Research summary of recent leukodystrophy research and clinical trials, includes article summaries and direct links to websites and articles.
Clinical trial updates
GM1 Gangliosidosis and GM2 Gangliosidosis
Azafaros’ lead drug Nizubaglustat has been granted orphan drug designation in both the United States and the European Union for the treatment of GM1 gangliosidosis. Clinical Trial Application (CTA) for global Phase 3 study investigating the drug’s efficacy and safety in GM1/GM2 gangliosidoses was approved by multiple European countries and is expected to initiate in the second quarter of 2025.
Research summaries
Adrenoleukodystrophy (ALD)
Optical coherence tomography angiography reveals abnormal retinal vascular density and perfusion in patients with X-linked adrenoleukodystrophy: a cross-sectional study
https://pmc.ncbi.nlm.nih.gov/articles/PMC11727801
X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder that progressively affects the brain and nervous system by accumulating very long chain fatty acids (VLCFA). Early manifestations include visual impairments, and this study looked at how X-ALD affects the small blood vessels in the eyes by using a special imaging tool called optical coherence tomography angiography (OCTA). This single time-point observational study carried out in China included 52 X-ALD patients and 47 healthy controls. X-ALD participants were classified as symptomatic and less symptomatic based on their medical history and neurological assessment via the Expanded Disability Status Score (EDSS) and the Severity Scoring System for Progressive Myelopathy (SSPROM) which assess the severity of their disease. Compared to the control and less symptomatic groups, symptomatic X-ALD individuals showed reduced blood flow and fewer small blood vessels in certain areas of the superficial retinal microvasculature. At the same time, both measures were increased in certain areas of the deeper layer. They also found that these changes moderately correlated with the severity of the disease (EDSS score) and increased plasma VLCFA. These data suggest that this non-invasive OCTA-based eye scan might become helpful in monitoring disease progression. However, larger cohorts and longer follow-up studies are needed to confirm these preliminary observations.
Insights From Minnesota on Newborn Screening for Adrenoleukodystrophy: A 5-Year Update
https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63995?af=R
Newborn screening for adrenoleukodystrophy (ALD) has enabled early detection and intervention, improving outcomes for affected children. This study examined cases identified through newborn screening in Minnesota, highlighting key findings related to cerebral ALD, adrenal insufficiency (AI), genetic variations, and biochemical markers. Two children diagnosed through newborn screening developed cerebral ALD at ages 3.6 and 5 years. Both underwent haematopoietic stem cell transplantation (HSCT), which stabilised disease progression. Four other children had non-progressive brain abnormalities, and one child with Down syndrome exhibited brain changes unrelated to ALD. Adrenal insufficiency was diagnosed in six children, with one developing complete AI by 8 months old. Five others initially had partial AI and later progressed to complete AI, which required daily hydrocortisone treatment. Routine adrenal function monitoring proved critical for early detection and management. Genetic analysis revealed that most affected individuals inherited pathogenic ABCD1 gene variants from their mothers (97.6%), with only two cases resulting from new (de novo) mutations (2.3%). Additionally, variant classification inconsistencies among laboratories emphasised the need for standardised genetic interpretation. Some cases were associated with variants of uncertain significance, complicating diagnosis, and risk assessment. Biochemical analysis demonstrated that higher levels of C26:0-lysophosphatidylcholine (C26LPC) correlated with more pathogenic gene variants. This suggests that C26LPC may be a more reliable marker than traditional C26:0 VLCFA levels in assessing disease severity. Further findings also indicate a higher-than-expected incidence of ALD, particularly in males, compared to historical estimates. Overall, this study emphasises the value of newborn screening for ALD in enabling timely treatment and reducing disease complications. The findings support expanding ALD screening to other regions and highlight the need for further research to optimise screening and treatment strategies.
Progression of Spinal Cord Disease in Adult Men With Adrenoleukodystrophy
https://pmc.ncbi.nlm.nih.gov/articles/PMC11706703/#jimd12845
Adrenoleukodystrophy (ALD) is a genetic disorder that can affect the spinal cord, leading to mobility and sensory issues. This study followed 79 adult men with ALD over 7 years to understand how spinal cord disease progresses in this condition and is the longest follow up study in this cohort to date. ALD often leads to a condition called adrenomyeloneuropathy (AMN), which causes symptoms such as bladder problems, walking difficulties, and sensory issues. Researchers used tests like the Expanded Disability Status Scale (EDSS) and Severity Score System for Progressive Myelopathy (SSPROM) which shows severity of the disease, a 6 minute walking test (6MWT), and quality of life questionnaires to track changes over time. The results showed that disability worsened gradually and predictably. The study also found that 50% of patients developed spinal cord symptoms by age 50, with sensory changes like reduced vibration sense often being an early sign. Interestingly, urinary symptoms and quality of life scores did not change significantly over time, suggesting these measures may not be sensitive enough to track disease progression. Psychological concerns were more common in middle-aged patients, emphasising the need for mental health support. The study also found that spinal cord damage often begins with sensory loss, supporting earlier research. This research provides important insights for designing clinical trials and counselling patients while highlighting the need for better ways to track disease progression. Current clinical trial measures require long follow-up periods and many participants. New, more sensitive tests—such as body sway analysis—may help detect changes earlier, allowing for better treatment strategies in the future.
Clinical spectrum of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia in individuals of Korean ancestry
https://www.nature.com/articles/s41598-024-84665-w
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter disease leading to progressive neurological decline. Although the CSF1R gene is the primary causative gene for ALSP, it is unclear how many individuals clinically suspected to have ALSP present mutations in the CSF1R gene. This retrospective study explored the prevalence of CSF1R mutations in ALSP patients and detailed the clinical features, specifically in the Korean population. Researchers genetically screened 28 patients classified as probable (n=6) or possible (n=22) ALSP based on clinical and radiological diagnostic criteria from Konno et al. A definitive genetic diagnosis of ALSP was made for five probable and four possible ALSP cases. One individual tested negative for CSF1R mutations but was definitively diagnosed as ALSP based on histopathological features. All ten patients presented with cognitive and psychiatric symptoms and characteristic bilateral brain imaging findings aligning with the clinical features reported in other countries. Researchers further found that age of onset, rapid progression, and diffuse hyperintensity (white spot on an MRI that is brighter than other areas suggesting abnormality) in the splenium (part of the corpus collosum, the largest white matter structure of the brain) were more prevalent in patients with CSF1R mutations than without, suggesting these features as key indicators of ALSP. Despite some limitations to the study (e.g. small sample size), this research highlights the value of CSF1R genetic testing and brain imaging in providing diagnostic insights.
Pelizaeus-Merzbacher disease (PMD)
Clinical characteristics of the Ala21Val variant in the myelin proteolipid protein 1 (PLP1) gene associated with Pelizaeus-Merzbacher disease in a Brazilian male patient
https://www.nature.com/articles/s41439-024-00306-8
Pelizaeus-Merzbacher disease (PMD) is a rare genetic disorder and a form of X-linked leukodystrophy that affects the nervous system, leading to problems with movement, muscle control, and vision. It is caused by mutations in the PLP1 gene, which plays a role in producing myelin, a substance that helps nerve cells communicate. PMD has different levels of severity, ranging from mild muscle stiffness to severe developmental delays and inability to walk. This report describes a 29-year-old man from Brazil with classic PMD. His symptoms began in infancy with weak muscle tone, involuntary eye movements, and difficulty coordinating movement. As he grew older, he developed spastic paraparesis (stiffness and weakness in the legs), optic atrophy (vision loss due to nerve damage), trouble swallowing, and worsening head tremors. He also experienced intellectual disability, behavioural changes (such as aggression and mood swings), and appendicular ataxia (loss of coordination in the limbs). Brain scans showed abnormal white matter and loss of brain tissue in key areas, confirming a hypomyelination disorder. Genetic testing confirmed the Ala21Val mutation in the first transmembrane domain of PLP1, a region crucial for myelin function. The mutation was inherited from his mother, who showed mild tremors but no major neurological impairments. Although similar mutations in this region of PLP1 have been linked to PMD, this specific variant had not been well-documented. Advanced genetic analysis tools predicted this mutation to be highly damaging, further supporting its role in causing PMD. This case expands our understanding of PMD and highlights the importance of genetic testing in diagnosing rare diseases. Identifying more cases like this can improve patient care and provide insights into how different PLP1 mutations affect disease severity.
Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte‐lineage cells established from patients with Sjögren‐Larsson syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11608845
Sjögren-Larsson syndrome (SLS) is a rare neurological disease characterised by hypomyelination and lipid accumulation. SLS is caused by the loss-of-function of the ALDH3A2 gene that encodes the FALDH enzyme involved in lipid metabolism. In this study, researchers used special stem cells (induced pluripotent stem cells or iPSCs) from SLS patients to investigate SLS pathophysiology. This cellular model allowed them to specifically grow brain-supporting cells called oligodendrocytes, which help with myelin formation. They found that these patient-derived cells had too much of a certain type of fat called ether phospholipids, which is consistent with a previously reported result showing the accumulation of such lipids in the brain tissue of an SLS patient. These data suggest that using patient-derived iPSCs may help better understand the lipid accumulation observed in SLS patients.
Concise Articles
Final analysis from the IGNITE Phase 2 clinical trial is planned for the second quarter of 2025. The Company will pursue an accelerated approval pathway for iluzanebart in ALSP and expects to share an update on its progress when the final analysis is reported.
Metachromatic Leukodystrophy (MLD)
Orchard Therapeutics to receive WORLD Symposium New Treatment Award for Lenmeldy.
First U.S. patients being treated with Lenmeldy in a commercial setting. Reimbursement agreement for Libmeldy reached with Spanish National Health System enabling access to all eligible patients in the country. Application to include MLD in its national newborn screening program submitted by patient advocates in Germany.