Familial mtDNA T8993C transition causing both the NARP and the MILS phenotype in the same generation

Sirs: Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP) and severe infantile subacute necrotising encephalomyopathy (Maternally Inherited Leigh Syndrome, MILS) are the main clinical syndromes of a maternally inherited mitochondrial disorder caused by a point mutation in the nucleotide position 8993 of the mitochondrial DNA (mtDNA), in the ATPase6 gene. The most common mutation is a heteroplasmic T8993G transversion, a few cases being associated with a T8993C transition [1, 5]. Different phenotypes can coexist in the same family [8]. Proton magnetic resonance spectroscopy (1H-MRS) allows non-invasive measurement of brain metabolites in patients with mitochondrial disorders [4, 7]. We report a new case of familial T8993C transition causing both the NARP and the MILS phenotype in the same generation. Case report – A 27 year old woman from central Italy came to our observation with a 20-year history of slowly progressive psychomotor retardation. Delivery was vaginal, but complicated by placental dysfunction (weight at birth = 1.8 kg). She did well until the age of seven years when she had measles and began to show gait unsteadiness, fatigability and frequent falls. She had two episodes of brief loss of consciousness. Neurological examination revealed generalised hypotonia, muscle weakness, ataxic gait, reduced tendon reflexes, and finger-to-nose dysmetria. A diagnosis of postmeasles encephalitis was made and antiepileptic treatment (sodium valproate) started. Ataxia and muscle weakness slowly progressed and, in addition, learning difficulties were noticed at school. At age 25 years she was diagnosed as having sensorineural hypoacusia and retinitis pigmentosa. In our hospital, neurological examination showed proximal muscle weakness, generalised hypotonia, reduced tendon reflexes, bilateral Babinski sign, standing unsteadiness, truncal and gait ataxia, finger-to-nose and heel-to-knee dysmetria. Neuropsychological tests disclosed an acquired selective mental retardation (memory, comprehension). EMG was myopathic, brain MRI showed ponto-cerebellar atrophy (Fig. 1B) and EEG bitemporal slow wave activity. Blood lactate was normal, ECG showed sinusal tachycardia with AV conduction in the low normal range. Her only sister had died of cardiac arrest, in 1989, at age 3 years, after a one month history of progressive deterioration of consciousness, respiratory insufficiency, epileptic seizures and hyperthermia. Brain MRI revealed bilateral T2 hyperintense areas in the basal ganglia, lamina quadrigemina, caudate nucleus, posterior bulb, and in periventricular grey and in hemispheric white matter. CSF lactate was increased (46 mg/dl = 5.1 mmol/L, normal values = 10.9–17.2 mg/dl, or 1.2–1.9 mmol/L; serum lactate was normal = 12.3) These findings had led to a diagnosis of subacute necrotising encephalopathy. The 49 year old mother was short, affected with hypothyroidism. Her clinical examination revealed clinical signs of peripheral neuropathy. The remaining family history was not significant (Fig. 1A). The proband’s skeletal muscle biopsy specimen was normal on both light and electron microscopy. Southern blot analysis revealed no mtDNA rearrangements, but Restriction Fragment Length Polymorphism (RFLP) analysis with Msp I enzyme showed the presence of a heteroplasmic T to C base substitution at nucleotide 8993 of mtDNA (90.5 % mutation, determined by densitometry). The same mutation was detected on leukocyte-extracted DNA (88.4 % mutated mtDNA) (Fig. 1C and D). At 1 H MRS examination, the Lactate/Creatine (Lac/Cr) ratio was increased in the occipital lobe (3.7, nv 0–1), slightly increased in the frontal lobe (1.4), and normal in the cerebellum (0.6) [Spectra obtained at 1.5 T by a PRESS sequence (Te = 270), reference values expressed as arbitrary units after contemporary examination of ageand sex-matched normal subjects]. The T8993C mutation was also found in blood DNA from the patient’s mother (13.2 % mutated mtDNA). No tissues were available from the sister. In our T8993C family, both severe MILS and a NARP-like phenotype (without electromyographic evidence of peripheral neuropathy) are present in the same generation, the mother being mildly symptomatic. As described for this and other LETTER TO THE EDITORS