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Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report.

ABSTRACT: Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors.Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C>G and the already known m.14459G>A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G>A was heteroplasmic in the mother's blood-derived DNA.The m.14459G>A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G>A-mutated patients does not explain this large clinical heterogeneity.

SUBMITTER: Ronchi D

PROVIDER: S-EPMC3148968 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report.

Ronchi Dario D Cosi Alessandra A Tonduti Davide D Orcesi Simona S Bordoni Andreina A Fortunato Francesco F Rizzuti Mafalda M Sciacco Monica M Collotta Martina M Cagdas Sophie S Capovilla Giuseppe G Moggio Maurizio M Berardinelli Angela A Veggiotti Pierangelo P Comi Giacomo P GP

BMC neurology 20110712

<h4>Background</h4>Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors.<h4>Case presentation</h4>Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscl ...[more]

PMID: 21749722

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Project description:BackgroundMitochondrial diseases, also known as oxidative phosphorylation (OXPHOS) disorders, with a prevalence rate of 1:5000, are the most frequent inherited metabolic diseases. Leigh Syndrome French Canadian type (LSFC), is caused by mutations in the nuclear gene (2p16) leucine-rich pentatricopeptide repeat-containing (LRPPRC). It is an autosomal recessive neurogenetic OXPHOS disorder, phenotypically distinct from other types of Leigh syndrome, with a carrier frequency up to 1:23 and an incidence of 1:2063 in the Saguenay-Lac-St Jean region of Quebec. Recently, LSFC has also been reported outside the French-Canadian population.Patient presentationWe report a male Italian (Sicilian) child, born preterm at 28 + 6/7 weeks gestation, carrying a novel LRPPRC compound heterozygous mutation, with facial dysmorphisms, neonatal hypotonia, non-epileptic paroxysmal motor phenomena, and absent sucking-swallowing-breathing coordination requiring, at 4.5 months, a percutaneous endoscopic gastrostomy tube placement. At 5 months brain Magnetic Resonance Imaging showed diffuse cortical atrophy, hypoplasia of corpus callosum, cerebellar vermis hypoplasia, and unfolded hippocampi. Both auditory and visual evoked potentials were pathological. In the following months Video EEG confirmed the persistence of sporadic non epileptic motor phenomena. No episode of metabolic decompensation, acidosis or ketosis, frequently observed in LSFC has been reported. Actually, aged 14 months corrected age for prematurity, the child shows a severe global developmental delay. Metabolic investigations and array Comparative Genomic Hybridization (aCGH) results were normal. Whole-exome sequencing (WES) found a compound heterozygous mutation in the LRPPRC gene, c.1921-7A > G and c.2056A > G (p.Ile686Val), splicing-site and missense variants, inherited from the mother and the father, respectively.ConclusionsWe first characterized the clinical and molecular features of a novel LRPPRC variant in a male Sicilian child with early onset encephalopathy and psychomotor impairment. Our patient showed a phenotype characterized by a severe neurodevelopmental delay and absence of metabolic decompensation attributable to a probable residual enzymatic activity. LRPPRC is a rare cause of metabolic encephalopathy outside of Québec. Our patient adds to and broaden the spectrum of LSFC phenotypes. WES analysis is a pivotal genetic test and should be performed in infants and children with hypotonia and developmental delay in whom metabolic investigations and aCGH are normal.

Dataset Information

Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report.

Publications

Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report.

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