De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.

Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.

The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy.

Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.

The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia.

Frataxin is an evolutionarily conserved mitochondrial protein responsible for iron homeostasis and metabolism. A deficiency of frataxin (encoded by FXN) leads to Friedreich's ataxia (FRDA), a progressive disorder that affects both the central and peripheral nervous systems, most commonly via a pathogenic GAA trinucleotide expansion. In contrast, pathogenic variants in ALG1 in humans cause a form of congenital disorder of glycosylation. Here, we present a 15-year-old boy with a clinical presentation that raised concern for complex hereditary spastic paraplegia (HSP), with motor features including progressive spastic paraparesis, cervical dystonia, cerebellar dysfunction, and diminished lower extremity reflexes. The proband was initially found to have a novel compound heterozygous variant in ALG1 on exome sequencing, along with N-glycan profiling revealing evidence of defective mannosylation and Western blot analysis demonstrating an 84% reduction in ALG1 expression. Although several of his clinical features could be explained by the ALG1 variant specifically or considered as part of the presentation of CDGs in general, there were additional phenotypes that suggested an alternative, or additional, genetic diagnosis. Subsequently, he was found to have biallelic pathogenic GAA repeat expansions in FXN on genome sequencing, leading to a diagnosis of FRDA. Given that FRDA explained all his clinical features, the ALG1 variant may have been a hypomorphic form and/or a biochemical phenotype. Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.

An update on autophagy disorders.

Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common "clinical signature" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.

BACKGROUND: Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by pathogenic biallelic variants in AP4B1, AP4M1, AP4E1, and AP4S1. OBJECTIVE: The aim was to explore blood markers of neuroaxonal damage in AP-4-HSP. METHODS: Plasma neurofilament light chain (pNfL) and glial fibrillary acidic protein (GFAP) levels were measured in samples from patients and age- and sex-matched controls (NfL: n = 46 vs. n = 46; GFAP: n = 14 vs. n = 21) using single-molecule array assays. Patients' phenotypes were systematically assessed using the AP-4-HSP natural history study questionnaires, the Spastic Paraplegia Rating Scale, and the SPATAX disability score. RESULTS: pNfL levels increased in AP-4-HSP patients, allowing differentiation from controls (Mann-Whitney U test: P = 3.0e-10; area under the curve = 0.87 with a 95% confidence interval of 0.80-0.94). Phenotypic cluster analyses revealed a subgroup of individuals with severe generalized-onset seizures and developmental stagnation, who showed differentially higher pNfL levels (Mann-Whitney U test between two identified clusters: P = 2.5e-6). Plasma GFAP levels were unchanged in patients with AP-4-HSP. CONCLUSIONS: pNfL is a potential disease marker in AP-4-HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.

Childhood-onset hereditary spastic paraplegia and its treatable mimics.

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype. OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST. METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants.

Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.

Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.

Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy.

Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and gender-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PXD016757. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen-identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.

Axenfeld-Rieger Anomaly and Neuropsychiatric Problems-More than Meets the Eye.

OBJECTIVE: The main purpose of this article is to demonstrate the co-occurrence of Axenfeld-Rieger anomaly and neuropsychiatric problems as clinical signs of genetically determined cerebral small vessel disease in two patients. CASE STUDY: We report on two adolescent individuals with ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) presenting with neuropsychiatric symptoms. Both patients underwent cerebral magnetic resonance imaging showing white matter T2-hyperintensities involving different brain regions, suspective of cerebral small vessel disease. Genetic analysis revealed pathogenic mutations in the FOXC1 gene (patient 1) and the COL4A1 gene (patient 2), respectively. CONCLUSION: We report on the co-occurrence of ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) and neuropsychiatric symptoms as clinical signs of genetically determined cerebral small vessel disease in two patients. In both patients, the cerebral lesions involved the frontotemporal regions, brain regions that control social behavior as well as executive and cognitive function, highlighting the fact that neuropsychiatric symptoms may be early clinical presentations of cerebral small vessel disease. We further provide a review of monogenic causes of pediatric cerebral small vessel disease, emphasizing the links to childhood-onset neuropsychiatric disease.

[Recommendations for gene therapy of spinal muscular atrophy with onasemnogene abeparvovec-AVXS-101 : Consensus paper of the German representatives of the Society for Pediatric Neurology (GNP) and the German treatment centers with collaboration of the medical scientific advisory board of the German Society for Muscular Diseases (DGM)]. / Handlungsempfehlungen zur Gentherapie der spinalen Muskelatrophie mit Onasemnogene Abeparvovec ­ AVXS-101 : Konsensuspapier der deutschen Vertretung der Gesellschaft für Neuropädiatrie (GNP) und der deutschen Behandlungszentren unter Mitwirkung des Medizinisch-Wissenschaftlichen Beirates der Deutschen Gesellschaft für Muskelkranke (DGM) e. V.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending. OBJECTIVE: This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice. CONCLUSION: Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.

[Gene therapies for neuromuscular diseases]. / Gentherapien für neuromuskuläre Erkrankungen.

BACKGROUND: For a long time the treatment of neuromuscular diseases was considered to be purely symptomatic. Due to new technologies in recent years novel causal forms of treatment could be developed. Gene therapies for spinal muscular atrophy, Duchenne muscular dystrophy, limb-girdle muscular dystrophy, myotubular myopathy and hereditary motor and sensory neuropathy type 1A are currently being evaluated in clinical trials. Initial preliminary results are promising and the first preparation onasemnogene abeparvovec-xioi (Zolgensma®) for the treatment of spinal muscular atrophy has recently been approved by the U.S. Food and Drug Administration (FDA). OBJECTIVE: This review describes the principles of gene therapy, summarizes the interim results published so far and provides an overview of currently active or soon to be initiated gene therapy trials. CONCLUSION: Gene therapies have the potential to significantly influence the course of neuromuscular diseases. First positive intermediate results have been published and the first treatment has recently been approved in the USA. Long-term data on sustained effects and toxicity of gene therapies are not yet available. These novel treatment options will present new challenges for the healthcare systems concerning diagnosis, treatment and reimbursement.

Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases.

Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Emerging evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of LSD-associated neurodegeneration. Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration. Here, we review the current evidence for mitochondrial dysfunction in neuronal models of seven LSD, including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann Pick disease type C and the neural ceroid lipofuscinoses and outline current experimental therapies aimed at restoring mitochondrial function and neuroprotection in LSD.

Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism.

Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.