Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, Anne-Marie; Vriendt, Els De; Deconinck, Tine; Merlini, Luciano; Bergh, Peter Van den; Rašić, V. Milić; Robberecht, Wim; Fischer, Dirk; Morales, Raúl Juntas; Mitrović, Zoran D.; Seeman, Pavel; Mazanec, Radim; Kochański, Andrzej; Jordanova, Albena; Auer‐Grumbach, Michaela; Enden, Apollonia T J M Helderman-van den; Wokke, John H. J.; Nelis, Eva; Jonghe, Peter De; Timmerman, Vincent

doi:10.1093/brain/awn029

Cited by 110 publications

(90 citation statements)

References 36 publications

(49 reference statements)

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“…[17][18][19] In some forms of ALS, such as the SETX-associated ALS type 4, the phenotype is so atypical that some authors suggest they should be considered as separate disease entities rather than ALS. 20,21 60% of patients with disease onset between 20 and 40 years of age have predominantly upper motor neuron involvement, and relatively few of these patients (15%) have bulbar-onset disease. 15 Older age at onset is associated with decreased likelihood of upper motor neuron involvement (20%), increased probability of bulbar onset (some studies report up to 50% with onset after 80 years of age), and poor prognosis.…”

Section: Age At Onsetmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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| Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset-a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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Section: Age At Onsetmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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“…Mutations in Hsp27 have been detected in patients with hereditary motor neuropathy, but so far no mutations in the phosphoacceptor sites have been reported (see, e.g., [168,169]). …”

Section: Hsp27 Phosphorylation and Other Diseasesmentioning

confidence: 99%

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

Kostenko

Moens

2009

Cell. Mol. Life Sci.

312

314

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The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27. As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases will be presented.

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“…Mutations in HSPB8 occur in both distal HMN and CMT2 patients (Dierick et al 2008). Among other genes, the identification of small Hsp gene mutations offer an intriguing connection into the role of the small Hsps in maintaining normal function in both the central and peripheral nervous system.…”

Section: Hereditary Motor Neuropathiesmentioning

confidence: 99%

The Small Heat-Shock Proteins: Cellular Functions and Mutations Causing Neurodegeneration

d’Ydewalle¹,

Krishnan²,

Timmerman³

et al. 2010

Folding for the Synapse

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Small heat-shock proteins (small Hsps) are a family of highly conserved proteins involved in multiple cellular mechanisms. Apart from their central role as chaperones in protecting cells during stressful conditions (as outlined in the previous two chapters), small Hsps also function to maintain cellular homeostasis in physiological conditions. Correct protein refolding to avoid aggregation, targeting misfolded proteins for degradation, proper cytoskeletal organization, and anti-apoptotic functions are some of the extensively studied attributes of small Hsps. One or more of these cellular mechanisms may malfunction in specific sets of neurons leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disorders, and amyotrophic lateral sclerosis. Many in vitro models of these diseases have demonstrated the beneficial roles of small Hsps pointing out their protective role in attenuating the neurodegenerative phenotype. Interestingly, mutations in small Hsps themselves were linked to other degenerative disorders like inherited peripheral neuropathies and familial myopathies. Although not much is known regarding the exact patho-mechanism ("loss of function" or "gain of function") of mutations in causing disease, these discoveries reiterate the importance of small Hsps in maintaining neuronal health and indicate that the small Hsp family of proteins might have more functions than meets the eye. This chapter reviews the current knowledge regarding these enigmatic proteins, including their structure and function and how mutations in these once "forgotten proteins" might alter their functions and cause neurodegeneration.

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Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Cited by 110 publications

References 36 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

The Small Heat-Shock Proteins: Cellular Functions and Mutations Causing Neurodegeneration

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