Effects of antiretroviral therapy in patients with Charot-Marie-Tooth disease type 1A.

Abstract

Sirs: Since their introduction, the nucleoside analogues zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) have all been associated with dose-limiting peripheral neuropathy. The clinical symptoms do not differ from those of HIV-associated distal sensory polyneuropathy and, burning, painful dysesthesias and numbness involving the feet are the main clinical features [6]. Moreover, it is well-known that the history of a pre-existing peripheral nerve disorder is a significant risk factor for developing neurotoxicity by nucleosides and, therefore, the identification of atrisk patients is an important consideration prior to the administration of these antiretroviral agents [5]. Charcot-Marie-Tooth disease type 1A (CMT1A) is among commonest hereditary neuropathies. Interestingly, CMT1A patients appear to be extremely vulnerable to neurotoxic effect of certain chemotherapeutic drugs [2, 4]. Indeed, a devastating vincristine neuropathy has been described in patients with CMT1A and there is general agreement that this medication should be avoided in any subject with antecedents of hereditary peripheral neuropathy [2]. We report an unusual association between HIV infection and CMT1A. Our observation provides some evidence suggesting that nucleosides could be not absolutely contraindicated in CMT1A-HIV seropositive individuals. The patient is an homosexual 40-year-old man who was diagnosed with HIV infection in June 1999. The family antecedents for neurological disorders were unremarkable. He had a past history of pes cavus and absent tendon reflexes but these data were not considered relevant at that time. His CD4 count and load viral were 534 cells/μL and 43.8000 copies/ml, respectively. By September 1999, antiretroviral treatment combining ddI (400 mg/24 h), d4T (40 mg/12 h) and nevirapine (200 mg/12 h) was started. Four months later, the patient noted insidiously intense paresthesias and numbness in both feet and mild tingling in the hands. Neurological examination disclosed normal strength except for mild difficulty in walking on heels, pes cavus, universal arreflexia, hypoesthesia in a stocking and glove distribution and preservation of joint position sense. Electrophysiological studies showed the presence of an uniform sensorimotor demyelinating neuropathy in keeping with the diagnosis of CMT1. Subsequently, the molecular analysis using the microsatellite markers D17S921 and DS17S955 revealed that the patient was a carrier of a 17p11.2 duplication, typical for CMT1A. Cerebrospinal fluid was not obtained. By then, his viral load had decreased to less than 200 copies/ml and the CD4 count had risen to 697 cell/μL. In March 2000, ddI and d4T were discontinued and changed to zidovudine (250 mg/12 h) and lamivudine (150 mg/12 h). In the following six months, the patient reported substantial improvement of his sensory complaints but distal paresthesias and cramps in the legs persisted. A repeat neurological examination was unchanged. At present, the patient’s symptoms of tingling and numbness in the hands have mostly resolved; however, he still has numbness and paresthesias in the distal parts of the lower extremities. During this period, he never developed weakness or gait disturbances. It is broadly recognised that the individuals with clinical or subclinical hereditary neuropathic disorders are predisposed to symptomatic toxic neuropathies. This assumption is based on several reports describing a catastrophic and rapidly progressive neuropathy in CMT1 patients treated with vincristine [2, 3, 4]. Similarly, the incidence of nucleoside analoguerelated distal sensory polyneuropathy seems to be higher in those subjects with previous history of hereditary or acquired peripheral nerve disorders [5]. However, there is little information concerning the consequences of antiretroviral therapy in CMT1A patients. It could be speculated that these patients can suffer from an intense exacerbation of their neuropathy after the exposure to nucleoside analogues similar to that observed with vincristine. Consequently, some authors have emphasised the importance of determining if the use of these antiretroviral agents is justified in HIV-subjects with hereditary neuropathies [1]. Our case provided the chance to test this possibility. Both vincristine and nucleosides cause a predominantly sensory axonopathy. While mitochondrial toxicity constitutes the main mechanism for nucleoside analogue-related polyneuropathy, interruption of axoplasmic transport has been demonstrated as the basis of neural damage by vincristine [2, 5]. Furthermore, it is also known that vincristine induces damage in large axons and CMT1A is a disease of large myelinated nerves in which demyelination leads to a secondary axonal LETTER TO THE EDITORS