Age at onset and symptom spread in primary adult‐onset blepharospasm and cervical dystonia

Martino, Davide; Berardelli, Alfredo; Abbruzzese, Giovanni; Bentivoglio, Anna Rita; Esposito, Marcello; Fabbrini, Giovanni; Guidubaldi, Arianna; Girlanda, Paolo; Liguori, Rocco; Marinelli, Lucio; Morgante, Francesca; Santoro, Lucio; Defazio, Giovanni

doi:10.1002/mds.25088

Cited by 53 publications

(59 citation statements)

References 15 publications

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“…This spread usually occurs within 5 years of blepharospasm onset (101, 102). The lifetime risk of generalization to craniocervical dystonia has been reported to be as high as 60%, though the evidence for this comes from cohort studies recruited from tertiary movement disorders centers, where the study population may not be representative of all patients with blepharospasm (103, 104). Greater age of onset, female sex, and a prior history of minor head trauma have been identified as risk factors (105).…”

Section: Blepharospasmmentioning

confidence: 99%

Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

Hamedani

Gold

2017

Front. Neurol.

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Eye movement abnormalities are among the earliest clinical manifestations of inherited and acquired neurodegenerative diseases and play an integral role in their diagnosis. Eyelid movement is neuroanatomically linked to eye movement, and thus eyelid dysfunction can also be a distinguishing feature of neurodegenerative disease and complements eye movement abnormalities in helping us to understand their pathophysiology. In this review, we summarize the various eyelid abnormalities that can occur in neurodegenerative, neurogenetic, and neurometabolic diseases. We discuss eyelid disorders, such as ptosis, eyelid retraction, abnormal spontaneous and reflexive blinking, blepharospasm, and eyelid apraxia in the context of the neuroanatomic pathways that are affected. We also review the literature regarding the prevalence of eyelid abnormalities in different neurologic diseases as well as treatment strategies (Table 1).

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Section: Blepharospasmmentioning

confidence: 99%

Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

Hamedani

Gold

2017

Front. Neurol.

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“…Dystonia spreads in a significant portion of patients [16][17][18] suggesting that slowing or halting clinical progression may be of interest; however, developing such a disease-modifying therapy will probably require a better understanding of the disease mechanism. A trial aimed at slowing disease progression would require long-term evaluations and outcomes, or a validated, short-term surrogate outcome, which is currently lacking for dystonia.…”

Section: Clinical Characteristics Of Dystonia and Associated Challengesmentioning

confidence: 99%

Designing Clinical Trials for Dystonia

et al. 2014

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With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

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“…No associations have been found with age-related medical conditions such as hypertension and diabetes which were present in two of our patients. Patients with BSP often show spread of dystonia to contiguous craniocervical anatomical segments, most commonly within 5 years, as seen our proband [3]. …”

Section: Discussionmentioning

confidence: 99%

“…BSP is a relatively common form of focal dystonia, with prevalence estimates ranging from 1.6 to 13.3/100,000 worldwide [2]. Mean age of onset is from 50 to 60 years and women are more commonly affected than men [1, 3]. Genetic factors are believed to play an important role in the etiopathogenesis of BSP given that 10 to 27% of affected individuals report a positive family history of dystonia [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Blepharospasm in a multiplex African-American pedigree

Xiao

Thompson

Vemula

et al. 2016

Journal of the Neurological Sciences

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Background Isolated blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetic studies of BSP have been limited by the paucity of large multiplex pedigrees. Although sequence variants (SVs) in THAP1 have been reported in rare cases of BSP, the genetic causes of this focal dystonia remain largely unknown. Moreover, in the absence of family history and strong in silico or in vitro evidence of deleteriousness, the pathogenicity of novel SVs in THAP1 and other dystonia-associated genes can be indeterminate. Methods A large African-American pedigree with BSP was phenotypically characterized and screened for mutations in THAP1, TOR1A and GNAL with Sanger sequencing. Whole-exome sequencing of the proband was used to examine other dystonia-associated genes for potentially pathogenic SVs. In silico and co-segregation analyses were performed for a novel THAP1 SV identified in the proband. Results Seven family members exhibited increased blinking and/or stereotyped bilateral and synchronous orbicularis oculi spasms with age of onset ranging from early childhood to late adult life (7 to 54 years). The proband was found to harbor a novel THAP1 SV (c.314T>C, p.L105S). However, the p.L105S SV did not co-segregate with blepharospasm in the pedigree. Moreover, in silico analyses suggest that p.L105S is benign. No pathogenic or likely pathogenic SVs in other dystonia-associated genes were identified with whole-exome sequencing. Conclusions Blepharospasm can be familial and may be hereditary in African-Americans. A comprehensive array of in silico tools, and, if possible, co-segregation analysis should be used to classify SVs in dystonia-associated genes.

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Age at onset and symptom spread in primary adult‐onset blepharospasm and cervical dystonia

Abstract: The convergent age of spread in BSP and cervical dystonia is a novel finding indicating age as a factor modulating spread of dystonia. These findings may assist in informing prognostication for patients with primary adult-onset focal dystonia.

Cited by 53 publications

References 15 publications

Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

Designing Clinical Trials for Dystonia

Blepharospasm in a multiplex African-American pedigree

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