Marfanoid habitus is a nonspecific feature of Perrault syndrome

Abstract

The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype-phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders

“…Neurological signs have been reported in patients with PRLTS and mutations in the HSD17B4 , TWNK , CLPP and LARS2 genes [4, 7, 8, 10–16, 20; and this work]. For CLPP and LARS2 , there are also reports of patients without neurological signs [6, 7, 12, 14, 17–19], like all the patients with mutations in HARS2 or ERAL1 who have been reported to date [5, 9, 14]. However, it would be premature to define genotype–phenotype correlations on these bases, as the picture could change after careful follow-up of the already reported patients over the years, and after novel reports of cases with mutations in HARS2 or ERAL1 , still underrepresented.…”

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

“…Cerebral MRIs performed at adult age showed extensive white matter abnormalities and additional signs of early-onset vascular abnormalities were observed in two patients [13]. However, as most patients were relatively young at genetic diagnosis, it remains unclear whether neurological symptoms may develop later [5]. In our patient, the fact that the diagnosis was made at an early age was crucial for this young girl.…”

“…A comparison of the literature showed that bilateral hearing loss was highly variable, ranging from moderate to profound, and sometimes progressive. Of note, all individuals with a p.Thr522Asn Perrault syndrome, either homozygous or compound heterozygous, presented with sensorineural hearing loss, which was worse at low frequencies [5,10]. Age of onset also varied between 18 months and 32 years, but it was difficult to evaluate as detailed information was not always available.…”

“…LARS2 encodes mitochondrial leucyl-tRNA synthetase (mtLeuRS), a 903 amino acid protein [4,5]. Aminoacyl-tRNA synthetases then attach specific amino acids to the 3′ ends of their cognate tRNAs, which is required in the cytoplasm and mitochondria for the translation of nuclear and mitochondrial encoded genes, respectively.…”

The Bacterial ClpXP-ClpB Family is Enriched with RNA-Binding Protein Complexes

“…A scheme summarizing the mitochondrial causes of similar infertility and deafness is shown in Figure 4. The mammalian findings clearly point to ClpP acting in the same pathway of mitochondrial transcription/translation as the many other known PRLTS disease proteins: Mutations in PEO1/TWNK (encoding the nucleoid-associated helicase and primase Twinkle) cause PRLTS5 [70,72,[82][83][84][85][86][87][88][89]; the homozygous variant Arg232Cys in TFAM (encoding the nucleoid-associated transcription factor A of mitochondria) was observed in one Pakistani PRLTS patient [74]; ERAL1 (encoding a mitochondrial rRNA chaperone involved in mitoribosome assembly) was associated with PRLTS6 in a Dutch family [31]; HARS2 (encoding the tRNA amino acid synthase for histidine) mutations in many patients and a mouse model trigger PRLTS2 [72,[90][91][92][93][94][95]; LARS2 (encoding the tRNA amino acid synthase for leucine) is associated with PRLTS4 in many families [70,72,74,[96][97][98][99][100][101][102][103]; RMND1 (encoding a mitoribosome-associated factor) mutations were found in a Portuguese proband and in two Polish sisters with Perrault-like syndrome plus renal involvement [104,105]; PRORP (encoding the metallonuclease subunit of mitochondrial RNAse P) caused Perrault syndrome in four families, sometimes resulting in developmental delay [106]. Thus, the phenotype produced by ClpP mutations with a combination of infertility and of sensorineural hearing impairment is highly specific; it corresponds to the typical consequences of mitochondrial DNA and RNA processing problems.…”