Maike Franziska Dohrn

• MD
• Medical Doctor at University of Miami

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665)...

Background Chronic immune-mediated neuropathies are clinically heterogeneous and require regular, objective, and multidimensional monitoring to individualize treatment. However, established outcome measures are insufficient regarding measurement quality criteria (e.g., reliability, objectivity) or functional relevance. Wearables such as data gloves...

Background The lead symptom of small fibre neuropathy (SFN) is neuropathic pain. Recent functional magnetic resonance imaging (fMRI) studies have indicated central changes in SFN patients of different etiologies. However, less is known about brain functional connectivity during acute pain processing in idiopathic SFN. Methods We conducted fMRI wit...

Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data includ...

Background Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the...

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumu...

ATP1A1 encodes a sodium‐potassium ATPase that has been linked to several neurological diseases. Using exome and genome sequencing, we identified the heterozygous ATP1A1 variant NM_000701.8: c.2707G>A;p.(Gly903Arg) in two unrelated children presenting with delayed motor and speech development and autism. While absent in controls, the variant occurre...

Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies. The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differe...

Small-fiber neuropathy (SFN) is defined by degeneration or dysfunction of peripheral sensory nerve endings. Central correlates have been identified on the level of gray matter volume (GMV) and cortical thickness (CT) changes. However, across SFN etiologies knowledge about a common structural brain signature is still lacking. Therefore, we recruited...

Objective: Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect speci...

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumu...

Background Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS . SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. Methods We used the G...

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 g...

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 thes...

CADM3 has been recently reported causing a rare axonal Charcot–Marie–Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with...

Effective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify...

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary coenzym...

Background Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants in ATP1A1 were associated with axonal and intermediate CMT. ATP1A1 encodes for the catalytic α1 subunit of the Na⁺/ K⁺ ATPase. Besides neuropathy, other associated phenotypes are spastic paraple...

Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subj...

Sjögren’s syndrome is a potentially treatable cause of Small Fiber Neuropathy (SFN)—a condition that severely affects patients’ quality of life. We therefore aimed to characterize patients with SFN and Sjögren’s syndrome to raise awareness of this disease and facilitate its early recognition as an essential step for appropriate treatment. In 97 SFN...

Patel K et al. Diabetic neuropathies. Muscle Nerve 2021. doi: 10.1002/mus.27014 Diabetische Neuropathien sind die häufigsten Nervenerkrankungen in der klinischen Praxis. Das Spektrum reicht von asymptomatischen Formen bis hin zu schwerwiegenden Symptomen. Da hierbei neben dem peripheren Nervensystem auch das Herz-Kreislauf-System und der Magen-Darm...

Purpose The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP...

Objective: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineatio...

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have rec...

Effective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify...

Background: Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Methods: After unremarkable whole-exome sequencing (WES) analys...

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes like hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only sixteen families have been re...

By whole-exome sequencing, we found the heterozygous POLG variant c.3542G>A; p.Ser1181Asn in a family of four affected individuals, presenting with a mixed neuro-myopathic phenotype. The variant is located within the active site of polymerase gamma, in a cluster region associated with an autosomal dominant inheritance. In adolescence, the index dev...

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...

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gl...

Hereditary transthyretin (TTR) amyloidosis (ATTRv) is an autosomal dominant, systemic disease transmitted by amyloidogenic mutations in the TTR gene. To prevent the otherwise fatal disease course, TTR stabilizers and mRNA silencing antisense drugs are currently approved treatment options. With 90% of the amyloidogenic protein produced by the liver,...

Hereditary neuropathies are of variable genotype and phenotype. With upcoming therapies, there is urgent need for early disease recognition and outcome measures. High-resolution nerve and muscle ultrasound is a dynamic, non-invasive, well-established tool in the field of inflammatory and traumatic neuropathies. In this study, we defined nerve and m...

Background: Spinocerebellar ataxia (SCA) is a progressive, autosomal dominant neurodegenerative disorder typically associated with CAG repeat expansions. Objective: We assessed the pathogenicity of the novel, heterozygous missense variant p.Cys256Phe (C256F) in the pore-forming α1-subunit of the Cav2.1 Ca2+ channel found in a 63-year-old woman w...

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Uni...

Progressive multifocal leukoencephalopathy (PML) is a subacute brain infection by the opportunistic John Cunningham (JC) virus. Herein, we describe seven patients with PML, lymphopenia, and sarcoidosis, in three of whom PML was the first manifestation of sarcoidosis. At onset, the clinical picture comprised rapidly progressive spastic hemi- or limb...

Hereditary sensory neuropathies (HSN) are a group of rare neurological disorders with heterogeneous clinical and genetic characteristics. Although at least 17 different genes have already been associated with HSN, the epidemiology of the disorder in Brazil is still unknown. Performing whole genome sequencing (WGS) in 23 unrelated Brazilian families...

With emerging treatment approaches, it is crucial to correctly diagnose and monitor hereditary and acquired polyneuropathies. This study aimed to assess the validity and accuracy of magnet resonance imaging (MRI)-based muscle volumetry.Using semi-automatic segmentations of upper- and lower leg muscles based on whole-body MRI and axial T1-weighted t...

Zusammenfassung Von weltweit mehr als 400 Mio. Menschen mit Diabetes mellitus entwickeln bis zu 50% im Laufe ihrer Erkrankung eine Neuropathie. Trotz oder gerade wegen dieser Häufigkeit darf jedoch nicht jede Neuropathie, die in Koinzidenz mit einem Diabetes mellitus auftritt, unkritisch als diabetische Neuropathie diagnostiziert werden. Eine präzi...

Guideline development on motor neuron disease (MND) in Germany is driven mainly by the German Neurological Society and German Association for Muscle Diseases. Greater research funding, a national strategy, and programs on MND are still lacking. General and specialized palliative care home services, palliative care units, or hospice care are accessi...

Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension...

The liver‐derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild‐type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review sum...

Lambert-Eaton myasthenic syndrome (LEMS) is a rare, autoimmune or paraneoplastic condition characterized by muscle weakness and fatigability. In cancer therapy, immune checkpoint inhibitors (ICI) sensitize the immune system for tumor antigens. We report a 62-year-old, female patient with paraneoplastic LEMS as first manifestation of Merkel cell car...

PurposePeripheral nerve sheath tumors are hallmark findings in neurofibromatosis types 1 and 2. With increasing size, they typically lead to neurological symptoms, and NF1 patients have a lifetime risk of 8–13% for developing malignant peripheral nerve sheath tumors. Medical imaging is therefore highly needed for early detection and exact localizat...

Der 86-jährige Patient wurde aktuell aufgrund eines Sturzes in der Notaufnahme vorstellig. Er war erst einige Tage zuvor von unserer Stroke Unit nach einem Teilinfarkt im Stromgebiet der A. cerebri media links (Abb. 1a) bei nicht-antikoaguliertem Vorhofflimmern entlassen worden. Die damalige Klinik bestand aus einer Feinmotorikstörung rechts, die s...

Purpose of review: 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 futur...

Background Half of all diabetics are affected by a diabetic neuropathy. Microangiopathy, dysfunctional Schwann cell interactions, accumulation of toxic metabolites, and inflammatory processes all contribute to nerve damage.Objective Overview and perspectives of the pathophysiology as well as the current and future treatment implications.Methods Lit...

Zusammenfassung Die neuropathische Osteo(arthro-)pathie, auch Charcot-Fuß genannt, ist eine progressive, nicht-infektiöse Schwellung mit Überwärmung und Demineralisierung, gefolgt von Knochendestruktion und Deformierung, die in ca. 75% unilateral auftritt und in einer Defektheilung zum Stillstand kommt. Resultierende Fehlstellungen können zu neurop...

Introduction: Muscle MRI is of increasing importance for neuromuscular patients to detect changes in muscle volume, fat-infiltration, and oedema. We developed a method for semi-automated segmentation of muscle MRI datasets. Methods: An active contour-evolution algorithm implemented within the ITK-SNAP software was used to segment T1-weighted MRI...

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. The mutation causes a...

Zusammenfassung Die elektrophysiologische Untersuchung von Hirnstammreflexen ist eine funktionelle Methode, die Rückschlüsse auf Läsionen in unterschiedlichen Bereichen des Hirnstamms und beteiligter Hirnnerven ermöglicht. Wie relevant ist diese Diagnostik im Zeitalter der MR-Bildgebung noch im klinischen Alltag? Der Artikel befasst sich mit der Du...

Background The causes for neuropathic pain are manifold and remain unexplained in the majority of cases. In recent years a growing number of pain syndromes have been attributed to mutations in genes encoding voltage-gated sodium channels. Hence, this group of rare diseases should be considered in the differential diagnostics of neuropathic pain. M...

Introduction Charcot-Marie-Tooth (CMT) disease is a progressively disabling syndrome phenotypically comprising distal muscle weakness and atrophy, foot deformities, sensory loss, and reduced or absent tendon reflexes. In spastic paraplegia (SPG), a hereditary disorder affecting the upper motor neuron only, pareses are spastic, and deep tendon refle...

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot‐Marie‐Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generat...

Aim Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsie...

Plasma sphingolipids. (XLSX)

Sural nerve biopsies. (XLSX)

Demographic features and metabolic parameters in blood. (XLSX)

Clinical scores. (XLSX)

Nerve conduction studies. (XLSX)

Background and purpose: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correl...

Familial amyloid polyneuropathy (FAP) is a progressive systemic autosomal dominant disease caused by pathogenic mutations in the transthyretin (TTR) gene. We studied clinical, electrophysiological, histopathological, and genetic characteristics in 15 (13 late-onset and two early-onset) patients belonging to 14 families with polyneuropathy and mutat...