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Background: Leukodystrophies are a group of rare genetic diseases that primarily affect the white matter of the central nervous system. The broad spectrum of metabolic and pathological causes leads to manifestations at any age, most often in childhood and adolescence, and a variety of symptoms. Leukodystrophies are usually progressive, resulting in severe disabilities and premature death. Progressive visual impairment is a common symptom. Currently, no overview of the manifold neuro-ophthalmologic manifestations and visual impact of leukodystrophies exists. Methods: Data from 217 patients in the Hamburg leukodystrophy cohort were analyzed retrospectively for neuro-ophthalmologic manifestations, age of disease onset, and magnetic resonance imaging, visual evoked potential, and optical coherence tomography findings and were compared with data from the literature. Results: In total, 68% of the patients suffered from neuro-ophthalmologic symptoms, such as optic atrophy, visual neglect, strabismus, and nystagmus. Depending on the type of leukodystrophy, neuro-ophthalmologic symptoms occurred early or late during the course of the disease. Magnetic resonance imaging scans revealed pathologic alterations in the visual tract that were temporally correlated with symptoms. Conclusions: The first optical coherence tomography findings in Krabbe disease and metachromatic leukodystrophy allow retinal assessments. Comprehensive literature research supports the results of this first overview of neuro-ophthalmologic findings in leukodystrophies.

Background Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. Results Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. Conclusion Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

Background: Alexander disease (AxD) is a rare severe leukodystrophy that has no cure to date. A pathogenic gain-of-function variant in the GFAP gene affects the astrocytes and subsequently the function of the white matter in the CNS. Methods: We retrospectively analyzed the most frequent symptoms of nine AxD cases, classified them according to published classifications, and described the need of care and support. Results: The description of the courses of disease of nine cases with AxD reflects the broad spectrum of different phenotypes of AxD, with often occurring apnoea. Data about care and support for AxD patients indicate a high and heterogeneous need of support. Treatment with steroids reduced symptoms in two patients. Some patients showed lasting improvement during their course of disease. Conclusions: The course of AxD is very heterogeneous. Thus, we extracted relevant key features to describe the severity of the disease, namely feeding problems, epilepsy, age-appropriate motor function, failure to thrive, age-appropriate language and apnoea. We recommend early evaluation for clinical care and support. For some AxD patients, treatment with steroids may alleviate symptoms. Further development of efficient treatments is necessary.