Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

Elsayed, Liena; Babai, Arwa; Salih, Mustafa A.; El-Sadig, Sarah Misbah; Amin, Mutaz; Koko, Mahmoud; Abubakr, Rayan; Idris, Razaz; Taha, Shaimaa; Elmalik, Salah A.; Brice, Alexis; Ahmed, Ammar; Stevanin, Giovanni

doi:10.1186/s12883-018-1180-7

Cited by 15 publications

(17 citation statements)

References 14 publications

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“…The older sibling was diagnosed due to the diagnosis of the younger siblings. 9 In our study, both siblings with DARS2 deficiency had global developmental delay within the first year of life. Younger sibling presented with motor regression after a viral infection at the age of 6 months.…”

Section: Discussionsupporting

confidence: 45%

“…Two younger siblings had infantile onset global developmental delay and the oldest sibling presented with a mild lower limb spasticity at the age of 20 years. The older sibling was diagnosed due to the diagnosis of the younger siblings . In our study, both siblings with DARS2 deficiency had global developmental delay within the first year of life.…”

Section: Discussionmentioning

confidence: 59%

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Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

et al. 2019

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Mitochondrial aminoacyl‐tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl‐tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl‐tRNA synthetase deficiencies including DARS2, EARS2, PARS2, and RARS2 deficiencies. Siblings with DARS2 deficiency presented with global developmental delay within the first year of life. DARS2, EARS2, PARS2, and RARS2 deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in PARS2 deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in EARS2 deficiency for the first time. One patient with RARS2 deficiency had compound heterozygous variants in RARS2. One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl‐tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non‐invasive biochemical investigations are non‐specific for the diagnosis of mitochondrial aminoacyl‐tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl‐tRNA synthetase deficiencies.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 59%

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

et al. 2019

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“…One study of DARS2 missense mutations in LBSL patients has been shown that the mutations have variable effects on the enzyme activity, protein expression, localization, and dimerization of protein [20]. Another report observed that the same compound heterozygous mutations presented with phenotypic variability, from a healthy individual to disabled patients, within a family with DARS2-related LBSL [21]. Three siblings with LBSL who presented with nystagmus, slurring of speech, muscle tonus abnormality, ataxic gait, hypo or hyperreflexia, tremor, and mental retardation caused by DARS2 mutation were considered to display a severe form of LBSL [22].…”

Section: Discussionmentioning

confidence: 99%

Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Borna

Kishita

Sakai

et al. 2020

Genes

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Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

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“…In general, earlier onset of symptoms predicted more severe neurological deterioration in the first decade after disease onset [22]. Case reports of affected siblings have shown that both mild and severe disease phenotypes can manifest even when the DARS2 mutations are identifical [41, 42].…”

Section: Lbsl Patterns Of Disease Progressionmentioning

confidence: 99%

Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination

Fine

Nemeth

Kaufman

et al. 2019

J Neurodevelop Disord

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Background: The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. Body: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. Conclusion: The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.

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Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

Cited by 15 publications

References 14 publications

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination

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