A number sign (#) is used with this entry because of evidence that Perrault syndrome-4 (PRLTS4) is caused by homozygous or compound heterozygous mutation in the LARS2 gene (604544) on chromosome 3p21.

Biallelic mutation in the LARS2 gene can also cause the more severe disorder HLASA (617021).

Perrault syndrome-4 (PRLTS4) is an autosomal recessive disorder primarily characterized by early-onset sensorineural hearing loss in both males and females, and premature ovarian failure (POF) in females. Affected individuals may also develop neurologic involvement, including developmental delay or learning difficulties in childhood or onset of progressive movement abnormalities, such as spasticity, in adulthood. Brain imaging may show progressive leukodystrophy (summary by Pierce et al., 2013, Kosaki et al., 2018 and van der Knaap et al., 2019).

For a discussion of genetic heterogeneity of Perrault syndrome, see PRLTS1 (233400).

Pierce et al. (2013) reported a consanguineous family of Palestinian ancestry in which the 17-year-old female proband presented with primary amenorrhea and postmenopausal levels of follicle-stimulating hormone and luteinizing hormone (FSH and LH; see 118850). Her uterus was prepubertal in size, and her ovaries were not visualized on abdominal ultrasound. The proband and her 2 brothers were all diagnosed with sensorineural hearing loss at 3 to 5 years of age. Hearing loss in the brothers was severe at lower frequencies and less severe at higher frequencies, resulting in unusual upsloping audiograms. The proband had a similar pattern of hearing loss in her right ear, resulting in an upsloping audiogram, whereas hearing loss remained mild in her left ear; she did not use a hearing aid. Pierce et al. (2013) also studied a second family, of Slovenian ancestry, in which the proband presented with POF and severe hearing loss. She had apparently normal menarche at age 13 years and regular menses until age 18 years, but she had no cycles between ages 19 and 30 years, and her FSH levels at age 30 years were high. Both probands had 46,XX karyotypes, normal neurologic function, and normal intelligence.

Solda et al. (2016) reported a sister and brother, born of unrelated Italian parents, with Perrault syndrome. Both had profound congenital sensorineural hearing loss and received cochlear implants. The sister had normal menarche, but presented with premature ovarian failure at age 31. Abdominal ultrasound showed a bicornuate uterus, hypoplastic left ovary, and probable dysgenesis of the right ovary.

Clinical Variability

Kosaki et al. (2018) reported 2 Japanese sisters, born of unrelated parents, with PRLTS4 and additional neurobehavioral symptoms. Both presented in infancy with sensorineural hearing loss and later showed absent ovaries and primary amenorrhea. In addition, both girls had normal early psychomotor development, but started to show delayed development at about 12 months of age. They had cognitive and behavioral problems, learning difficulties, and poor performance on IQ tests. One sister also had osteoporosis and gait ataxia. The authors suggested that they should be classified as 'type 2' Perrault syndrome due to the neurodevelopmental features. These findings were in contrast to the description of earlier patients with Perrault syndrome due to LARS2 mutations, and suggested that patients with PRLTS4 may be at risk for neurologic impairment.

Van der Knaap et al. (2019) reported 4 unrelated patients, 2 females and 2 males, with PRLTS4. The females presented with congenital sensorineural deafness and were later diagnosed with ovarian failure. Patient 1, a female, had mildly delayed early development, but was able to work as an adult. Following a fall at age 33 years, she showed progressive neurologic decline, with cerebellar ataxia, spasticity, supranuclear gaze palsy, and dysphagia. She died at age 35.5 years. The other woman (patient 4) had normal psychomotor development, but began to have progressive coordination problems with ataxia and pyramidal dysfunction in her forties. By age 48, she was unable to walk due to spasticity. Brain imaging of both women as adults showed progressive leukoencephalopathy in the cerebral white matter with later involvement of subcortical regions. The thalamus, internal capsule, corpus callosum, and pyramidal tracts were involved. Postmortem examination of patient 1 showed cystic degeneration of the deep white matter with loss of myelin and oligodendrocytes, astrocyte defects with some reactive gliosis, and mild neuronal loss. Axonal spheroids were also identified, particularly in the midbrain. Patient 2 was a 37-year-old man who presented in infancy with hypotonia, delayed development, and sensorineural hearing loss. As a young adult, he showed behavioral abnormalities, including autistic feature and hyperactivity, as well as atypical seizures, ataxic gait, gaze palsy, and extrapyramidal dysfunction with tremor and dystonia. He had severe strokes, resulting in spasticity with loss of ambulation and independent function. Brain imaging as an adult showed progressive leukoencephalopathy, microbleeds, and lacunar infarcts. Patient 3 was an 8-year-old boy with sensorineural hearing loss, global developmental delay with hypotonia and behavioral problems, and mild pyramidal signs. Brain imaging at age 3 was normal. CSF lactate was mildly increased in 2 patients, whereas blood lactate levels and mitochondrial respiratory chain enzymes were normal. Van der Knaap et al. (2019) concluded that PRLTS4 can be associated with neurologic features and leukodystrophy.

Riley et al. (2020) reported a 55-year-old man (patient 3) with profound congenital sensorineural hearing loss. Family history revealed that he had 2 sisters with congenital sensorineural hearing loss and primary ovarian failure who had onset of progressive neurologic decline resulting in death in their thirties. The sisters showed cognitive impairment, muscle weakness, spasticity, and ataxia. At least 1 had leukodystrophy on brain imaging. Although DNA from the sisters was not available, the genetic findings suggested that they carried the same mutations (see MOLECULAR GENETICS). In vitro functional studies of the variants showed that they resulted in variably decreased aminoacylation activity compared to controls. The variable phenotype suggested that other genetic or environmental factors may influence the disease manifestations in patients with LARS2 mutations.

Carminho-Rodrigues et al. (2020) reported an 8-year-old girl, born of unrelated French parents, with onset of sensorineural deafness in the first decade of life. Development was normal and she had no neurologic symptoms. Hormonal assessments were normal. Pelvic ultrasound showed a normal prepubertal uterus, and 1 normal ovary was clearly visualized. After exome sequencing identified compound heterozygous missense mutations in the LARS2 gene (see MOLECULAR GENETICS), she was diagnosed with Perrault syndrome. Functional studies of the variants were not performed, but they were classified as pathogenic according to ACMG criteria. The authors noted that pubertal development and attention to possible neurologic problems would be monitored in this patient.

The transmission pattern of PRLTS4 in the families reported by Pierce et al. (2013) was consistent with autosomal recessive inheritance.

In a consanguineous family of Palestinian ancestry with PRLTS4, Pierce et al. (2013) performed exome sequencing followed by filtering and identified only 1 homozygous variant, a missense mutation in the LARS2 gene (T522N; 604544.0001), that segregated with disease. In a similarly affected proband from a family of Slovenian ancestry, they identified compound heterozygosity for a missense mutation (T629M; 604544.0002) and a 1-bp deletion (604544.0003) in the LARS2 gene. None of the mutations were found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server.

In a sister and brother, born of unrelated Italian parents, with PRLTS4, Solda et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene (T300M, 604544.0004 and E638K, 603544.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional studies and studies of patient cells were not performed.

In 2 Japanese sisters with PRLTS4, Kosaki et al. (2018) identified compound heterozygous missense mutations in the LARS2 gene (E294K, 604655.0007 and T519M, 604544.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found among 2,049 Japanese controls, but both were found at very low frequencies in the ExAC database. Functional studies of the variants were not performed, but they were considered 'likely pathogenic' according to ACMG criteria. The report expanded the phenotypic spectrum to include neurologic symptoms.

In 4 unrelated patients, 2 females and 2 males, with PRLTS4, Van der Knaap et al. (2019) identified compound heterozygous mutations in the LARS2 gene (see, e.g., 604544.0007; 604544.0009-604544.0011). The mutations, which were found by whole-genome or whole-exome sequencing, segregated with the disorder in all patients from whom parental DNA was available. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls).

Riley et al. (2020) reported a man (patient 3) with congenital-onset profound sensorineural hearing loss who was found to carry biallelic missense mutations in the LARS2 gene (Q147P and P536L) on exome sequencing.

In an 8-year-old girl with onset of sensorineural deafness in the first decade of life, normal development, no neurologic symptoms, and normal uterus with at least 1 normal ovary, Carminho-Rodrigues et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene (N153H and T522N; 604544.0001) Each mutation was inherited from an unaffected parent.