5 research outputs found
Pure myopathy with enlarged mitochondria associated to a new mutation in MTND2 gene
To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red \u2013 COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions. Biochemical assays revealed a severe isolated complex I deficiency. We identified a novel, heteroplasmic mutation m.4831G > A in the MTND2 gene, causing the p.Gly121Asp substitution in the ND2 protein. The mutation was present in the 95% of mitochondrial genomes from patient's muscle tissue, at a lower level in cells from the urinary tract and at a lowest level in lymphocytes from patient's blood; the base substitution was absent in fibroblasts and in the tissues from proband's healthy mother and brother. The specific skeletal muscle tissue involvement can explain the childhood-onset and the relatively benign, exclusively myopathic course of the disease
Cardiac phenotype in ATP1A3-related syndromes A multicenter cohort study
Objective
To define the risks and consequences of cardiac abnormalities in
ATP1A3-related syndromes.
Methods
Patients meeting clinical diagnostic criteria for rapid-onset
dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC),
and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and
sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at
least 1 cardiac assessment were included. We evaluated the cardiac
phenotype in an Atp1a3 knock-in mouse (Mashl(+/-)) to determine the
sequence of events in seizure-related cardiac death.
Results
Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female,
mean age 17 years) were included. Resting ECG abnormalities were found
in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%)
with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with
AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC
and RDP with either repolarization or conduction abnormalities.
Echocardiography was normal. Cardiac intervention was required in 3 of
98 (approximate to 3%) patients with AHC. In the mouse model, resting
ECGs showed intracardiac conduction delay; during induced seizures,
heart block or complete sinus arrest led to death.
Conclusions
We found increased prevalence of ECG dynamic abnormalities in all
ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm
abnormalities equivalent to that in established cardiac channelopathies
(approximate to 3%). Sudden cardiac death due to conduction abnormality
emerged as a seizure-related outcome in murine Atp1a3-related disease.
ATP1A3-related syndromes are cardiac diseases and neurologic diseases.
We provide guidance to identify patients potentially at higher risk of
sudden cardiac death who may benefit from insertion of a pacemaker or
implantable cardioverter-defibrillator