Sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) is a characteristic clinical triad, which has been attributed to mutations of the gene encoding the mitochondrial DNA polymerase gamma enzyme (POLG1). Most cases present with an initial stage of sensory neuropathy, a second stage of progressive external ophahlmoplegia and dysarthria, which is then followed by other symptoms, often with epilepsia or myoclonus (2
). Different dominant and recessive missence mutations of this gene have been described with various clinical phenotypes (3
). Our patients had a characteristic clinical triad of SANDO, and both with dysphagia/dysarthria.
Patient 1 presented with a p.A467T and p.W748S compound heterozygous mutations. Both mutations are known, and several case histories with these compound mutations have been published (6
). Central nervous system involvement is characteristic of these mutations, as epilepsy, myoclonus, headache and bilateral high signal lesions of the posterior horn. Our patient also presented with central nervous system symptoms, as she had myoclonus, EEG abnormalities, and presumably her anxiety and depression could also – at least partly - be attributed to metabolic brain disturbances. Vissing and co-workers published case histories of two sisters with features of neurogastrointestinal encephalomyopathy (MNGIE), without signs of leukoencephalopathy (8
). They demonstrated multiple mtDNA deletions, but could not find any thymidine phophorylase (TP) gene mutation, the usual genetic background of MNGIE. Further molecular genetic investigation found three missense mutations in POLG1 gene, of which two (N846S and P587L) mutations were not described before, and the third one was a known T251I mutation (9
). Besides dysphagia, our patient was also suffering from continuous constipation, mimicking the symptoms of MNGIE. Gonadal hypofunction and premature menopause have been described as a sign of multi-organ involvement in POLG1 mutations (4
). These symptoms also complicated the clinical picture of our case. Multi-organ involvement and progressive course of our patient support the finding of Tzoulis and colleagues, that compound heterozygous p.A467T and p.W748S POLG1 mutations present a severe clinical phenotype of SANDO (7
The second patient had p.T251I, and p.G848S compound heterozygous mutations. These mutations have previously been published, only in two publications. Lamantea and co-workers reported a member of a family, with ophthalmoplegia with proximal muscle weakness, but no detailed clinical picture and disease course were described (3
). These authors also presented several individuals with an isolated p.T251I heterozygous mutation without any clinical symptoms. Weiss and co-workers published a case with late onset, when these two mutations were compound, and combined with a third, p.P587L heterozygous mutation (10
). The leading symptoms of their patient were ophthalmoplegia, severe nasal flaccid dysarthria and mild tongue weakness. Besides vibration and joint position sensation loss, moderate gait ataxia and mild proximal muscle weakness were found. In our patient, the symptoms also developed relatively late, in his fifties, with slowly progressive sensory loss and moderate ataxia, which later on complicated with expressed dysarthria/ dysphagia and moderate ophthalmoplegia.
Our patients had no definite paresis in the skeletal muscles of the extremities, but the muscle biopsies taken from m. tibialis anterior demonstrated identical pathology, with ragged-red, COX negative fibres and mitochondrial ultra structural abnormities. The degree of the pathological changes did not correlate with the severity of the clinical symptoms.
Both patients demonstrated characteristics of SANDO, with axonal neuropathy, ataxia, dysarthria and ophthalmoplegia. Dysphagia was also present in both cases. The symptoms of the p.A467T and p.W748S compound heterozygous patient 1 started in early adulthood and showed severe neuromuscular symptoms with intestinal and multi-organ involvement, and this case history gave a further evidence of POLG mutation, as a genetic background of MNGIE-like syndrome. The patient 2 with p.T251I, and p.G848S compound heterozygous mutations presented with late onset, dominantly with bulbar symptoms. This case history shows that dysarthria/dysphagia could occur late in the life, as a sign of a genetically determined mitochondrial metabolic disorder.