Objective: To present a patient with homozygous mutation in Receptor Expression-Enhancing Protein 1 (REEP1) gene manifesting a severe congenital Distal spinal muscular atrophy (SMA) with vocal cord and diaphragmatic paralysis.

Background: Heterozygous mutations in REEP1 frequently cause autosomal dominant hereditary spastic paraplegia1 (HSP) and in two families have been associated with autosomal dominant spinal type of Charcot‐Marie‐Tooth disease2,3. 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 reported4.

Method: A 9-year-old girl who was born to healthy consanguineous Iranian parents presented with congenital proximal and distal muscle weakness in all the limbs, proximal and distal arthrogryposis, permanent inability to stand up and/or walk, progressive muscular atrophy starting from the lower limbs and progressing to the upper limbs, diaphragmatic palsy which resulted in fever associated breathing difficulties, weak voice, and preserved cognition. She is currently bed-ridden and non-ambulatory. On neurological examination she had marked plantar flexion contractures in the ankles and flexion contractions in the wrists, brisk deep tendon reflexes in the knees, absent Achilles reflex, no Babinski sign and normal reflexes in the upper limbs. There was low muscle tone and wasting in the limbs. Neurophysiology showed distal axonal degeneration, fibrillations and marked changes in motor unit action potentials in the right and left tibialis anterior muscles on. Sural nerve biopsy showed chronic demyelinating neuropathy with secondary focal axonal and nerve fibers loss. SMN1genes testing was normal. The clinical diagnosis of Distal SMA with vocal and diaphragmatic paralysis was made. Single nucleotide polymorphism Array genotyping in combination with Exome sequencing was performed on the DNA extracted from proband’s peripheral blood.

Results: We revealed a homozygous missense pathogenic variant (c.124T>C) (p.Trp42Arg) in REEP1 (nomenclature refers to NM_022912) encompassing by 59 Mb region of homozygosity.

Conclusion: Our study confirms the causality of REEP1 in Spinal Muscular Atrophy with Respiratory Distress and demonstrates that the same allele in one gene can lead to two different phenotypes.

References: 1. Züchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am. J. Hum. Genet. 2006;79:365–369 2. Beetz C, Pieber TR, Hertel N, et al. Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet 2012;91: 139–145. 3. Bock A, Günther S, Mohr J et al. A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR-encoded, aggregation-inducing motif. HumanMutation. 2018;39:193–196. 4. Schottmann G, Seelow D, Seifert F et al. Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy Neurol. Genet. 2005,1, e32.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-p-trp42arg-reep1-mutation-associated-with-autosomal-recessive-distal-spinal-muscular-atrophy-with-vocal-cord-and-diaphragmatic-paralysis/