Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase‐3 deficiency

Abstract

Introduction: Pathogenic variants in PLOD3, encoding lysyl hydroxylase-3 (LH3), can cause a hereditary connective tissue disorder that has rarely been reported. It is a multi-system disease, presenting with craniofacial dysmorphisms, skeletal and eye manifestations, sensorineural hearing loss, and variable skin manifestations. Severe central nervous system involvement has not been reported. Case presentation: A 10-month-old girl was admitted with development delay and clustered epileptic spasms. Hypertelorism, an upturned nose, and low-set ears were noted in physical examination. Cerebral magnetic resonance imaging showed multiple intracranial malacias and bleeding foci, extensive abnormal signals in the white matter, and obvious brain atrophy, which was consistent with cerebral small vessel disease (SVD). Electroencephalography suggested hypsarrhythmia. The vertebrae were flattened. The distal end of the metacarpal bone in the left hand was irregular. She was diagnosed with West syndrome. Whole-exome sequencing revealed a novel homozygous variant of c.1216_1218delCTC (p.L406del) in PLOD3, which was found to be inherited from her heterozygous parents. Conclusion:We report a patient with pathogenic PLOD3 mutation who presented with cerebral SVD. This report expands the phenotypic spectrum of LH3 deficiency.

Lysyl hydroxylase 3–mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV)

“…Consistent with this finding, Plod3 deficiency in the mouse caused basement membrane defects ( 44 , 45 ), suggesting that PLOD3 pathogenic variants may also contribute to intracerebral hemorrhages (ICHs), which constitute a central pathophysiological hallmark of Gould syndrome caused by COL4A1 and COL4A2 pathogenic variants ( 13 , 14 , 15 , 67 , 68 , 69 , 70 , 71 ). In addition, cerebrovascular hemorrhages have been reported in three patients with a connective tissue disorder caused by biallelic pathogenic variants of PLOD3 ( 39 , 43 ). To investigate the potential involvement of PLOD3 in ICH, we specifically evaluated the presence of PLOD3 variants in exome sequencing data from a fetal ICH cohort consisting of 113 probands who did not have COL4A1 or COL4A2 pathogenic variants.…”

“…DNA analysis showed biallelic PLOD3 variants (p.N223S/p.C691AfsX9) located in a conserved region of the LH3 amino acid sequence responsible for collagen glycosyltransferase and LH activities. Recently, a homozygous PLOD3 small inframe deletion was shown to cause a cerebral small vessel disease characterized by multiple white matter hypersignals and bleeding foci in an infant with a few dysmorphic features ( 43 ). To evaluate the contribution of PLOD3 pathogenic variants to cerebrovascular manifestations, we analyzed a series of 113 cases of fetal ICH that were negative for COL4A1 and COL4A2 pathogenic variants.…”

“…Indeed, clinical features of patients with biallelic loss of function PLOD3 variants include craniofacial dysmorphisms, skeletal and ocular disorders, sensorineural hearing loss, and variable skin manifestations. Interestingly, in addition to clinical manifestations overlapping Stickler-like syndrome and epidermolysis bullosa, cerebral hemorrhages have been reported in three cases with PLOD3 variants ( 39 , 43 ). LH3 is proposed to have substrate preference for heavily glycosylated collagens ( 44 , 45 , 46 ) such as type IV collagen ( 28 , 32 ), raising the possibility that PLOD3 pathogenic variants could also cause Gould syndrome.…”

Integrated Systems Analysis Deciphers Transcriptome and Glycoproteome Links in Alzheimer’s Disease

“…Although no direct evidence of PLOD3 in AD has been reported, it is known to play an essential role in the formation of collagen, a major component of the ECM 84 . For instance, defects in PLOD3 (or Lysyl hydroxylase 3; LH3) have been implicated in causing inherited connective tissue disorders and have been shown to cause cerebral small vessel injury 85,86 , maintenance of the structural integrity of cerebral blood vessels, regulating inflammatory processes 87 . This enzyme is also a promising biomarker in AD, since its expression has been reported to fluctuate in cell-free RNA expression using blood samples from AD patients 88 .…”

Whole Exome Sequencing Reveals Two Novel Homozygous Variants in the TRAPPC9 and PLOD3 Genes Leading to Intellectual Disability and Bone Fragility with Contractures

“…The PLOD3 gene was further characterized the clinical features, which included joint contractures, low bone mineral density and fractures, scoliosis, myopia, sensorineural deafness, dysmorphic features, skin and nail abnormalities, and rupture of a vascular aneurysm (Ewans et al, 2019;Vahidnezhad et al, 2019). A recent study showed a homozygous mutation of c.1216_1218delCTC (p.L406del) in PLOD3, which was inherited from heterozygous parents (Zhou et al, 2022).…”