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

Abstract

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 s...

Long‐term outcome of Leigh syndrome caused by the NARP‐T8993C mtDNA mutation

“…To asses phenotypic variability, we examined available clinical data on all reported cases with T8993C mutation and LS using medline database searches [van Erven et al, 1987;de Vries et al, 1993;Santorelli et al, 1994Santorelli et al, , 1996Chakrapani et al, 1998;Fujii et al, 1998Fujii et al, , 2002Suzuki et al, 1998;Vilarinho et al, 2001;Hurvitz et al, 2002;Sciacco et al, 2003;Morava et al, 2006]. Developmental milestones, age at first signs, neurological and ophthalmological status at the last examination, clinical outcome, MRI, and molecular data were reviewed.…”

Central Nervous System Imaging in Mitochondrial Disorders

“…Similar but less prominent alterations can be found in the grey matter 67 . The most frequent finding on MRS in MCD with CNS involvement is an increased lactate peak 15,18,33,65,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] , which may precede the SLLs 15 . High levels of intra-ventricular lactate are usually associated with severe neurologic impairment 6 .…”

A 41-year-old woman with progressive leg weakness and numbness, dizziness, and myalgia

“…22 Phenotypic variability has been observed also in the same generation. 23 T8993C generally causes a milder phenotype than the previously reported T8993G. T8993G results in a similar clinical spectrum in which developmental delay, muscle weakness, peripheral neuropathy, ataxia, retinitis pigmentosa, and seizures may coexist in different combinations.…”