Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-06-02

AUTHORS

Boglarka Bansagi, Thalia Antoniadi, Sarah Burton-Jones, Sinead M. Murphy, John McHugh, Michael Alexander, Richard Wells, Joanna Davies, David Hilton-Jones, Hanns Lochmüller, Patrick Chinnery, Rita Horvath

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies. More... »

PAGES

1899-1908

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00415-015-7778-4

DOI

http://dx.doi.org/10.1007/s00415-015-7778-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008382223

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26032230


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27 schema:description Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.
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34 schema:keywords CMT
35 CMT2
36 Charcot-Marie
37 Ireland
38 Irish origin
39 Kingdom
40 SIX family
41 Tooth disease
42 United Kingdom
43 aaRS
44 acid
45 action potentials
46 activity
47 acylation activity
48 additional families
49 alanyl-tRNA synthetase (AARS) mutations
50 amino acids
51 amino acylation activity
52 aminoacyl-tRNA synthetases
53 axonal damage
54 axonal degeneration
55 axonal form
56 axonal lesions
57 axonal neuropathy
58 axonal protein dysfunction
59 background
60 clinical manifestations
61 clinical presentation
62 clinical spectrum
63 cognate tRNA
64 cohort
65 cohort of patients
66 conduction studies
67 correlation
68 damage
69 date six families
70 defect needs
71 deformity
72 degeneration
73 demyelination
74 diagnostic difficulties
75 difficulties
76 disease
77 distal hereditary motor neuropathy
78 distal lower limb predominant sensorimotor neuropathy
79 dominant AARS
80 dominant missense alanyl-tRNA synthetase (AARS) mutations
81 dysfunction
82 editing defect need
83 essential role
84 family
85 findings
86 form
87 function variants
88 further diagnostic difficulties
89 gene mutations
90 genetic background
91 genotype/phenotype correlation
92 hand deformities
93 hereditary motor neuropathy
94 heterogeneity
95 heterogeneous axonal neuropathies
96 heterogeneous clinical presentation
97 impaired amino acylation activity
98 impairment
99 intermediate CMT
100 lesions
101 limb impairment
102 limb predominant sensorimotor neuropathy
103 loss
104 lower limb predominant sensorimotor neuropathy
105 manifestations
106 missense alanyl-tRNA synthetase (AARS) mutations
107 missense variants
108 motor
109 motor neuropathy
110 mutations
111 need
112 nerve
113 nerve conduction studies
114 neuropathy
115 novel missense variant
116 origin
117 pathology
118 pathomechanism
119 pathomechanism of CMT2
120 patients
121 phenotype correlation
122 phenotypic heterogeneity
123 phenotypic manifestations
124 potential
125 predominant sensorimotor neuropathy
126 presentation
127 primary axonal damage
128 protein dysfunction
129 protein translation
130 recurrent loss
131 role
132 sensorimotor neuropathy
133 sensory nerves
134 significant demyelination
135 sixth family
136 spectra
137 split hand deformity
138 study
139 synthetase (AARS) mutations
140 synthetases
141 tRNA
142 translation
143 underlying pathology
144 upper limb impairment
145 variants
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