Developing a National Network for Leukodystrophy Research and Care in Canada

Abstract

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.

Introduction

Rare diseases in Canada are defined as those affecting less than 1 in 2,000 people.¹ Though individually rare, these diseases collectively affect millions of Canadians, underscoring the urgent need for a coordinated and comprehensive approach to address the specific needs of these families. Estimates suggest that approximately 1 in 12 Canadians are affected by a rare disorder,¹ and this proportion may increase with the availability of low-cost sequencing technologies.² Rare diseases are often complex, progressive, and multisystemic conditions that necessitate interdisciplinary care and therefore represent a significant public health challenge. Recognizing this, the Canadian federal government recently invested $1.5 billion into a National Strategy for Drugs for Rare Diseases, aimed at reducing the cost and accessibility of rare disease treatments for all Canadians.² As such, there is no better time to invest resources toward understanding and developing treatments for rare diseases.

To address the needs of rare disease communities in Canada, national and provincial research networks such as the Canadian Rare Disease Network, Care4Rare, Canadian Rare Diseases Models and Mechanisms (RDMM), Pediatric Rare Disease Clinical Trials and Treatment Network (RareKids-CAN), RARE.Qc (Quebec), and the Inform Rare Network have emerged. These networks have been successful in focusing and uniting rare disease research efforts across Canada.^3-6 Building on these successes, we have developed a Canadian network specifically focused on a group of rare disorders known as leukodystrophies (LDs).

LDs are a heterogenous group of more than 100 inherited white matter disorders, with a collective incidence of approximately 1 in 4,700 live births.⁷ Disease onset ranges from infancy to late adulthood, with the majority of LDs following a neurodegenerative course, leading to severe disability and early death.⁸ Owing to the complex and progressive nature of LDs, patients require a multidisciplinary team to manage both neurologic and systemic manifestations as well as ongoing disease progression. In the United States and some European countries, national LD consortia and networks have been established to coordinate research, develop specialized centers, improve access to care, and accelerate therapy development. However, Canada lacks a unified effort to address the needs of Canadian families affected by LDs, which our network, the Canadian Association for Research Excellence in Leukodystrophies (CARELeuko), aims to address. While CARELeuko's work is currently centered in Montreal, QC, our vision is to expand nationwide. By fostering collaboration among researchers, clinicians, patient partners, and patient advocacy groups (PAGs), CARELeuko seeks to bridge the gaps in care, research, and treatment, and ultimately improve the quality of life for those living with LDs in Canada.

Critical Gaps in the International and Canadian Leukodystrophy Landscapes

In the past few decades, significant advancements in LD research have expanded our understanding of these disorders. Despite this progress, substantial knowledge gaps persist. To address these, on September 25, 2024, we convened with Canadian experts across the fields of LDs, complex care, disease modeling, therapeutic development, and clinical trial design, together with patient advocates and patient organizations, to discuss and itemize critical gaps in LD care and research, both internationally and with a particular focus on Canada.

Many of the pressing unmet needs highlighted during this discussion reflect shared challenges faced by patients and caregivers worldwide, underscoring the vital importance of maintaining focused efforts in 4 primary areas: advancing diagnostics, elucidating disease mechanisms, developing effective therapies, and establishing robust clinical characterization and evidence-based guidelines.

Despite rapid advancements in sequencing technologies, approximately 20%–30% of pediatric and 51%–70% of adult patients with leukodystrophy remain without a molecular diagnosis.^7,9 This leaves many families without definitive answers or targeted care plans. Furthermore, the expanding number of recognized LDs over the past 2 decades has outpaced our understanding of the underlying pathophysiology. For many newly identified LDs, the lack of representative disease models significantly hampers efforts to uncover disease mechanisms and develop therapies. As a result, almost all LDs still lack disease-modifying treatments. Compounding this issue, the absence of natural history data and surrogate markers for many LDs presents a significant barrier to evaluating therapeutic efficacy, thus delaying the transition from preclinical development to clinical trials. Furthermore, this contributes to a lack of evidence-based guidelines for the comprehensive care of individuals and their families.

Within Canada, we face additional challenges and knowledge gaps specific to our health care system, policy framework, and geography. The purpose of CARELeuko is to contribute to international efforts addressing these global gaps while also focusing on how we can address barriers unique within Canada, detailed below.

Limited Clinical Expertise and National Guidelines

The benefit of specialized knowledge and clinical expertise for patients with rare disease, including LDs, is well established.^10,11 Specialized LD centers/clinics offer expert care, resources, and support for patients diagnosed with LDs, bringing together multidisciplinary teams with knowledge of the various manifestations and evolutions of LDs and providing comprehensive psychosocial support.^12-14

Unfortunately, a number of factors impede Canadian patients with LDs from accessing these specialized resources. Canada's expansive landscape and population distribution create unique challenges for patients, with major health care centers spread across large distances.^15,16 Many affected families must therefore travel significant distances to meet their basic health care needs. To our knowledge, specialized LD clinics are currently siloed to Montreal, QC (The Montreal Neurological Hospital and Montreal Children's Hospital), and London, ON (Children's Hospital), limiting access for millions of Canadians distant from these regions. As such, many patients with LDs are followed at tertiary genetic, metabolic, and pediatric clinics across the country, which may lack the specific expertise required for comprehensive LD care. Accessing these specialized LD clinics can impose heavy financial and logistical burdens on families, who must coordinate transportation, accommodations, and multiple medical appointments. The complex and multisystemic nature of LDs further complicates travel, adding mental, physical, and financial stress for patients and caregivers. Adding to these challenges is the current structure of existing LD clinics in Canada, which are run by a single (pediatric/adult) neurologist without support from dedicated nursing staff or other specialists. As a result, these clinicians must refer patients to the various specialists they need, complicating care coordination to meet the needs of patients.

These challenges underscore the critical need to prioritize, improve, and expand Canada's clinical LD expertise nationwide. The current scarcity of specialized centers/clinics restricts patient access and limits the sharing of best practices among health care practitioners (HCPs). Furthermore, many patients and families may be unaware of available resources and expertise within the country, exacerbating their stress and uncertainty. LD clinics in Canada, both current and future, require dedicated funding and integrated multidisciplinary teams to better address patients' needs and reduce caregiver burden.

The limited availability of specialized LD centers/clinics in Canada contrasts sharply with the well-established networks in the United States and some European countries, where comprehensive, multidisciplinary care is more accessible and streamlined^12,17,18 (Figure). Canada can draw from these examples to expand access to LD-specific care. In implementing a more comprehensive approach to LD care across Canada, we can prioritize the development of LD clinical care guidelines for HCPs, specific training for pediatric and adult neurologists, and the establishment of nationally recognized LD centers of excellence. By equipping HCPs with specialized knowledge, Canadian patients will have greater access to timely diagnoses, innovative treatments, and improved care coordination. These efforts would significantly improve the quality of life for those living with LDs and help close the gap in treatment access for patients across the country.

Figure. Geographical Representation of Specialized LD Centers or Networks Located Mainly in North America and Europe.

Canadian centers where LD specialists' practice is highlighted in red. LD = leukodystrophy.

Newborn Screening

Newborn screening (NBS) is a highly effective strategy for improving early diagnosis, access to treatment, and quality of life for many progressive disorders where effective therapies are available. Inclusion of a new disease in a NBS panel requires careful consideration of the available scientific evidence on a variety of key factors, including the natural history of a disease, the feasibility and reliability of screening tests, the availability and efficacy of treatments, and the cost-effectiveness of implementing the screening program.^19,20 Despite the devastating nature of LDs and the availability of several disease-modifying therapies since at least the 1990s, no LDs are currently included in any provincial/territorial NBS programs in Canada. This includes LDs such as adrenoleukodystrophy (ALD; MIM: 300100), metachromatic leukodystrophy (MLD; MIM: 250100), and Krabbe disease (MIM: 245200), for which hematopoietic stem cell transplantation (HSCT) is the standard of care for specific forms of the disease,²¹ and cerebrotendinous xanthomatosis (CTX; MIM: 213700), which has been successfully treated using bile acid replacement therapy.²² More recently, significant advancements have led to the approval of HSCT gene therapy (HSCT-GT) for specific subtypes of ALD²³ and MLD²⁴ in Europe and the United States. These therapies have been effective in alleviating symptoms and slowing/halting disease progression, particularly when administered early. However, the optimal timing varies across LDs/LD subtypes,^25–31 and the window for intervention is often narrow due to rapid disease progression. This poses challenges for HSCT and gene therapy, which require complex preparation and coordination. Without NBS or a known family history, diagnosis is often delayed until symptoms have already manifested, by which point a given treatment may no longer be effective.^25,32 Unfortunately, presymptomatic patients are typically identified only if an older sibling has already been diagnosed, limiting therapeutic access significantly. Efforts to implement these LDs into NBS programs have been underway for many years in the U.S. and Europe, with effective screening tests developed for ALD,^33,34 MLD,³⁵ Krabbe disease,³⁶ and CTX.^37,38 Specifically, ALD and infantile Krabbe disease have been included in the federally recommended uniform screening panel in the United States since 2016 and 2024, respectively, and ALD screening has been adopted in Taiwan³⁹ and the Netherlands,⁴⁰ with pilot studies ongoing in Japan^e1 and Italy,^e2 and a pilot project for Krabbe disease is underway in Italy.^e3 Notably, Ontario has announced a pilot NBS program for ALD set to launch in 2025, marking Canada's first leukodystrophy NBS initiative.^e4 While MLD and CTX have not yet been added to the US RUSP, ongoing pilot projects are underway in several countries,^37,e5,e6 and Norway recently incorporated MLD into its national NBS program.

Cost considerations remain a significant factor to expanding NBS programs, particularly for rare disorders. While implementation is expensive, evaluation of cost-effectiveness can support their inclusion. Estimates from the United States suggest that individuals with LDs incur health care costs over fivefold higher than the average pediatric patients.^e7 Early detection through NBS has the potential to offset long-term health care expenditures by mitigating the need for intensive care and advanced disease management. Several studies have highlighted the cost-effectiveness of NBS for ALD,^e8 MLD,^e9,e10 and Krabbe disease,^e11 within both private and public health care systems.

Based on the demonstrated benefits of early screening and their fulfillment of recommended inclusion criteria, we strongly advocate for the incorporation of ALD, MLD, Krabbe disease, and CTX in Canada's NBS programs. The inclusion of these conditions in NBS panels in the United States and Europe, as well as their evaluation in pilot projects globally, demonstrates the feasibility and importance of early diagnosis for these LDs. It is important that consensus guidelines for ALD,^e12 MLD,^e13 and Krabbe disease^e14 already exist to guide clinical management and support families following diagnosis.

Barriers in Accessing Newly Approved Therapies in Canada

The rapid evolution of targeted therapies and personalized medicine has revolutionized the treatment of neurodegenerative diseases, particularly through the development of gene and cell replacement therapies, antisense oligonucleotides, and small molecules. Within LDs, there has been a significant expansion in the development of novel therapeutics, particularly for classic and more prevalent LDs such as ALD, MLD, Alexander disease (AxD; MIM: 203450), Pelizaeus-Merzbacher disease (PMD; MIM: 312080), Canavan disease (MIM: 271900), and Vanishing White Matter (VWM; MIM: 603896, 620312, 620313, 620314, 620315), to name a few. Unfortunately, Canadian families face significant delays in accessing clinical trials and newly approved therapies, depriving them of timely access to potentially life-saving treatments. A combination of regulatory and market factors contributes to these limitations. Health Canada's regulatory process is complex, involving multiple reviews that can result in substantial approval delays, particularly for orphan drugs.^e15 Indeed, comparative studies have shown that Canada faces some of the most significant delays in drug access among high-income countries.^e16,e17 In addition, Canada has fallen behind in developing a comprehensive national strategy for rare diseases, with orphan drugs undergoing the same consideration process for health technology assessments (HTA) and price negotiations with the pan-Canadian Pharmaceutical Alliance (pCPA) as drugs for more common conditions. This creates additional hurdles in obtaining approval because the HTA process heavily relies on robust evidence from randomized controlled trials, which are difficult to conduct in rare disease populations. Canada also faces the challenge of attracting new therapies to its market. There is a substantial decrease in the availability of advanced therapies in Canada compared with major markets in Europe and the United States.^e18 Limited access for Canadians is the result of regulatory delays and fewer drugs being submitted for approval in Canada compared with the European Medicine Agency or the US Food and Drug Administration.^e18 Among those submitted, only half successfully complete price negotiations with the pCPA and even fewer secure public reimbursement.^e18 The relatively smaller size and lower profitability of Canada's pharmaceutical market likely drive this disparity, leaving less incentive for companies to prioritize bringing treatments to the Canadian market. The low probability of drug approval, coupled with the complexities of price negotiations for orphan drugs and the uncertainty of public funding from the provinces/territories, further discourages companies from submitting applications for new drugs. Consequently, some of the most advanced gene and cell therapies available are not yet accessible to Canadians, leaving patients and families with fewer options domestically, and leading some to seek treatments abroad. Furthermore, therapeutic access can also be hindered by a lack of infrastructure necessary to administer advanced treatments. Many clinics/hospitals are not equipped to handle complex therapies such as RNA-based, gene-based, and cell-based therapies, which often require specialized facilities, trained personnel, and strict handling protocols. This infrastructural gap can further delay the availability of these therapies to patients, even after receiving regulatory approval.

Canada's recent establishment of a National Strategy for Drugs for Rare Diseases aims to streamline approvals and improve the regulatory environment for rare disease therapies, thus expecting to attract more pharmaceutical investment. In the short term, promising steps can be taken to improve the situation, including proactive collaboration and early engagement with pharmaceutical companies and policymakers to help expedite access. CARELeuko is well-positioned to play a pivotal role in incentivizing companies to bring LD therapies to the Canadian market, serving as a bridge between industry, researchers, clinicians, and patient advocates. By encouraging the alignment of pharmaceutical interests with Canada's regulatory processes, and by facilitating principal investigator-initiated trials, CARELeuko is committed to advancing access to innovative therapies in Canada. Furthermore, CARELeuko, in collaboration with Rare-Kids-CAN, aims to address infrastructural challenges in treatment delivery by advocating for investments in clinic/hospital readiness, facilitating training programs, and working to ensure advanced therapies can be effectively delivered to patients across Canada.

Adult LDs: Unique Challenges and Transition of Care

Identifying adult-onset LDs remains a major challenge, delaying diagnosis, management, and access to care for this population. This gap is largely due to the vast phenotypic heterogeneity of adult LDs, which often imitate common, acquired white matter disorders, namely, neuroinflammatory/demyelinating diseases and acquired small vessel diseases.^e19-e21 With 50%–70% of adult-onset LD cases remaining genetically undiagnosed, diagnosis relies heavily on MRI pattern recognition. However, several challenges limit its effectiveness. Disease-specific MRI patterns are more distinct in early disease stages, yet many adult LDs present with nonspecific, slowly progressive symptoms that are not initially investigated by neuroimaging. By the time an MRI is performed, white matter abnormalities are often so extensive that they lack the specificity for interpretation,^e22 a challenge further complicated by aging and/or comorbidities that can alter MRI patterns, rendering them nonspecific.^e22-e24

Furthermore, advancements in health care over the past few decades have extended the life expectancy of patients with pediatric-onset LDs, leading to a growing population of adults with LDs. Ideally, a timely and efficient transition of pediatric patients to the adult health care system is needed to allow for progressive adjustment, minimization of secondary illnesses, planning for long-term needs, and promotion of relative autonomy.^e25 However, the reality for many patients followed in different Canadian centers is that there is no transition program or policy in place. Consequently, many patients, particularly those with complex needs, may undergo a challenging transfer, and may receive insufficient and/or late transition planning. Ultimately, this can result in reduced regular visits and increased use of emergency care.^e26

CARELeuko aims to address gaps in diagnosing adult-onset LDs and improve the transition from pediatric to adult care. To address the former, CARELeuko aims to partner with and support the White Matter Rounds Network (WMRN), established by Dr. La Piana at the Montreal Neurological Institute.^e27 The WMRN brings together an international multidisciplinary group of physicians and scientists who meet monthly to discuss complex white matter cases and emerging research, ultimately enhancing the diagnostic accuracy for adult-onset LDs. For transition to adult care, best practices suggest a gradual transition beginning by age 13, with joint visits between pediatric and adult HCPs whenever logistically feasible.^e28 However, these guidelines must be adapted to the Canadian context, considering provincial health care differences, geographic barriers, and population needs. CARELeuko is committed to developing tailored solutions to ensure a structured, patient-centered transition process.

Canadian Subpopulations With High LD Incidence

As LDs are genetic disorders, their relative incidence rates across a country vary according to its unique and evolving demography. In Canada, certain regions and communities have documented elevated incidences of specific LDs and related white matter disorders (referred to here as genetically determined leukoencephalopathies; gLE) (Table). These variations from Hardy-Weinberg equilibrium often result from factors such as reduced gene flow within geographically or culturally isolated populations, particularly in rural or remote areas. Often, the types of LDs prevalent in these areas have distinct clinical presentations and therefore represent specific subtypes of the disease, which can complicate diagnosis and management. Research on these conditions has typically focused on the classic presentations, leaving these specific subtypes underrepresented in research.

Table.

Examples of Known LD and gLE Clusters Across Canada

Disease entity	MIM	Gene	Recurrent variant(s)	Region(s)	Inheritance
Metachromatic leukodystrophy (MLD)e29,e30	250100	ARSA	c.635C>T; p.A212V c.489_495del; p.P613fs	NS NB	AR
Vanishing white matter disease (VWM)e31,e32	620315	EIF2B5	c.584G>A; p.R195H (Cree leukoencephalopathy)	Northern QC, MB	ARAR
			c.260C>T; p.A87V	QC
4H leukodystrophy (POLR3-related leukodystrophy)e33	607694	POLR3A	c.2015G>A; p.G672E	QC	AR
Biotinidase deficiencye34	253260	BTD	c.380C>T; p.P127L c.629A>G; p.Y210C c.1330G>C; p.D444H	MB, SK, AB	AR
PRUNE1-related disordere35	617481	PRUNE1	c.521-2A>G	Northern MB	AR
Canavan diseasee36	271,900	ASPA	c.693C>A; p.Y231* c.854A>C; p.E285A	MB, SK, AB QC ON	AR
Zellweger spectrum disorder (ZSD)e37-e39	214100	PEX1	c.2097_2098insT; p.I700fs	QC	AR
	614862	PEX6	c.802_815del; p.D268fs	QC	AR
I-cell disease (ICD)e37	252500	GNPTAB	c.3503_3504delTC; p.L1168fs	QC	AR
Tay-sachs diseasee40-e43	272800	HEXA	c.-2,564_253 + 5128delinsG c.1274_1277dup; p.Y427fs c.1421 + 1G>C	QC ON	AR
Leigh syndromee37	220111	LRPPRC	c.1061C>T; p.A354V	QC	AR
Carnitine palmitoyltransferase 1A (CPT1A) deficiencye44	255120	CPT1A	c.1436C>T; p. P479L	YT NWT NU BC	AR
Neuronal ceroid lipofuscinosis 6 (CLN6)e45	601780, 204300	CLN6	c.268_271dup; p.V91fs	Southern NL	AR
Leber hereditary optic neuropathy (LHON)e46	NA	MT-ND6	c.190A>G; p.M64V	QC	mtDNA-linked
Aicardi-goutières syndromee47-e49	225750	TREX1	c.490C>T (p.R164*) (Cree encephalitis)	QC MB	AR

Abbreviations: AB = Alberta; AR = autosomal recessive; BC = British Columbia; MB = Manitoba; mtDNA = mitochondrial DNA; NA = not available; NB = New Brunswick; NL = Newfoundland and Labrador; NS = Nova Scotia; NU = Nunavut; NWT = Northwest Territories; ON = Ontario; QC = Quebec; SK = Saskatchewan; YT = Yukon.

Recognizing and addressing these regional variations is essential to ensure equitable access to care. Tailored approaches, such as community-specific genetic screening programs, can facilitate earlier diagnosis and intervention in higher-risk populations or regions. In addition, the unique disease subtypes prevalent in these populations often exhibit distinct natural histories, which may influence clinical management, the selection of therapeutic strategies and clinical trial endpoints.

CARELeuko is dedicated to collaborating alongside communities that experience increased LD prevalence to better understand their needs and advocate for increased awareness and resources. This includes supporting the development of tailored diagnostic and therapeutic strategies, facilitating access to specialized care, and promoting patient-focused research to ensure all equitable access to emerging therapies for these LDs.

CARELeuko and the Future Directions of a Canadian Leukodystrophy Network

Canada currently possesses a wealth of knowledge and developed expertise across many domains, including genomics, therapy development, pediatric medicine, and rare diseases. As such, many Canadian institutions, clinicians, and researchers have garnered international recognition in their respective fields, establishing the country as a leader in innovative research and clinical care. CARELeuko seeks to unite these experts and resources to collaboratively advance the understanding, diagnosis, and treatment of LDs.

With initial funding from the McGill University Health Centre Research Institute, CARELeuko was established to bridge existing gaps and spearhead a national effort to improve the lives of Canadian patients and families affected by LDs. CARELeuko is a growing network of clinicians, scientists, HCPs, students, PAGs, and patient representatives from across Canada, working toward national expansion. International membership is welcomed, offering collaborators the opportunity to contribute to our collective efforts for patients with LD across Canada and globally.

CARELeuko aims to implement several key initiatives, dependent on obtaining additional funding. First, CARELeuko aims to develop a national patient registry to provide a comprehensive platform for identification of LDs within Canada, investigation of their specific natural histories, and to connect patients with clinicians, research groups, and care centers specific to their diagnosis or to specialized expertise to facilitate diagnoses. Furthermore, CARELeuko will spearhead innovative translational research, ensuring that findings from the laboratory are rapidly applied to clinical settings. By initiating and facilitating clinical trials within Canada, the network will advocate for the development and approval of new therapies for the many LDs for which no therapeutic option currently exists. Finally, through strategic partnerships with PAGs, industry representatives, and policymakers, CARELeuko aims to collaborate on establishing LD Centers of Excellence in Canada, implementing NBS programs, facilitating access to clinical trials and new therapies, and developing guidelines for the management of LDs within the Canadian health care system.

Conclusion

In this study, we highlight the urgent need to address critical knowledge gaps and challenges faced by Canadian patients affected by LDs and their families. These include limited clinical expertise, the near absence of LDs in NBS programs, decreased access to novel therapies, inadequate focus on adult LDs, and unique challenges posed by founder populations with distinct clinical presentations. CARELeuko represents a novel and dedicated initiative, formed to address these pressing needs. By uniting researchers, clinicians, patient advocates, and policymakers, CARELeuko seeks to close critical gaps in diagnostics, therapeutic development, and clinical care while fostering equitable access to resources and expertise nationwide.

Glossary

HCP

health care practitioner

HSCT

hematopoietic stem cell transplantation

HTA

health technology assessment

LD

leukodystrophy

NBS

newborn screening

PAG

patient advocacy group

pCPA

pan Canadian Pharmaceutical Alliance

RDMM

rare diseases models and mechanisms

Author Contributions

A. Chapleau: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. A. Le: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. J. Simo: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design. S. Venkateswaran: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. T. Lacaze-Masmonteil: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. V.E.C. Piscopo: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. S. Gauthier: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. F. Villa Tobón: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. S.S. Alam: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. L. Lentini: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. B. Brais: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C. Ernst: analysis or interpretation of data. J.J. Mitchell: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. D.C. Vinh: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. Y. Zhou: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. T.E. Kennedy: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. N. Goloff: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. B. Riham: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. R. Chapleau: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. B. Smith: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. V. Greger: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. J. Della Rocca: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. L.-M. Louis: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A. Dike: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. L.L. McIntyre: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. D.F. McIntyre: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. J. Tardif: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. É. Lapointe: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. J. Barnett: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. V. Loignon: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. G. Bardai: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. S. Contant: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. T.M. Durcan: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. R. La Piana: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. G. Bernard: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.

Study Funding

This work was supported by grants from the Research Institute of the McGill University Health Centre (Networks Competition, Phase 1). A. Chapleau has received a Doctoral Research Award from the Canadian Institutes of Health Research (CIHR, 2022–2025). J. Simo has received a joint master's research award from CIHR and Fonds de recherche du Québec—Santé (FRQS, 2023-2025) and a doctoral research award from FRQS (2025-2029). D.C. Vinh was supported by the FRQS Clinician-Scientist Senior Award. He has received funding support from the Jeffrey Modell Foundation, FRQS, CIHR, and the MUHC-Foundation (SDR Project). R. La Piana has received the Research Scholar Junior 1 Award from the FRQS and research funds from the CIHR (Project Grant 506913), Roche Canada, Ataxia Canada, the Spastic Paraplegia Foundation and the Canadian Radiological Foundation. G. Bernard has received the Clinical Research Scholar Junior 1 Award from the FRQS (2012–2016), the New Investigator Salary Award from the CIHR (2017–2022), the Clinical Research Scholar Senior Award from the FRQS (2022–2025), and the Chercheur de Mérite Award from the FRQS (2025–2029). S. Venkateswaran has been supported by grants from Bethany's Hope Foundation, Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders Association, the Canadian Radiological Foundation and the Children's Hospital of Eastern Ontario Research Institute (CHEO-RI).

Disclosure

A. Chapleau, A. Le, J. Simo, S. Venkateswaran, T. Lacaze-Masmonteuil, V.E.C. Piscopo, and S. Gauthier report no disclosures on the manuscript; F.V. Tobón is a subinvestigator for the IONIS ION373 Trial for Alexander's disease; S.S. Alam, L. Lentini, B. Brais, and C. Ernst report no disclosures on the manuscript; J. Mitchell is a chair of the scientific advisory board for the Canadian mucopolysaccharidosis (MPS) association of Canada, a site investigator for the MPS II gene therapy trial of Regenxbio (2021–present), the MPS II clinical trial of Denali (2022–present), the Biomarin Morquio A registry (2015–present), the Sanofi MPS I registry (2005–present), and has served as a subinvestigator on Krabbe (2021–2023) and GM1 gene therapy trials of Passage Bio (2021–2024); D.C. Vinh has served on advisory boards for Astra Zeneca, CSL Behring, Novartis Canada, Moderna, and Takeda, he has received speaker honoraria from CSL Behring and Merck Canada, he has a patent application pending (Electronic Filing System ID: 40101099) unrelated to this work; Y. Zhou, T.E. Kennedy, N. Goloff, B. Riham, R. Chapleau, B. Smith, V. Greger, J.D. Rocca, L.M. Louis, A. Dike, L.L. McIntyre, D. McIntyre, J. Tardif, E. Lapointe, J. Barnett, V. Loignon, G. Bardai, S. Contant, and T.M. Durcan report no disclosures on the manuscript; R. La Piana serves on the Medical and Scientific Advisory Committee of Sisters' Hope Foundation and is on the editorial boards of Annals of Neurology and is Review Editor for Frontiers in Genetics. G. Bernard is/was a consultant for Calico (2023–present), Orchard Therapeutics (2023), Passage Bio Inc (2020–2022), and Ionis (2019), she is/was a site investigator for the Vanishing White Matter trial of Calico/Abbvie (2025-present), Alexander's disease trial of Ionis (2021–present), Metachromatic leukodystrophy of Shire/Takeda (2020–2021), Krabbe (2021–2023), and GM1 gene therapy trials of Passage Bio (2021–2024), GM1 natural history study from the University of Pennsylvania sponsored by Passage Bio (2021–present), and Adrenoleukodystrophy/HSCT natural history study of Bluebird Bio (2019), a site subinvestigator for the MPS II gene therapy trial of Regenxbio (2021–present), and the MPS II clinical trial of Denali (2022–present). She has received an unrestricted educational grant from Takeda (2021–2022). She serves on the Scientific Advisory Board of the Pelizaeus-Merzbacher Foundation, the Yaya Foundation Scientific and Clinical Advisory Council and the Medical and Scientific Advisory Board of the United Leukodystrophy Foundation. She is a member of the Vanishing White Matter Consortium, H-ABC Clinical Advisory Board, MLC Clinical Expert Consortium, and the Chair of the POLR3-related (4H) Leukodystrophy Consortium. She is on the editorial boards of Neurology® Genetics, Frontiers in Neurology—Neurogenetics, and Journal of Medical Genetics. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.