Roussy-Lévy syndrome: a case of genotype–phenotype correlation

Abstract

Roussy-Lévy syndrome (RLS) is an uncommon variant of the Charcot-Marie-Tooth (CMT) type 1 (CMT-1B) disease, a dominantly inherited form of neuropathy. This condition was originally described in 1926 by Gabrielle Roussy and Gustave Lévy [1]. They characterized, under the original name of “dystasie areflexique hereditaire,” a large family with peculiar features: mild sensory gait ataxia, bilateral pes cavus, areflexia, peroneal muscular atrophy, bilateral postural, and kinetic tremor. As pointed out by the authors since their seminal description, this condition is relatively mild, with little or null progression over time, as opposed to most CMTs. The original family has been extensively investigated several decades after the original work. Descendants were identified and studied: all showed the same “classic” clinical picture. In addition, nerve biopsies, neurophysiological, and genetic tests were carried out [2]. Sural nerve biopsy, carried out on three out of seven patients, showed a reduction of myelinic axons, demyelinated areas alternating with hypermyelinated spots; onion bulbs (typical of the most frequently seen CMT1B variant) were found in one of the examined members. Small fibers were spared. Nerve conduction studies (NCS) revealed, in upper limbs, a motor nerve conduction velocity (NCV) of about 16 m/s in six out of seven patients. The DNA of four of these seven patients was sequenced, and they were found to harbor a heterozygous C→A missense transversion in position 727 on the third exon of the myelin protein zero P0 (MPZ gene), i.e., a Asn131Lys variation. This study has been approved by our appropriate ethics committee (Comitato Etico Lazio 2) and has been performed in accordance with the ethical standards laid down in the Declaration of Helsinki. We received written informed consent by the patient. Here, we describe a novel case, outside the original kindred depicted by Roussy and Lévy, with the same clinical, neurophysiological, and genetic features. The patient was referred to our center, at the age of 18. His parents reported moderately delayed motor milestones. On examination, bilateral pes cavus, genu recurvatum, mild sensory gait ataxia and positive Romberg sign, mild weakness and amyotrophy of the peroneal muscles, distal areflexia in all four limbs, distal sensory abnormalities with severe loss of vibration sense in lower limbs, and postural and kinetic tremor were found. The onset of symptoms had been around 3 years of age, with very little progression. From a clinical point of view, and since the very slight worsening, the hypothesis of RLS was proposed. He underwent NCSs and EMG. Moreover, genetic analysis, including the asymptomatic parents, was performed. NCS gave unelicitable motor NCV responses in lower limbs, while in upper limbs, motor NCV was 12 m/s for median nerves and 13 m/s for ulnar nerves (normative values of our lab for upper limbs NCV: 50 m/s). EMG showed mild neurogenic signs in lower limbs, especially in the peroneal district. Direct sequence analysis revealed a C→A transversion in position 727 on the third exon of the MPZ gene, resulting in an Asn131Lys substitution in the extracellular domain of P0. Both parents were found to be wild type. So, the reported variation was considered de novo. In our patient, mild ENG/EMG neuropathic signs, postural and kinetic tremor in upper limbs, initially suggested a clinical diagnosis of mild CMT1. But the early onset of sensory gait ataxia with little progression over years of sensorimotor symptoms somehow differed from the classical and more severe picture of CMT1s, thus indicating the RLS phenotype. The identification of the Asn131Lys MPZ gene variation, the same identified in the original Roussy-Lévy family, completed the diagnostic picture. So far, this specific variation has not been reported as a hotspot [3], but it represents a new case of this rare genotype–phenotype correlation. Ever since the introduction and adoption of the CharcotMarie-Tooth eponymic classification of hereditary neuropathies, uncountable variations have been discovered and * Ettore Cioffi [email protected]