Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Abstract

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.

Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene

“…Although amelogenesis imperfecta discriminates between the two conditions this does not become apparent until the eruption of the secondary dentition. Retinal pigmentation is an inconsistent feature of were indicated with green frame (Ratbi et al, 2015). The mutation identified in this study was indicated with red frame.…”

“…In three previously reported caucasian families with Heimler syndrome due to PEX1 mutations, compound heterozygosity for a previously reported loss of function and a novel missense PEX1 variant was described (Ratbi et al, 2015) (Fig 3b). The patient reported here was homozygous for a novel hypomorphic PEX1 allele similar to that reported in another Moroccan family PEX1 (p.Trp1250*).…”

“…In the light of our recent description of visual phenotypes in many patients with Heimler syndrome (Ratbi et al, 2015), and the features of amelogenesis imperfecta and SNHL, we considered this diagnosis. Blood samples from the proband and her parents were collected after written informed consent (UK NHS Ethics Reference 11/H1003/3).…”

“…The degree of VLCFA plasma concentration elevation may vary, with a small percentage of individuals demonstrating only modest increases (Wanders et al, 2005). Where screening analyses of blood have been undertaken biochemical evidence of a PBD has been lacking in patients with Heimler syndrome (Ratbi et al, 2015).…”

“…Each family was characterised by at least one hypomorphic allele that results in mild peroxisomal dysfunction (Ratbi et al, 2015). These findings define Heimler syndrome as the mildest form of peroxisome biogenesis disorder (PBD).…”