Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Abstract

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient’s brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

Perrault syndrome type 3 caused by diverse molecular defects in CLPP

“…Although the physiological role of mitochondrial CLPP (and CLPX) remains poorly understood, a handful of studies suggest that mammalian CLPP similar to its bacterial homologs, plays a crucial role 10 , 44 – 46 . Consistently, a number of recent studies have linked mutations in human CLPP with PRLTS3 2 , 4 , 19 – 21 . Importantly, PRLTS3 patients share a number of phenotypes (such as deafness and infertility in both sexes) with CLPP null mice ( CLPP −/− ) which provides strong support for a link between the mutations in CLPP and PRLTS3.…”

“…Structurally, these mutations can be broadly classified into two regions. The first group of mutations (P142L, C144R, T145P, C147S and G162S) is located in, or around, the Hp of CLPP 2 , 4 , 19 . As this region is responsible for interaction with the ATPase component 2 , 4 , 16 , these mutations are proposed to impair CLPX interaction and as a consequence, CLPX-mediated proteolytic activity, but not CLPP peptidase activity 2 , 4 .…”

Two Novel Likely Pathogenic Variants of HARS2 Identified in a Chinese Family With Perrault Syndrome

“…Individuals with Perrault syndrome have been reported both with and without neurologic features [3,5,7]. Some patients have shown additional clinical features, but no consistent pattern has been observed for these features, even within families.…”

Two novel likely pathogenic variants of HARS2 identified in a Chinese family with Perrault syndrome

“…Due to the complex clinical phenotype of the disease, affected males without affected sisters are diagnosed with nonsyndromic deafness rather than Perrault syndrome. The diagnosis of Perrault syndrome is con rmed by the presence of biallelic pathogenic variants in one of six genes, such as CLPP, ERAL1, HARS2, HSD17B4, LARS2, and TWNK [1,[5][6][7][8][9]. Currently, these genes explain approximately 40% of the causes of Perrault syndrome, but the genetic bases of more than half the cases of Perrault syndrome remain unclear [4].…”