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Pathogenic variants in CWF19L1 lead to a rare autosomal recessive form of hereditary ataxia with only seven cases reported to date. Here, we describe four additional unrelated patients with biallelic variants in CWF19L1 (age range: 6-22 years) and provide a comprehensive review of the literature. The clinical spectrum was broad, including mild to profound global developmental delay; global or motor regression in infancy or adolescence; childhood-onset ataxia and cerebellar atrophy; and early-onset epilepsy. Since only two previously reported patients were adults, our cohort expands our understanding of the evolution of symptoms from childhood into early adulthood. Taken together, we describe that CWF19L1-related disorder presents with developmental and epileptic encephalopathy with treatment-resistant seizures and intellectual disability in childhood followed by progressive ataxia and other extrapyramidal movement disorders in adolescence., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q 10 (CoQ 10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ 10 deficiency leads to an early-onset mitochondrial multi-organ disorder., Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines., Results: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ 10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone., Conclusion: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses., Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics., Results: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts., Conclusion: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations., Objective: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs., Methods: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments., Results: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage., Conclusions: We introduce NERD ND as adult-onset neurodegeneration ( ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERD ND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction/aims: Hereditary transthyretin amyloidosis with polyneuropathy (hATTRPN) is an autosomal dominant multi-organ disorder manifesting in the third to fifth decade with the key clinical features of distal and painful sensory loss of the lower limbs and autonomic dysregulation. Motor neuropathy and cardiomyopathy evolve in the course of the disease. Pompe disease is an autosomal recessive disease leading to decreased levels of lysosomal enzyme acid α-glucosidase and proximal muscle weakness. We report the clinical features and diagnostic workup in the rare case of a patient with ATTR amyloidosis and late-onset Pompe disease, both genetically confirmed., Methods: We performed a detailed clinical assessment, exome sequencing, and biochemical measurements., Results: The patient presented with a distal, painful hypaesthesia of both legs, a cardiomyopathy, and a muscle weakness in the form of a girdle-type pattern of the arms and legs at the beginning and a spreading to distal muscle groups in the course of disease., Discussion: This study highlights the importance of searching for co-occurrence of rare monogenetic neuromuscular diseases, especially in cases in which all clinical features can be readily explained by a single gene defect.

Background: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT., Methods: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes., Results: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes., Conclusion: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G > A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n = 42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Tubulointerstitial fibrosis (TIF) is a pivotal pathophysiological process in patients with diabetic nephropathy (DN). Multiple profibrotic factors and cell types, including transforming growth factor beta 1 (TGF-β1) and interstitial myofibroblasts, respectively, are responsible for the accumulation of extracellular matrix in the kidney. Matrix-producing myofibroblasts can originate from different sources and different mechanisms are involved in the activation process of the myofibroblasts in the fibrotic kidney. In this study, 16-week-old db / db mice, a model for type 2 DN, were treated for two weeks with continuous erythropoietin receptor activator (CERA), a synthetic erythropoietin variant with possible non-hematopoietic, tissue-protective effects. Non-diabetic and diabetic mice treated with placebo were used as controls. The effects of CERA on tubulointerstitial fibrosis (TIF) as well as on the generation of the matrix-producing myofibroblasts were evaluated by morphological, immunohistochemical, and molecular biological methods. The placebo-treated diabetic mice showed significant signs of beginning renal TIF (shown by picrosirius red staining; increased connective tissue growth factor (CTGF), fibronectin and collagen I deposition; upregulated KIM1 expression) together with an increased number of interstitial myofibroblasts (shown by different mesenchymal markers), while kidneys from diabetic mice treated with CERA revealed less TIF and fewer myofibroblasts. The mechanisms, in which CERA acts as an anti-fibrotic agent/drug, seem to be multifaceted: first, CERA inhibits the generation of matrix-producing myofibroblasts and second, CERA increases the ability for tissue repair. Many of these CERA effects can be explained by the finding that CERA inhibits the renal expression of the cytokine TGF-β1., Competing Interests: The authors declare no conflict of interest.