Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy

Abstract

Objective:To identify the underlying genetic cause of a congenital neuropathy in a 5-year-old boy as part of a cohort of 32 patients from 23 families with genetically unresolved neuropathies.Methods:We used autozygosity mapping coupled with next-generation sequencing to investigate a consanguineous family from Lebanon with 1 affected and 2 healthy children. Variants were investigated for segregation in the family by Sanger sequencing. A splice site mutation was further evaluated on the messenger RNA level by quantitative reverse transcription PCR. Subsequently, a larger cohort was specifically screened for receptor expression-enhancing protein 1 (REEP1) gene mutations.Results:We detected a homozygous splice donor mutation in REEP1 (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912) that cosegregated with the phenotype in the family, leading to complete skipping of exon 4 and a premature stop codon. The phenotype of the patient is similar to spinal muscular atrophy with respiratory distress type 1 (SMARD1) with additional distal arthrogryposis and involvement of the upper motor neuron manifested by pronounced hyperreflexia.Conclusion:To date, only dominant REEP1 mutations have been reported to be associated with a slowly progressive hereditary spastic paraplegia. The findings from our patient expand the phenotypical spectrum and the mode of inheritance of REEP1-associated disorders. Recessive mutations in REEP1 should be considered in the molecular genetic workup of patients with a neuromuscular disorder resembling SMARD1, especially if additional signs of upper motor neuron involvement and distal arthrogryposis are present.

Further supporting evidence for REEP1 phenotypic and allelic heterogeneity

“…To date, only 1 homozygous mutation has been reported in REEP1 ; this affects a splice donor site (p.Phe62Lysfs23*) and was found in a Lebanese patient presenting with a SMARD1-like phenotype which included distal arthrogryposis, congenital axonal neuropathy, hyperreflexia, and respiratory distress, but without any cognitive or language impairment. 4 Although there was a significant phenotypic overlap between this reported individual and our patient, arthrogryposis involving proximal and distal joints was more pronounced in our patient, whereas diaphragmatic palsy seems to be more severe in the homozygous p.Phe62Lysfs23* carrier. In addition, our case adds data on peculiar electromyographic changes that were not reported in the former report.…”

“…6 It has been speculated in a Drosophila model that REEP1 -associated disorders could be ER stress diseases expressing variable phenotypes depending on the type of impaired function in the ER. 4 Furthermore, REEP1 could have a direct role in the control of mitochondrial network morphology through interaction with the crucial protein involved in mitochondrial fission, named DRP1. It has been shown that important alterations take place in the mitochondrial morphology in the primary fibroblasts of patients with REEP1 HSP compared with control cells.…”

“…3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported. 4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern.…”

Expansion of the genetic landscape of ERLIN2‐related disorders

“… One report, however, identified a recurrent heterozygous missense variant (c.386G> C; p.Ser129Thr) in multiple affected individuals from two large unrelated families . Overall, these data lend support to the notion that there are autosomal‐recessive and autosomal‐dominant forms of ERLIN2 ‐related disorders, similar to a small number of other genetic causes of HSP, such as defects in ATL1 (SPG3A), KIF1A (SPG30), KIF1C (SPG58), REEP1 (SPG31), and SPG7 (SPG7) …”

Whole-exome sequencing in neurologic practice

“…Several articles in the current issue highlight the role of NGS in this effort. For example, Schottman et al 2 identified REEP1 mutations as the cause of a severe axonal neuropathy with a spinal muscular atrophy with respiratory distress (SMARD) phenotype. This gene was previously associated with a hereditary spastic paraplegia phenotype.…”