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DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.

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Title: DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.
Authors: Saveri, Paola (AUTHOR), Magri, Stefania (AUTHOR), Maderna, Emanuela (AUTHOR), Balistreri, Francesca (AUTHOR), Lombardi, Raffaella (AUTHOR), Ciano, Claudia (AUTHOR), Moda, Fabio (AUTHOR), Garavaglia, Barbara (AUTHOR), Reale, Chiara (AUTHOR), Lauria Pinter, Giuseppe (AUTHOR), Taroni, Franco (AUTHOR), Pareyson, Davide (AUTHOR), Pisciotta, Chiara (AUTHOR)
Source: European Journal of Neurology. Jul2022, Vol. 29 Issue 7, p2056-2065. 10p.
Subjects: Charcot-Marie-Tooth disease, Parkinson's disease, Foot movements, Polyneuropathies, Phenotypes, Leg muscles, Glycogen storage disease type II
Abstract: Background and purpose: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. Methods: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. Results: Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson's disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients' skin. Conclusions: Our results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Label: Title
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  Data: DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.
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  Data: <searchLink fieldCode="AR" term="%22Saveri%2C+Paola%22">Saveri, Paola</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Magri%2C+Stefania%22">Magri, Stefania</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Maderna%2C+Emanuela%22">Maderna, Emanuela</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Balistreri%2C+Francesca%22">Balistreri, Francesca</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lombardi%2C+Raffaella%22">Lombardi, Raffaella</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ciano%2C+Claudia%22">Ciano, Claudia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Moda%2C+Fabio%22">Moda, Fabio</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Garavaglia%2C+Barbara%22">Garavaglia, Barbara</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Reale%2C+Chiara%22">Reale, Chiara</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lauria+Pinter%2C+Giuseppe%22">Lauria Pinter, Giuseppe</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Taroni%2C+Franco%22">Taroni, Franco</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pareyson%2C+Davide%22">Pareyson, Davide</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pisciotta%2C+Chiara%22">Pisciotta, Chiara</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Journal+of+Neurology%22">European Journal of Neurology</searchLink>. Jul2022, Vol. 29 Issue 7, p2056-2065. 10p.
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  Data: <searchLink fieldCode="DE" term="%22Charcot-Marie-Tooth+disease%22">Charcot-Marie-Tooth disease</searchLink><br /><searchLink fieldCode="DE" term="%22Parkinson's+disease%22">Parkinson's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Foot+movements%22">Foot movements</searchLink><br /><searchLink fieldCode="DE" term="%22Polyneuropathies%22">Polyneuropathies</searchLink><br /><searchLink fieldCode="DE" term="%22Phenotypes%22">Phenotypes</searchLink><br /><searchLink fieldCode="DE" term="%22Leg+muscles%22">Leg muscles</searchLink><br /><searchLink fieldCode="DE" term="%22Glycogen+storage+disease+type+II%22">Glycogen storage disease type II</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background and purpose: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. Methods: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. Results: Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson's disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients' skin. Conclusions: Our results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/ene.15326
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        Text: English
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        PageCount: 10
        StartPage: 2056
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      – SubjectFull: Charcot-Marie-Tooth disease
        Type: general
      – SubjectFull: Parkinson's disease
        Type: general
      – SubjectFull: Foot movements
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      – SubjectFull: Polyneuropathies
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      – SubjectFull: Phenotypes
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      – SubjectFull: Leg muscles
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      – SubjectFull: Glycogen storage disease type II
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              Text: Jul2022
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