Charcot-Marie-Tooth type 2 and distal hereditary motor neuropathy: Clinical, neurophysiological and genetic findings from a single-centre experience

Luigetti, Marco; Fabrizi, Gian Maria; Bisogni, Giulia; Romano, Ângela; Taioli, Federica; Ferrarini, Moreno; Bernardo, Daniela; Rossini, Paolo Maria; Sabatelli, Mario

doi:10.1016/j.clineuro.2016.03.007

Cited by 17 publications

(16 citation statements)

References 36 publications

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“…Interestingly, our case description is only the second from the American continent. 22 We confirmed that the majority of mutations (18/34 [53%], Table 2) involved the α-crystallin domain as shown in Figure 1C, 3,5,15,18,19,[23][24][25] reflecting its critical role in HSP chaperon activity. 13 The occurrence of redundant mutations highlights the presence of highly pathogenic amino acid sites ( Figure 1C, underlined letters).…”

Section: Hspb1 Mutations: Genetics and Genotypephenotype Correlationssupporting

confidence: 67%

“…HSPB1mutations are associated with an adult onset neuropathy, with mean onset at 33 years, but with a wide age range (1-65 years), similar to previous reports. 3,5,15,18,19,[23][24][25] This is clearly different from the most common form of CMT, CMT1A,…”

Section: Cmt2f/dhmnii: a Clinical And Electrophysiological Spectrummentioning

confidence: 83%

“…A predominant motor involvement with weakness and atrophy and a distal and symmetrical distribution, as expected for a lengthdependent axonal neuropathy, were the most common clinical manifestations of HSPB1 confirming previous case series. 3,5,15,18,19,[23][24][25] As a result, LL were almost always affected (95% of reports). The pattern of distal LL weakness was quite stereotyped with preferential involvement of plantar over dorsal flexion, as confirmed by Rossor et al 19 Although reported in a minority (50/351 patients considered in Table 2) and by only 38% of cases (19/50) and thus not sensitive, this pattern may be specific 40 as it is not common for other axonal neuropathies, including acquired and genetic etiologies.…”

Section: Cmt2f/dhmnii: a Clinical And Electrophysiological Spectrummentioning

confidence: 99%

“…two entities may represent a continuum of phenotypes, as sensory involvement may be subclinical in CMT2 patients, and motor predominant cases resembling dHMN may develop sensory disturbances over time. 3 Two subtypes of CMT2/dHMN, that is, CMT2 type F (CMT2F) and dHMN type 2 (dHMN2), have a common causative gene in the small heat shock protein HSPB1. 4,5 Following the original description by Evgrafov et al, 4 more than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported.…”

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confidence: 99%

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A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

Taga

Cornblath

2020

J Peripheral Nervous Sys

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Mutations in the HSPB1 gene are associated with Charcot‐Marie‐Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype‐phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture.

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Section: Hspb1 Mutations: Genetics and Genotypephenotype Correlationssupporting

confidence: 67%

Section: Cmt2f/dhmnii: a Clinical And Electrophysiological Spectrummentioning

confidence: 83%

Section: Cmt2f/dhmnii: a Clinical And Electrophysiological Spectrummentioning

confidence: 99%

mentioning

confidence: 99%

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A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

Taga

Cornblath

2020

J Peripheral Nervous Sys

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“…The heterozygous mutations in MME have been associated with late‐onset axonal Charcot‐Marie‐Tooth neuropathy (CMT2), unspecified polyneuropathy, amyotrophic lateral sclerosis, sensory ataxia, cluster headache, and dominant spinocerebellar ataxia with neuropathy (SCA43), whereas homozygous or compound heterozygous mutations in MME cause autosomal recessive CMT2 . Several forms of dHMNs exhibit phenotypic overlaps with CMT2 that is a motor‐predominant inherited neuropathy with subclinical sensory involvement . However, no patients with dHMN phenotype caused by MME variants have been reported to date.…”

Section: Introductionmentioning

confidence: 99%

Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Hong

Yao

et al. 2019

Ann Clin Transl Neurol

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Objective To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. Methods Whole‐exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. Results The clinical features of the patients showed late‐onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co‐segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense‐mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. Interpretation Variants in the MME gene were associated with not only a Charcot‐Marie‐Tooth neuropathy phenotype but also with an autosomal‐recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

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Early and late manifestations of neuropathy due to HSPB1 mutation in the Jewish Iranian population

Greenbaum

Ben‐David

Nikitin

et al. 2021

Ann Clin Transl Neurol

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Objective: Mutations in the HSPB1 gene are associated with a distal hereditary motor neuropathy type 2 (dHMN2) or Charcot-Marie-Tooth disease type 2F (CMT2F), usually with autosomal dominant inheritance. This study aimed to describe the phenotype of the HSPB1 c.407G>T (p.Arg136Leu) mutation at early and late stages of the disease course. Methods: We identified this mutation (previously reported in patients from Italy) in a heterozygous state, among 14 individuals from eight families of Jewish Iranian descent. The clinical, electrophysiological and ultrasonographic features were evaluated during early (less than 5 years, N = 9) or late disease course (N = 5). Results: The majority of subjects were males with a mean age at onset of 43.4 years (range 21-67). Common initial symptoms were gait imbalance, distal (often asymmetric) lower limb weakness and feet numbness. Neurological examination in early disease course showed distal lower extremity weakness in nearly all cases, and absent Achilles tendon reflex in about half. A minority had distal loss of pain, vibration or position sensation. These findings were more prevalent in late disease stage. Electrodiagnostic studies demonstrated a length-dependent axonal motor neuropathy, with typical preferential involvement of the tibial nerve. Muscle ultrasound showed a corresponding length-dependent increase of homogeneous echo-intensity, most noticeably in the gastrocnemius. One patient had a dual diagnosis of CMT2F and CMT2W. Interpretation: The HSPB1 c.407G>G (p.Arg136Leu) mutation causes an adult-onset, predominantly motor, axonal neuropathy in individuals of Jewish Iranian descent. Variable manifestations are noticed, and sensory involvement is more prominent in prolonged disease duration.

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Charcot-Marie-Tooth type 2 and distal hereditary motor neuropathy: Clinical, neurophysiological and genetic findings from a single-centre experience

Cited by 17 publications

References 36 publications

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Early and late manifestations of neuropathy due to HSPB1 mutation in the Jewish Iranian population

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