Neurodegenerative Disorder Related to AIMP1/p43 Mutation Is Not a PMLD

Boespflug‐Tanguy, Odile; Aubourg, Patrick; Dorboz, Imen; Bégou, Mélina; Giraud, G; Sarret, Catherine; Vaurs‐Barrière, Catherine

doi:10.1016/j.ajhg.2010.12.015

Cited by 18 publications

(16 citation statements)

References 9 publications

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“…In comments on the report of Feinstein et al, Biancheri et al (21) and Boespflug-Tanguy et al (22) stated that the clinical and neuroradiological features of those patients seemed consistent with a severe neuronal disease rather than a hypomyelinating leukodystrophy, such as PMLD. The authors argued that in patients with true hypomyelination, in contrast to patients with AIMP1 defects, brain atrophy is mild or absent.…”

Section: Hypomyelinating Leukodystrophy 3 (Aimp1 Related Disorder -Hld3)mentioning

confidence: 99%

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Charzewska¹,

Wierzba

Iżycka‐Świeszewska

et al. 2016

Clinical Genetics

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Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

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Section: Hypomyelinating Leukodystrophy 3 (Aimp1 Related Disorder -Hld3)mentioning

confidence: 99%

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Charzewska¹,

Wierzba

Iżycka‐Świeszewska

et al. 2016

Clinical Genetics

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“…It is also important to differentiate HLDs from neuronal diseases with secondary hypomyelination, which carry an independent differential diagnosis, such as AGC1 ‐, HSPD1 ‐, and AIMP1 ‐related disorders . Neuronal diseases with secondary hypomyelination have prominent GM symptoms, such as early onset epilepsy and severe intellectual disability.…”

Section: Diagnosis and Management Of Hldsmentioning

confidence: 99%

Hypomyelinating leukodystrophies: Translational research progress and prospects

Pouwels

Vanderver

Bernard

et al. 2014

Annals of Neurology

138

108

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Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials. ANN NEUROL 2014;76:5-19 T he concept of hypomyelinating disorders was originated by Schiffmann, van der Knaap, and colleagues.1-3 Among the inherited white matter (WM) disorders, hypomyelinating leukodystrophies (HLDs) are notable for abnormalities in myelin development rather than destruction. This class of disorders is distinguished by their characteristic appearance on magnetic resonance imaging (MRI), namely, lessening or absence of the T 2 hypointensity that typically signifies the presence of myelin, often without the significant lessening of T 1 hyperintensity seen in the other, nonhypomyelinating leukodystrophies. Other MRI features help to narrow the differential diagnosis and focus genetic and metabolic testing. 3 We are entering a phase of clinical research for HLDs where identification of outcome measures of potential treatment benefit is crucial. In ultrarare diseases, clinical features, and natural history are often This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. poorly known; therefore, clinical/neurological parameters alone are insufficient as endpoints for clinical efficacy studies. In this case, another possible acceptable clinical trial design includes the use of biomarkers as surrogate endpoints. The adoption of criteria for biomarkers of efficacy is an important feasibility step for the planning and execution of clinical studies because it provides an objective endpoint at a defined period of time after an intervention has been initiated. Proposing a standard measure of myelination based upon magnetic resonance (MR) metrics as a reliable biomarker could therefore greatly encourage clinical research.With these challenges in mind, we organized a multidisciplinary group to address clinical and future research priorities for HLDs. The group ...

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“…6 However, this designation has been debated and currently 'primary neurodegenerative disease' is the favored classification. 6,7,28,29 The patients with truncating mutations in AIMP1 present with a severe phenotype encompassing a progressive neurological deterioration, severe failure to thrive and severe global developmental delay/ID, axial hypotonia, progressive spastic paraparesis, and seizures. Furthermore, their MRI scans show arrest of myelination.…”

Section: Aimp1 Variants-recessive Intellectual Disability Z Iqbal Et Almentioning

confidence: 99%

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

et al. 2015

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AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p. (Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

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Neurodegenerative Disorder Related to AIMP1/p43 Mutation Is Not a PMLD

Cited by 18 publications

References 9 publications

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Hypomyelinating leukodystrophies: Translational research progress and prospects

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

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