Biallelic variants in
            <i>LARS2</i>
            and
            <i>KARS</i>
            cause deafness and (ovario)leukodystrophy

Knaap, Marjo S. van der; Bugiani, Marianna; Mendes, Marisa I.; Riley, Lisa G.; Smith, Desirée E.C.; Rudinger-Thirion, Joëlle; Frugier, Magali; Breur, Marjolein; Crawford, Joanna; Gaalen, Judith van; Schouten, Meyke; Willems, Marjolaine; Waisfisz, Quinten; Mau-Them, Frédéric Tran; Rodenburg, Richard J.; Taft, Ryan J.; Keren, Boris; Christodoulou, John; Depienne, Christel; Simons, Cas; Salomons, Gajja S.; Mochel, Fanny

doi:10.1212/wnl.0000000000007098

Cited by 39 publications

(35 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…74 Diagnosis should be facilitated by aminoacylation assays as shown recently for patients with LARS2 and KARS mutations. 75 Mutations in KARS and GARS, which act in both the mitochondria and the cytosol, as well as several cytosolic aminoacyl tRNA synthetases open a new field of IMD since cytoplasmatic tRNA synthetases are necessary for all proteins of the cell and therefore all organelles. The same occurs for other factors related to cytoplasmatic protein synthesis (eg, regulatory factors like EIF2AK3, etc.…”

Section: Cellular Trafficking and Processing Disordersmentioning

confidence: 99%

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

Saudubray

Mochel

Lamari

et al. 2019

J of Inher Metab Disea

Self Cite

View full text Add to dashboard Cite

In view of the rapidly expanding number of IMD discovered by next generation sequencing, we propose a simplified classification of IMD that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large categories. We highlight the increasing importance of complex molecule metabolism and its connection with cell biology processes. Small molecule disorders have biomarkers and are divided in two subcategories: accumulation and deficiency. Accumulation of small molecules leads to acute or progressive postnatal “intoxication”, present after a symptom‐free interval, aggravated by catabolism and food intake. These treatable disorders must not be missed! Deficiency of small molecules is due to impaired synthesis of compounds distal to a block or altered transport of essential molecules. This subgroup shares many clinical characteristics with complex molecule disorders. Complex molecules (like glycogen, sphingolipids, phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogen and lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take place in organelles. They may interfere with fœtal development. Most present as neurodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxisomal disorders, CDG defects of intracellular trafficking and processing, recycling of synaptic vesicles, and tRNA synthetases also belong to this category. Only few have biomarkers and are treatable. Disorders involving primarily energy metabolism encompass defects of membrane carriers of energetic molecules as well as cytoplasmic and mitochondrial metabolic defects. This oversimplified classification is connected to the most recent available nosology of IMD.

show abstract

Section: Cellular Trafficking and Processing Disordersmentioning

confidence: 99%

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

Saudubray

Mochel

Lamari

et al. 2019

J of Inher Metab Disea

Self Cite

View full text Add to dashboard Cite

show abstract

“…Amenorrhea was most frequently primary and there appeared to be no obvious genotype-phenotype correlation [15].…”

Section: Discussionmentioning

confidence: 97%

LARS2-Perrault syndrome: a new case report and literature review

Carminho‐Rodrigues¹,

Klee

Laurent³

et al. 2020

BMC Med Genet

View full text Add to dashboard Cite

Background: Perrault syndrome is a rare recessive and genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and gonadal dysgenesis in females. Mutations in seven different genes have been identified: HARS2, HSD17B4, CLLP, C10orf, ERAL1, TWNK and LARS2. To date, 19 variants have been reported in 18 individuals with LARS2-Perrault syndrome. Case presentation: Here we describe the case of an 8-year-old girl with compound heterozygous missense mutations in the LARS2 gene. We identified two missense mutations [c.457A > C, p.(Asn153His) and c.1565C > A, p.(Thr522Asn)] and subsequent familial segregation showed that each parent had transmitted a mutation. Conclusions: These results have implications for genetic counseling and provide insight into the functional role of LARS2. This case highlights the importance of an early diagnosis. Systematic genetic screening of children with hearing loss allows the early identification of a Perrault syndrome in order to ensure specific endocrinological surveillance and management to prevent secondary complications. Clinical data are compared with the other cases reported in the literature.

show abstract

“…LARS2 variants associated with HLASA had a more severe effect on aminoacylation than those in the less severe phenotypes. Neurological symptoms have been reported in Perrault syndrome associated with variants in TWNK, CLPP, and HSD17B4 as well as LARS2 (Demain et al, 2017;Kosaki et al, 2018;Lerat et al, 2016;van der Knaap et al, 2019). A few cases of male infertility (azoospermia) have been reported in males with CLPP and HSD17B4 variants, and both male and female CLPP knockout mice are sterile (Demain et al, 2017;Lerat et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…However, we have previously reported an individual with a lethal multisystem disorder comprising hydrops, lactic acidosis, and sideroblastic anemia (HLASA; MIM# 617021) with LARS2 variants (Riley et al, 2016). More recently, individuals with Perrault syndrome and neurological symptoms caused by biallelic LARS2 variants have been reported (Kosaki, Horikawa, Fujii, & Kosaki, 2018;van der Knaap et al, 2019). Here we report three additional HLASA cases from two unrelated families who begin to bridge the phenotypic spectrum of LARS2-associated disease, where one individual from each family has survived the neonatal period but has sensorineural hearing loss and developmental delay.…”

Section: Introductionmentioning

confidence: 99%

The expandingLARS2phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy

et al. 2020

Self Cite

View full text Add to dashboard Cite

LARS2 variants are associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss, and with an infantile lethal multisystem disorder: Hydrops, lactic acidosis, sideroblastic anemia (HLASA) in one individual. Recently we reported LARS2 deafness with (ovario) leukodystrophy. Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA‐like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy, lactic acidosis, and developmental delay. Three HLASA cases from two unrelated families were identified. All were males with genital anomalies. Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss. A 55‐year old male with deafness has not displayed neurological symptoms while his female siblings with Perrault syndrome developed leukodystrophy and died in their 30s. Analysis of muscle from a child with a reversible myopathy showed reduced LARS2 and mitochondrial complex I levels, and an unusual form of degeneration. Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA‐associated variants having the most severe effect. A broad phenotypic spectrum should be considered in association with LARS2 variants.

show abstract

Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy

Cited by 39 publications

References 49 publications

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

LARS2-Perrault syndrome: a new case report and literature review

The expandingLARS2phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy

Contact Info

Product

Resources

About