMDR1/2A causes progressive weakness of upper and lower limbs, leading to difficulty walking and use of arms for overhead activities. The rate of progression of LGMDR1/2A is unknown because of the limited number of published cohorts and the lack of validated outcome measures. Quantifying the natural history of LGMDR1/2A using standardized outcome measures is critical for understanding the rate of disease progression and improving clinical care and clinical trial readiness. The aim of this cross-sectional study was to evaluate the suitability of the North Star Assessment for limb-girdle type muscular dystrophies (NSAD), 100-meter timed test (100MTT), and Performance of Upper Limb 2.0 (PUL) as outcome measures for quantifying disease presentation and progression in individuals with LGMDR1/2A.

People with university degrees have a lower incidence of Alzheimer disease (AD). However, the relationship between education and AD could be due to selection, collider, or ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. In this study, we use 2-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD.

β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation. Owing to the limited number of reported cases, information on the natural history of the disease and brain imaging is scarce. We report 6 new cases and review them together with all the previously reported cases in the literature.

Dominant pathogenic variants in ATP1A3 can occur anywhere in the coding sequence and can cause a wide range of clinical presentations. A practical problem is that sequencing services use one of 3 different mRNA transcripts with different lengths to number the candidate variants. Genetic reports often identify an ATP1A3 variant as a VUS when it is actually well validated. Only 1 transcript, the MANE Select transcript that encodes a protein of 1,013 amino acids, is well supported by evidence. Misidentification of variants in ATP1A3 is disadvantageous when it prevents a confident diagnosis. We illustrate the differences among the 3 transcripts and their merits. Sequencing services should use the MANE Select transcript.

The aim of this study was to investigate the endophenotypic potential of striatal dopamine transporter (DAT) uptake in carriers of Parkinson disease (PD)-associated genetic risk variants.

The aim of this study was to investigate whether the considerable phenotypic variation in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) is due to additional pathogenic coding variants in severely affected patients, by screening a panel of neuropathy-related genes.

Myelin protein zero (MPZ)-related neuropathies include demyelinating CMT1B and later-onset axonal forms (CMT2I/J). CMT1B pathogenic variants act through gain-of-function, destabilizing MPZ and activating the unfolded protein response (UPR), or loss-of-function, disrupting MPZ homomeric interactions in myelin. This study investigates early-onset (<18 years) CMT1B due to MPZ variants in a large Italian cohort, shedding light on clinical progression and genotype-phenotype correlations, with relevance to emerging UPR-targeted therapies.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by variants in the gene. The extracellular domain of NOTCH3 (N3ECD) has been proposed as a potential serum biomarker for CADASIL. However, its diagnostic utility remains uncertain. The aim of this study was to evaluate serum N3ECD levels in patients with CADASIL and assess their potential as a diagnostic or prognostic biomarker.

Variants of unknown significance (VUS) pose an extensive clinical challenge. Our objective was to explore the diagnostic pipeline from symptom onset to molecular diagnosis in autosomal recessive (Spastic ataxia type 2 [SPAX2], Mendelian Inheritance in Man [MIM] number 611302) caused by a new homozygous variant in the gene.

Myotonic dystrophy type 1 and type 2 (DM1/DM2) are multisystemic disorders that may affect heart function in addition to the progressive skeletal muscle weakness and myotonia that occur. There are limited population-based studies on the prevalence and risks associated with cardiac symptoms in DM1 and DM2.

A recent explosion in genomic testing has led to the identification of several genetic disorders that mimic CNS-specific autoimmune disorders. Such monogenic disorders, although rare, represent a diagnostic challenge because of their diverse phenotypes and overlapping features. Early recognition of these disorders is crucial not only to prevent overtreatment with immunotherapy but also to ensure that targeted treatments are available for many of these disorders. This review explores some of the monogenic disorders that can masquerade as neuroinflammatory phenotypes. These clinical vignettes are stratified according to neuroanatomical localization along the neuroaxis: supratentorial white matter, gray matter, brainstem, and spinal cord involvement. Through these cases, we discuss how clinical, laboratory, and neuroimaging red flags, such as early onset, relentless progression despite immunotherapy, and lack of CSF markers of inflammation, can guide specific diagnostic workup. In the next section, we highlight the approach to genetic testing in identifying monogenic mimickers. Finally, we discuss a selected list of currently available and emerging therapeutic strategies for some of these disorders. These include JAK inhibitors for Aicardi-Goutières syndrome, anti-TNF therapy for adenosine deaminase 2 deficiency (DADA2), and gene replacement therapy for X-linked adrenoleukodystrophy. By providing a comprehensive and systematic clinical approach, this review aims to equip neurologists with a framework to navigate diagnostic evaluations for such monogenic disorders.

hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome due to pathogenic germline variants in the gene. PHTS harbors a diverse range of clinical manifestations including an associated neurodevelopmental (ND) and neurologic phenotype, requiring a multidisciplinary approach to care. There are no clinical practice guidelines for the management of ND or neurologic comorbidities. The objective of these clinical guidelines was to use the latest knowledge to generate a resource for providers, researchers, and patients on the best practices in the practical management of neurologic and ND challenges in PHTS.

[This corrects the article on p. ii in vol. 11.][This corrects the article on p. ii in vol. 11.].