Multiple cranial nerve neuropathies, microcephaly, neurological degeneration, and “fork and bracket sign” in the MRI: A distinct syndrome

Mégarbané, André; Dorison, Nathalie; Tamraz, J.

doi:10.1002/ajmg.a.33417

Cited by 11 publications

(12 citation statements)

References 6 publications

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“…Axial slice through the mesencephalon showed bright signal from the oculomotor nuclear complex, and related degenerated internal fibers of the oculomotor nerves (Figure B). These highly unique “fork and bracket” MRI signs were previously described only once, in one of the SBF1 ‐mutated families . Our findings represent the second case described to date, delineating this MRI finding as a unique diagnostic sign.…”

Section: Resultssupporting

confidence: 73%

“…These highly unique "fork and bracket" MRI signs were previously described only once, in one of the SBF1-mutated families. 8 Our findings represent the second case described to date, delineating this MRI finding as a unique diagnostic sign.…”

Section: Clinical Characterizationsupporting

confidence: 60%

“…In the third family, two siblings of Syrian ancestry had a homozygous missense mutation resulting in multiple cranial neuropathies, microcephaly and neurological degeneration, described as “Fork and bracket” signs . Although sharing many features with the Saudi‐Arabian patients, there were clinical differences: they presented with normal proprioception, and neither syndactyly nor drop‐foot was evident.…”

Section: Discussionmentioning

confidence: 99%

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Novel SBF1 splice‐site null mutation broadens the clinical spectrum of Charcot‐Marie‐Tooth type 4B3 disease

et al. 2018

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Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus. Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels, previously described as "fork and bracket" signs. Genome-wide linkage analysis identified a single ~1.5 Mbp disease-associated locus on chromosome 22q13.33. Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1). SBF1 missense mutations were shown to underlie Charcot-Marie-Tooth (CMT) type 4B3 disease, a rare autosomal recessive subtype of CMT4. The novel SBF1 null mutation highlights distinct severe phenotypic manifestations, broadening the clinical spectrum of SBF1-related neuropathies: cerebellar and pyramidal signs evident in the first months of life with peripheral polyneuropathy emerging only toward the end of the first decade, together with unique MRI findings.

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Section: Resultssupporting

confidence: 73%

Section: Clinical Characterizationsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Novel SBF1 splice‐site null mutation broadens the clinical spectrum of Charcot‐Marie‐Tooth type 4B3 disease

et al. 2018

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“…34 . Rare and novel autosomal recessive disorders have been widely reported from communities with high consanguinity rates [35][36][37][38][39][40][41][42] , since the main impact of consanguinity is the increased expression of rare autosomal recessive genetic disorders.…”

Section: Health Impact Of Consanguinitymentioning

confidence: 99%

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

Hamamy

Antonarakis

Cavalli-Sforza

et al. 2011

Genetics in Medicine

268

244

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Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International ConsanguinityWorkshop from 3 rd to 7 th May 2010 to discuss the known and presumptive risks and benefits of close kin marriages, and to identify important future areas for research on consanguinity.The group highlighted the importance of evidence-based counselling recommendations for consanguineous marriages, and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances infor rapid high-throughput genome sequencing (HTS), and for the identification of copy number variants by comparative genomic hybridization (aCGH) offer a significantn unprecedented opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies.

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“…The phenotype of the first family is consistent with CMT4B with a demyelinating progressive sensory-motor neuropathy with myelin outfoldings without associated features; the 3 affected sisters were compound heterozygotes for two missense mutations, p.M417V and p.T1590A, 36 both predicted as benign or tolerated by in-silico analyses and therefore with a mild impact on the protein. Conversely, the Syrian family had an axonal motor neuropathy with microcephaly, intellectual disability, multiple cranial neuropathies, and "the fork and the bracket" signs on brain MRI showing the abnormal cranial nerves 52 ; the 2 affected siblings carried a homozygous mutation, p.L335P, located next to the critical dDENN domain and predicted to be highly deleterious for protein function. 34 The fork and bracket signs, first described by Megarbane et al 52 and later by Flusser et al in another CMT4B3 family, 32 have not been reported in other conditions thus far.…”

Section: Cmt4b3mentioning

confidence: 99%

A multicenter retrospective study of charcot‐marie‐tooth disease type 4B (CMT4B) associated with mutations in myotubularin‐related proteins (MTMRs)

Pareyson

Stojkovic

Reilly

et al. 2019

Annals of Neurology

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Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis.

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Multiple cranial nerve neuropathies, microcephaly, neurological degeneration, and “fork and bracket sign” in the MRI: A distinct syndrome

Cited by 11 publications

References 6 publications

Novel SBF1 splice‐site null mutation broadens the clinical spectrum of Charcot‐Marie‐Tooth type 4B3 disease

Novel SBF1 splice‐site null mutation broadens the clinical spectrum of Charcot‐Marie‐Tooth type 4B3 disease

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

A multicenter retrospective study of charcot‐marie‐tooth disease type 4B (CMT4B) associated with mutations in myotubularin‐related proteins (MTMRs)

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