Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms

Abstract

Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.

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

“…LARS2 encodes mitochondrial leucyl-tRNA synthase (mtLeuRS), which is dedicated to the charging of mitochondrial tRNA Leu . LARS2 variants have previously been associated with infantile multi-system disease27 and Perrault syndrome 28. KARS encodes lysyl-tRNA…”

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

“…Regarding the second mutation, p.Thr522Asn, has been already described several times. It has also been implicated in a LARS2 more severe phenotype described by Riley et al [13] They described a lethal, multisystem metabolic disorder characterized by severe lactic acidosis, hydrops and sideroblastic anemia, impaired cardiac function, disordered coagulation, pulmonary hypertension and progressive renal disease associated with the biallelic LARS2 p.Thr522Asn and p.Ala430Val mutations [7,11]. Thus, the presence of p.Thr522Asn in our patient reinforced the idea that an association with the p.Ala430Val variant would have been more likely to be more damaging than p.Thr522Asn already described in homozygosity in Perrault syndrome [8,10].…”

“…Apart from hearing loss and ovarian dysgenesis in females, some patients with Perrault syndrome may present neurological symptoms, such as learning disabilities, pyramidal signs, cerebellar ataxia and motor or sensory peripheral neuropathy [7]. Here, we report the case of a young girl with bilateral severe hearing loss and bi-allellic mutations in LARS2.…”

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

“…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).…”

“…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.…”