Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

Reumers, Stacha F. I.; Erasmus, Corrie E.; Bouman, Karlijn; Pennings, Maartje; Schouten, Meyke; Küsters, Benno; Duijkers, Floor A.M.; Kooi, Anneke J. van der; Jaeger, Bregje; Verschuuren‐Bemelmans, Corien C.; Faber, Catharina G.; Engelen, Baziel G. van; Kamsteeg, Erik‐Jan; Jungbluth, Heinz; Voermans, Nicol C.

doi:10.1111/cge.14054

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…Overall, our cohort confirmed that disease onset occurs predominantly in infancy and early childhood, 4 , 10 although DNM2 -related CNM was initially identified in families showing late-onset CNM. 9 This may be in part due to the nature of patient-reported retrospective data, whereby patients report symptoms years before presenting to medical care.…”

Section: Discussionsupporting

confidence: 73%

“…The most reported cases are boys with X-linked myotubular myopathy (XLMTM) due to mutations of MTM1 3 ; however, a recent study in the Netherlands found DNM2 to be a more common cause of CNM in their cohort. 4 Mutations of BIN1 , which is an autosomal recessive CNM, are relatively rare. 5 Mutations in TTN , RYR1 , and SPEG can also produce a congenital myopathy with internal nuclei.…”

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confidence: 99%

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Phenotypic Spectrum of DNM2 -Related Centronuclear Myopathy

et al. 2022

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Background and ObjectivesCentronuclear myopathy (CNM) due to mutations in the dynamin 2 gene,DNM2, is a rare neuromuscular disease about which little is known. The objective of this study was to describe the range of clinical presentations and subsequent natural history ofDNM2-related CNM.MethodsPediatric and adult patients with suspicion for a CNM diagnosis and confirmed heterozygous pathogenic variants inDNM2were ascertained between December 8, 2000, and May 1, 2019. Data were collected through a retrospective review of genetic testing results, clinical records, and pathology slides combined with patient-reported clinical findings via questionnaires.ResultsForty-two patients withDNM2-related CNM, whose ages ranged from 0.95 to 75.76 years at most recent contact, were enrolled from 34 families in North or South America and Europe. There were 8 differentDNM2pathogenic variants within the cohort. Of the 32 biopsied patients, all had histologic features of CNM. The disease onset was in infancy or childhood in 81% of the cohort, and more than half of the patients had high arched palates, indicative of weakness in utero. Ambulation was affected in nearly all (92%) the patients, and while the rapidity of progression was variable, most (67%) reported a “deteriorating course.” Ptosis, ophthalmoparesis, facial weakness, dysphagia, and respiratory insufficiency were commonly reported. One-third of the patients experienced restricted jaw mobility. Certain pathogenic variants appear to correlate with a more severe phenotype.DiscussionDNM2-related CNM has a predominantly early-onset, often congenital, myopathy resulting in progressive difficulty with ambulation and occasionally bulbar and respiratory dysfunction. This detailed characterization of the phenotype provides important information to support clinical trial readiness for future disease-modifying therapies.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Phenotypic Spectrum of DNM2 -Related Centronuclear Myopathy

et al. 2022

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“…The moderate or scarce cognitive defects reported in CNM patients might be related to compensatory mechanisms that could operate in humans, despite the potential impact of the p.R465W mutation on hippocampal neuronal morphology and synaptic function that we observed in a mouse model of the disease. Notably, there is no clear genotype–phenotype correlation in the autosomal dominant CNM; however, patients exhibit marked interfamilial and intrafamilial variability [115–117], suggesting other factors besides mutations might influence the neurological phenotype in the CNM context. Therefore, the p.R465W mutation, and other autosomal dominant mutations in Dyn2, may or may not cause evident neurological defects.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, there is no clear genotype-phenotype correlation in the autosomal dominant CNM; however, patients exhibit marked interfamilial and intrafamilial variability [115][116][117], suggesting other factors besides mutations might influence the neurological phenotype in the CNM context. Therefore, the p.R465W mutation, and other autosomal dominant mutations in Dyn2, may or may not cause evident neurological defects.…”

Section: Htz Defects In the Excitatory Synaptic Transmissionmentioning

confidence: 99%

A centronuclear myopathy‐causing mutation in dynamin‐2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease

Arriagada‐Diaz,

Flores‐Muñoz,

Gómez‐Soto

et al. 2023

Neuropathology Appl Neurobio

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AimsDynamin‐2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin‐2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2‐linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin‐2 CNM‐causing mutation influences the CNS function.MethodsHeterozygous mice harbouring the p.R465W mutation in the dynamin–2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests.ResultsHTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin‐2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition.ConclusionOur findings suggest that the dynamin‐2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.

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“…1 AD-CNM results from heterozygous mutations in the DNM2 gene, which encodes dynamin 2 (DNM2), 2,3 and to date, 37 mutations (mainly missense) have been identified. 2,[4][5][6][7][8][9][10][11] Dominant DNM2 mutations also cause rare cases of Charcot-Marie-Tooth pe-ripheral neuropathy (CMT) (MIM: 606482) 12 and hereditary spastic paraplegia. 13 DNM2 belongs to the superfamily of large guanosine triphosphatases (GTPases) and is involved in endocytosis and intracellular vesicle trafficking through its role in deformation of biological membranes by oligomerization at the neck of membranes invagination, leading to the release of vesicles.…”

Section: Introductionmentioning

confidence: 99%