CLPP – Perrault syndrome 3

Perrault syndrome type 3 (PRLTS3) is an autosomal recessive disorder characterized by sensorineural hearing impairment and variable neurological involvement, including epilepsy and psychomotor retardation (PMID:27899912).

Whole-exome sequencing in an infant with congenital deafness, psychomotor delay, and epilepsy identified a novel homozygous CLPP frameshift variant c.21del (p.Ala10ProfsTer) (PMID:27899912). Brain MRI revealed distinctive subcortical white matter and corpus callosum abnormalities, prompting targeted CLPP analysis in three additional unrelated patients, two of whom carried missense variants alongside a large genomic deletion.

All affected individuals harbor biallelic truncating, splice, or missense CLPP variants, consistent with autosomal recessive inheritance. No further segregating affected relatives have been reported to date.

The allelic spectrum in PRLTS3 includes frameshift (c.21del (p.Ala10ProfsTer)), splice (c.199-1G>C), missense, and large deletion alleles, underscoring significant genetic heterogeneity (PMID:27899912).

Biochemical studies on CLPP variants demonstrate that active-site mutation p.Tyr229Asp abolishes peptidase activity and disrupts CLPX docking, while hydrophobic-pocket mutants p.Thr145Pro and p.Cys147Ser variably impair oligomeric assembly and proteolytic function, confirming a loss-of-function mechanism (PMID:30150665).

Integration of MRI pattern recognition with genetic and functional data enhances early diagnosis of PRLTS3. Key Take-home: Biallelic CLPP mutations cause autosomal recessive Perrault syndrome 3, and MRI signatures combined with functional confirmation support precise molecular diagnosis.

References

• Frontiers in neurology • 2016 • Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects. PMID:27899912
• Scientific reports • 2018 • Perrault syndrome type 3 caused by diverse molecular defects in CLPP. PMID:30150665

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