Deoxy-sphingolipids, oxidative stress, and vitamin C correlate with qualitative and quantitative patterns of small fiber dysfunction and degeneration

Defined by dysfunction or degeneration of Aδ and C fibers, small fiber neuropathies (SFNs) entail a relevant health burden. In 50% of cases, the underlying cause cannot be identified or treated. In 100 individuals (70% female individuals; mean age: 44.8 years) with an idiopathic, skin biopsy-confirmed SFN, we characterized the symptomatic spectrum and measured markers of oxidative stress (vitamin C, selenium, and glutathione) and inflammation (transforming growth factor beta, tumor necrosis factor alpha), as well as neurotoxic 1-deoxy-sphingolipids. Neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). Despite the common use of pain killers (64%), the painDETECT questionnaire revealed scores above 13 points in 80% of patients. In the quantitative sensory testing (QST), a dysfunction of Aδ fibers was observed in 70% and of C fibers in 44%, affecting the face, hands, or feet. Despite normal nerve conduction studies, QST revealed Aβ fiber involvement in 46% of patients' test areas. Despite absence of diabetes mellitus or mutations in SPTLC1 or SPTLC2 , plasma 1-deoxy-sphingolipids were significantly higher in the sensory loss patient cluster when compared with those in patients with thermal hyperalgesia ( P 25 kg/m 2 ), or hyperlipidemia showed significantly lower L-serine (arterial hypertension: P < 0.01) and higher 1-deoxy-sphingolipid levels (arterial hypertension: P < 0.001, overweight: P < 0.001, hyperlipidemia: P < 0.01). Lower vitamin C levels correlated with functional Aβ involvement ( P < 0.05). Reduced glutathione was lower in patients with Aδ dysfunction ( P < 0.05). Idiopathic SFNs are heterogeneous. As a new pathomechanism, plasma 1-deoxy-sphingolipids might link the metabolic syndrome with small fiber degeneration

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot–Marie–Tooth disease with congenital cataracts

Background and purpose: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. // Methods: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot–Marie–Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. // Results: The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. // Discussion: In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy

summa cum laude; Thesis to obtain "Dr. med." title in Germany, Faculty of Medicine.status: publishe

Hereditary motor neuropathies

Hereditary motor neuropathies (HMN) comprise a broad genotypic and phenotypic spectrum of rare, progressively disabling diseases manifesting with length-dependent muscle weakness and atrophy. To date, more than half of the cases cannot be genetically explained. To provide symptomatic and disease-modifying treatments in the future, a better understanding of disease mechanisms is required. By whole exome and genome sequencing, the discovery of several novel genes (SCO2, TDRKH, SPTAN1, CADM3, and SORD) involved in the pathogenesis of HMN has now relevantly changed the pathophysiological knowledge. This recent success in causative understanding has mainly been driven by the development of functional models including cell culture, animal, and patient-derived induced pluripotent stem cell platforms. These models have an important impact on therapeutic advances including broader approaches to prevent or reverse axonal degeneration and individualized gene silencing attempts using sequence-specific RNA degradation mechanisms. In rare diseases such as HMN, the recent development of genetic sequencing and data interpretation methods has enabled a broader diagnostic approach, whereas treatment strategies are becoming more individualized. Significant milestones have been reached in the discovery of new genes, the establishment of functional disease models, and the preclinical development of mechanistic-based therapies

Does APC/CCDH1 control the human brain size?: An Editorial Highlight for ‘A novel human Cdh1 mutation impairs anaphase-promoting complex/cyclosome (APC/C) activity resulting in microcephaly, psychomotor retardation, and epilepsy’ on page 103

This editorial highlights a study by Rodriguez, Sanchez-Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3-ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/C confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/C may contribute to the regulation of the human brain size. (Figure presented.).JPB is funded by MINECO (SAF2016-78114-R), Instituto de Salud Carlos III (CIBERFES CB16/10/00282), Junta de Castilla y Leon (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigacion Biomedicina 2017 Fundacion BBVA, and Fundacion Ramon Areces