CASE REPORT A. Rojo Æ Y. Campos Æ J. M. Sa´nchez I. Bonaventura Æ M. Aguilar Æ A. Garcı´a L. Gonza´lez Æ M. J. Rey Æ J. Arenas M. Olive´ Æ I. Ferrer NARP-MILS syndrome caused by 8993 T > G mitochondrial DNA mutation: a clinical, genetic and neuropathological study Received: 2 October 2005 / Revised: 29 December 2005 / Accepted: 30 December 2005 / Published online: 9 March 2006 Ó Springer-Verlag 2006 Abstract The 8993 T > G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh’s syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients. We report a kindred with several members in the same generation suffering NARP or Leigh’s syndrome due to a 8993 T > G mutation. Post- mortem studies of the brain in one affected member clinically presenting with a neurological disorder inter- mediate between adult Leigh’s syndrome and NARP showed symmetrical lesions of the basal ganglia and brainstem closely resembling those usually described in typical Leigh’s syndrome. Analysis of mtDNA in differ- ent tissues showed a high proportion of mutant genome in brainstem, cerebral cortex, putamen, cerebellum and thalamus. These observations illustrate the continuum of clinical and neuropathological manifestations associated with the 8993 T > G mutation of the mtDNA. Keywords NARP Æ Leigh’s syndrome Æ Mitochondrial disease Æ 8993 T to G mutation Æ ATP synthase Æ Striatum necrosis Introduction Neuropathy, ataxia, retinitis pigmentosa (NARP) is a maternally inherited mitochondrial disorder, the main clinical manifestations of which include ataxia, retinitis pigmentosa and peripheral neuropathy, often associated with a combination of symptoms such as developmental delay, dementia and seizures [4]. The disease is usually caused by a heteroplasmic T > G transversion at posi- tion 8,993 in the ATPase 6 subunit gene [1, 13, 17]. The same mutation has been found to be the guilty party in a subset of patients suffering from subacute necrotizing encephalopathy (Leigh’s syndrome) [1, 2, 11, 13, 14, 16, 17]. Furthermore, a transition in the same position (8993 T > C) has been described in patients suffering from a mild variant of Leigh’s syndrome and NARP [12]. The degree of heteroplasmy correlates with the severity of the disease; patients with mutant loads above 95% in dif- ferent tissues (e.g. brain or muscle) usually present with typical maternally inherited Leigh’s syndrome (MILS), whereas when the percentage of mutant mtDNA is 70–90% this results in NARP syndromes [5, 11, 14–16]. NARP/MILS syndrome may co-exist in the same family [1, 2, 4, 10–12, 14–16]. MRI studies of NARP patients have shown cerebral and cerebellar atrophy, and, in most severe cases, symmetrical lesions of the basal ganglia and brainstem [16]. However, brain neuropa- thology in patients suffering from NARP has not been described. We report the clinical and genetic findings in a newly studied family affected by an 8993 T > G mutation in the ATPase 6 subunit of complex V, causing, in the same generation, different phenotypes ranging from NARP to Leigh’s syndrome. In addition, the results of post-mor- tem studies of the brain in one affected member are described. A. Rojo and Y. Campos contributed equally and should be con- sidered first authors A. Rojo Æ I. Bonaventura Æ M. Aguilar Neurology Services, Hospital Mu´ tua de Terrassa, Barcelona, Spain L. Gonza´lez Pathology Services, Hospital Mu´tua de Terrassa, Barcelona, Spain J. M. Sa´nchez Neurology Service, Hospital de Basurto, Vizcaya, Spain Y. Campos Æ A. Garcı´a Æ J. Arenas Investigation Center, Hospital 12 de Octubre, Madrid, Spain M. J. Rey Æ I. Ferrer University of Barcelona/Hospital Clinic Brain Bank, Barcelona, Spain M. Olive´ Æ I. Ferrer (&) Institute of Neuropathology and Brain Bank, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Carrer Feixa Llarga sn, 08907, Barcelona, Spain E-mail: 8082ifa@comb.es Fax: +34-93-2607503 Acta Neuropathol (2006) 111: 610–616 DOI 10.1007/s00401-006-0040-5