Neurofibromatosis Type 1: A Novel NF1 Mutation Associated with Mitochondrial Complex I Deficiency

Background. Neurofibromatosis type 1 is a multisystemic, progressive disease, with an estimated incidence of 1/3500-2500. Mitochondrial diseases are generally multisystemic and may be present at any age, and the global prevalence is 1/8500. The diagnosis of these disorders is complex because of its clinical and genetic heterogeneity. Case Report. We present a rare case of the association of these two different genetic diseases, in which a heterozygous missense mutation in the NF1 gene was identified which had not yet been described (p.M1149？V). Additionally, the patient is suspected of carrying an unspecified mutation causing respiratory chain complex I deficiency. Clinical presentation included hypotonia, global development delay, reduced growth rate, progressive microcephaly, and numerous café-au-lait spots. Discussion. To the best of our knowledge this is the first report of complex I deficiency in a patient with neurofibromatosis type 1. It is very important to maintain a high index of suspicion for the diagnosis of mitochondrial disorders. In this patient, both the laboratory screening and muscle histology were normal and only the biochemical study of muscle allowed us to confirm the diagnosis. 1. Introduction Neurofibromatosis type 1 (NF1), first described in 1882 by von Recklinghausen [1, 2], is a multisystemic [1, 3], progressive disease [2], with an estimated incidence of 1/3500-2500 [1–4]. In about half of the cases, it is an autosomal dominant inherited disorder, and in the remaining cases, it results from de novo mutations [1, 3]. It has high penetrance and variable phenotypic expression between and within families [1]. It results from mutations in the NF1 tumor suppressor gene located on chromosome 17 [2], responsible for encoding neurofibromin [1]. The three main characteristics of this disease are café-au-lait spots, multiple neurofibromas, and Lisch nodules (pigmented hamartomas of the Iris) [5]. Mitochondrial disorders are a heterogeneous group of diseases characterized by defects of mitochondrial structure and oxidative phosphorylation [6–8]. These disorders are generally multisystemic [6, 8] and may be present at any age [7], and the global prevalence, probably underestimated, is 1/8500 [7]. The organs with highest energy demand, such as, heart, brain, skeletal muscle tissue, and liver, are preferentially involved [6, 8–11]. Treatment is supportive [7, 12] and does not influence the natural course of the disease [8, 13], and the prognosis is often poor [11, 14]. Mitochondrial complex I deficiency is the most common defect of the