New <scp><i>AARS2</i></scp> Mutations in Two Siblings With Tremor, Downbeat Nystagmus, and Primary Amenorrhea: A Benign Phenotype Without Leukoencephalopathy

Michele, G. De; Galatolo, Daniele; Lieto, Maria; Maione, Luigi; Cocozza, Sirio; Santorelli, Filippo M.; Filla, Alessandro

doi:10.1002/mdc3.12991

Cited by 8 publications

(4 citation statements)

References 7 publications

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“…Spasticity is the most consistent finding, and dystonia, dysarthria, or tremor may also be present ( 7 , 10 , 18 ). All adult-onset patients reported thus far, except two ( 13 , 19 ), presented leukoencephalopathy. Typically, these patients advance to the point of no or limited interaction with the environment, non-ambulatory status, and in many cases, premature death within 5–10 years after the onset of the symptoms ( 7 , 10 , 18 ).…”

Section: Discussionmentioning

confidence: 95%

“…AARS2 pathogenic variants were first identified in infantile mitochondrial cardiomyopathy in 2011 ( 4 ), and later found to cause adult-onset leukodystrophy, MIM#615889 ( 5 ). All adult-onset patients, less than two, present leukoencephalopathy ( 13 , 19 ). All female patients, less than one ( 20 ) present ovarian failure, none has been described with uterus infantilis .…”

Section: Author's Notementioning

confidence: 99%

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Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report

Kazakova,

Téllez-Martínez,

Flores-Lagunes

et al. 2023

Front. Neurol.

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ObjectivesTo report the first Mexican case with two novel AARS2 mutations causing primary ovarian failure, uterus infantilis, and early-onset dementia secondary to leukoencephalopathy.MethodsDetailed clinical, clinimetric, neuroimaging features, muscle biopsy with biochemical assays of the main oxidative phosphorylation complexes activities, and molecular studies were performed on samples from a Mexican female.ResultsWe present a 41-year-old female patient with learning difficulties since childhood and primary amenorrhea who developed severe cognitive, motor, and behavioral impairment in early adulthood. Neuroimaging studies revealed frontal leukoencephalopathy with hypometabolism at the fronto-cerebellar cortex and caudate nucleus. Uterus infantilis was detected on ultrasound study. Clinical exome sequencing identified two novel variants, NM_020745:c.2864G>A (p.W955*) and NM_020745:c.1036C>A (p.P346T, p.P346Wfs*18), in AARS2. Histopathological and biochemical studies on muscle biopsy revealed mitochondrial disorder with cytochrome C oxidase (COX) deficiency.ConclusionsSeveral adult-onset cases of leukoencephalopathy and ovarian failure associated with AARS2 variants have been reported. To our best knowledge, none of them showed uterus infantilis. Here we enlarge the genetic and phenotypic spectrum of AARS2-related dementia with leukoencephalopathy and ovarian failure and contribute with detailed clinical, clinometric, neuroimaging, and molecular studies to disease and novel molecular variants characterization.

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Section: Discussionmentioning

confidence: 95%

Section: Author's Notementioning

confidence: 99%

Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report

Kazakova,

Téllez-Martínez,

Flores-Lagunes

et al. 2023

Front. Neurol.

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“…Conversely, mutations in genes involved in signal transduction, cell development, DNA and RNA maintenance, metabolism of complex lipids, transport proteins, intracellular transport, and electron transport appear less common [4,101]. Other cellular processes such as those involving tRNA synthetases are seldom affected [8,29].…”

Section: Discussionmentioning

confidence: 99%

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Galatolo

Michele

Silvestri

et al. 2021

IJMS

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The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

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“…AARS2 gene mutations cause two separate and extremely rare clinical phenotypes, namely infantile mitochondrial cardiomyopathy [ 2 ] and adult-onset leukoencephalopathy with early ovarian failure [ 3 , 4 ]. Due to the broader application of next-generation sequencing in clinical practice, we have been able to recognize the expanding phenotypic spectrum of AARS2 mutations, including a benign phenotype without leukoencephalopathy and lethal primary pulmonary hypoplasia [ 5 , 6 ]. Notably, some reported cases of familial pulmonary hypoplasia with AARS2 mutations had been linked to the European founder (c.1774C > T variant) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy

et al. 2022

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Background Missense mutations in the mitochondrial alanyl-tRNA synthetase 2 (AARS2) gene are clinically associated with infantile mitochondrial cardiomyopathy or adult-onset leukoencephalopathy with early ovarian failure. To date, approximately 40 cases have been reported related to AARS2 mutations, while its genetic and phenotypic spectrum remains to be defined. Case presentation We identified a 24-year-old Chinese female patient with adult-onset leukoencephalopathy carrying novel compound heterozygous pathogenic mutations in the AARS2 gene (c.718C > T and c.1040 + 1G > A) using a whole-exome sequencing approach. Conclusions Our findings further extend the mutational spectrum of AARS2-related leukoencephalopathy and highlight the importance of the whole-exome sequencing in precisely diagnosing adult-onset leukoencephalopathies.

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New AARS2 Mutations in Two Siblings With Tremor, Downbeat Nystagmus, and Primary Amenorrhea: A Benign Phenotype Without Leukoencephalopathy

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Cited by 8 publications

References 7 publications

Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report

Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy

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