Metachromatic leukodystrophy (MLD) is a rare inherited disorder of the white matter with higher incidences in consanguineous populations. In children, manifestations vary with age of onset: early forms present with motor regression and developmental delay, whereas later forms begin with motor difficulties followed by behavioural or cognitive decline. We describe a 7-year-old boy with previously normal development who exhibited progressive motor deficits, speech difficulties, cognitive impairment, and loss of bladder control. Neurological examination revealed generalized hypotonia, areflexia, gait ataxia, and axial spasticity. Audiovisual function was preserved. Laboratory workup showed elevated urinary sulfatide levels despite normal enzymatic activity of the main sulfatide-degrading enzyme. Additional metabolic tests were unremarkable aside from signs of increased ketone bodies. Neuroimaging revealed white matter abnormalities consistent with a leukodystrophic process, and electrophysiological studies confirmed peripheral demyelination. Genetic analysis revealed a homozygous PSAP c.777G>A variant, affecting a gene essential for sulfatide degradation and suggesting a possible atypical form of MLD. This case highlights the diagnostic complexity of non-classical presentations and underscores the value of comprehensive metabolic and genetic evaluation. This case illustrates that MLD can present with normal enzymatic assays and highlights the importance of combined biochemical, neuroimaging, and genomic testing in children with rapid motor and cognitive decline.

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.

Metachromatic leukodystrophy (MLD) is a life-limiting neurodegenerative disease due to pathogenic variants in the ARSA gene. Patients experience severe neurological symptoms, developmental regression, and early death. Aim of the study was to analyze disease burden and healthcare utilization in different stages of the disease in children with late infantile and juvenile MLD in Germany. Out of a nationwide total cohort study (TC) (n = 83), we undertook telephone interviews in a representative follow-up cohort (FC) defined by advanced disease stages (n = 19). The FC allowed detailed long-term data of the disease in addition to cross-sectional data of the TC. Nearly all patients showed spasticity, truncal hypotonia and dysphagia, and about half of the patients developed epilepsy. Most children required special education; none finished regular school. Analysis of the FC showed that neuronal intestinal burden was extensive, including obstipation (57%), micturition problems (47%), and tube feeding (63%). Gallbladder polyposis was seen in 52%. General well-being did not strongly correlate with motor function, whereas pain was associated with reduced well-being. Baclofen, Omeprazole, Vigabatrin and Polyethyleneglycol were the most frequently used drugs. Patients took up to 15 different drugs daily. Altogether, 127 hospitalisations (485 treatment days) were registered in the FC (median age 9 years, median one inpatient stay per patient per year). Diagnostic procedures were main reasons for hospitalization (29 hospitalizations, 128 treatment days), and accounted for the main burden for families (68%). The median use of 15 different devices (maximum 29) throughout life illustrated a high burden of the disease. During disease course, there was a change from more "active" devices (e.g., walker) to more "passive" devices (e.g., form seat). Physical therapy was the most relevant therapy in advanced disease stages (100%), while occupational therapy or speech therapy primarily were used in early disease stages. State welfare benefits, home- and palliative care were used broadly. Diagnostic and treatment routine pathways and sociomedical support in MLD require extensive resources. We provide detailed cross-sectional and long-term data of MLD-associated disease burden in different stages of disease. This data may serve as a reference when analyzing disease- and healthcare burden also after gene-/stem cell-therapy.

Understanding pathological changes in the brain is essential for guiding treatment decisions in brain injuries and diseases. Despite significant advances in brain imaging techniques, clinical practice still faces challenges due to infrastructure reliance and high resource demands. This review explores the current knowledge on blood-based biomarkers that indicate brain pathology, which can assist in identifying at-risk patients, diagnosing patients, predicting disease progression, and treatment response. We focus on the inherited metabolic disorders X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) which share remarkable phenotypic variability. Disease-specific increases in the lipid metabolites lyso-PC26:0 in X-ALD and sulfatides in MLD might contribute to predicting clinical manifestation. Disease-unspecific biomarkers for axonal damage (neurofilament light chain protein, NfL) and glial degeneration (glial fibrillary acidic protein, GFAP) are able to distinguish X-ALD and MLD phenotypes at the group level. The implementation of X-ALD into newborn screening programs in various countries, including several U.S. states, has increased the demand for predictive blood-based biomarkers capable of detecting the early conversion from the pre-symptomatic to the early neuroinflammatory cerebral form of X-ALD. Among different biomarkers, NfL has proven most effective in reflecting neuroinflammation and correlating with brain lesion volume and the magnetic resonance imaging (MRI)-based severity scores. We discuss how NfL has moved from initial proof-of-principle towards proof-of-concept studies in brain disorders such as multiple sclerosis and how this knowledge could be applied for the clinical implementation of NfL in rare inherited metabolic disorders such as X-ALD.

Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive disorder of lipid metabolism characterized by deficiency of arylsulfatase A (ARSA), which leads to an accumulation of sulfatides in central and peripheral nerve system and eventually to progressive demyelination. The adult form of MLD may be misinterpreted as a psychiatric disease, since behavioral signs may precede intellectual decline. Here we report the case of a 53-year-old woman initially admitted to a psychiatric ward with symptoms of depression. The behavioral changes were initially attributed to psychosocial stressors within the family, particularly long-term emotional abuse by the patient's former partner. However, detailed anamnesis with the patient's mother revealed progressive behavioral and cognitive decline, urinary and fecal incontinence, that is, features suggestive of an underlying neurological disorder. Notably, laboratory investigations recommended 6 years earlier had not been performed. Neurological examination revealed signs of a frontal syndrome, bilateral pyramidal tract involvement, and mild polyneuropathy. Magnetic resonance imaging (MRI) demonstrated abnormal white matter signal alterations. Further diagnostic investigations showed reduced serum ARSA activity, elevated urinary sulfatides, and a homozygous pathogenic variant in the ARSA gene, confirming the diagnosis of adult-onset MLD. The homozygous mutation indicated parental consanguinity, suggesting early trauma embedded within the family. This case underscores the complexity of diagnosing MLD and emphasizes the importance of integrating psychiatric, neurological, and systemic family perspectives in the diagnostic process of rare and slowly progressing illnesses.