Infantile Liver Failure Syndrome 1 associated with a novel variant of the <scp><i>LARS1</i></scp> gene: Clinical, genetic, and functional characterization

Tabolacci, Elisabetta; Molinario, Clelia; Marangi, Giuseppe; Nobile, Veronica; Arena, Vincenzo; Mendes, Marisa I.; Smith, Desirée E.C.; Salomons, Gajja S.; Tana, Milena; Costa, Simonetta; Vento, Giovanni; Genuardi, Maurizio

doi:10.1111/cge.13893

Cited by 3 publications

(1 citation statement)

References 5 publications

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“…The phenotype of ILFS1 is heterogeneous, with multisystem involvement that includes severe intrauterine growth retardation (IUGR), microcytic anaemia, fulminant liver failure, and more. However, as reported cases are few, correlation of clinical, histopathologic, and genetic features with prognosis of LARS1 disease is incomplete [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Early onset and liver failure indicating poor prognosis of infant liver failure syndrome type 1

Li,

Feng,

et al. 2024

Orphanet J Rare Dis

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Background Infantile liver failure syndrome type 1 (ILFS1, OMIM #615,438), caused by leucyl-tRNA synthase 1 (LARS1, OMIM *151,350) deficiency, is a rare autosomal-recessive disorder. The clinical manifestations, molecular-genetic features, and prognosis of LARS1 disease remain largely elusive. Methods Three new instances of ILFS1 with confirmed variants in LARS1, encoding LARS1, were identified. Disease characteristics were summarized together with those of 33 reported cases. Kaplan-Meier analysis was performed to assess prognostic factors in ILFS1 patients. Results The 3 new ILFS1 patients harbored 6 novel variants in LARS1. Among the 36 known patients, 12 died or underwent liver transplantation. The main clinical features of ILFS1 were intrauterine growth restriction (31/32 patients in whom this finding was specifically described), failure to thrive (30/31), hypoalbuminemia (32/32), microcytic anemia (32/33), acute liver failure (24/34), neurodevelopmental delay (25/30), seizures (22/29), and muscular hypotonia (13/27). No significant correlations were observed between genotype and either presence of liver failure or clinical severity of disease. Kaplan-Meier analysis indicated that age of onset < 3mo (p = 0.0015, hazard ratio = 12.29, 95% confidence interval [CI] = 3.74–40.3), like liver failure (p = 0.0343, hazard ratio = 6.57, 95% CI = 1.96-22.0), conferred poor prognosis. Conclusions Early age of presentation, like liver failure, confers poor prognosis in ILFS1. Genotype-phenotype correlations remain to be established.

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Section: Introductionmentioning

confidence: 99%

Early onset and liver failure indicating poor prognosis of infant liver failure syndrome type 1

Li,

Feng,

et al. 2024

Orphanet J Rare Dis

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Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

Uehara,

Seki,

Nonoda

et al. 2024

American J of Med Genetics Pt A

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Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl‐tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17‐month‐old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high‐intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1‐related disorder.

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MRI in LARS1 deficiency—Spectrum, patterns, and correlation with acute neurological deterioration

Hammann,

Lenz,

Bianzano

et al. 2024

J of Inher Metab Disea

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Leucine aminoacyl tRNA‐synthetase 1 (LARS1)‐deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever‐associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1‐deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro‐active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.

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Infantile Liver Failure Syndrome 1 associated with a novel variant of the LARS1 gene: Clinical, genetic, and functional characterization

Cited by 3 publications

References 5 publications

Early onset and liver failure indicating poor prognosis of infant liver failure syndrome type 1

Early onset and liver failure indicating poor prognosis of infant liver failure syndrome type 1

Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

MRI in LARS1 deficiency—Spectrum, patterns, and correlation with acute neurological deterioration

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