A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder

SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while 1H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles. Decreased biochemical activities of mitochondrial respiratory chain enzymes containing mtDNA-encoded subunits and mtDNA depletion were observed in muscle and fibroblasts. A novel homozygous mutation in SUCLA2, the first one in the ligase coenzyme A (CoA) domain of the protein, was identified. Escalating doses of CoQ10 up to 2000 mg daily were associated with improvement of muscle weakness and stabilization of the disease course. The findings indicate the importance of screening for mitochondrial dysfunction in patients with complex movement disorders without brain MRI lesions and further investigation for potential secondary CoQ10 deficiency in patients with SUCLA2 mutations

Fhl1 W122S causes loss of protein function and late-onset mild myopathy

A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice

Coenzyme Q10 deficiencies in neuromuscular diseases

páginas, 2 figuras, 1 tabla. Editado por Carmen Espinós, Vicente Felipo y Francesc Palau.Coenzyme Q (CoQ) is an esssential component of the respiratory chain but also participates in other mitochondrial functions such as regulation of the transition pore and uncoupling proteins. Furthermore, this compound is a specific substrate for enzymes of the fatty acids β-oxidation pathway and pyrimidine nucleotide biosynthesis. Furthermore, CoQ is an antioxidant that acts in all cellular membranes and lipoproteins. A complex of a least ten nuclear (COQ) genes encoded proteins synthesis CoQ but its regulation is unknown. Since 1989, a growing number of patients with multsystemic mitochondrial disorders and neuromuscular disorders showing deficiencies of CoQ have been identified. CoQ deficiency caused by mutation(s) in any of the COQ genes in designated primary deficiency. Other patients have displayed other genetic defects independent on the CoQ biosynthesis pathway, and are considered to have secondary deficiencies. This review updates the clinical and molecular aspects of both types of CoQ deficiencies and proposes new approaches to understanding their molecular bases.This work has been partially supported by the European Union contract LSHB-CT-2004-005151 and the NIH grant 1R01HD057543-01.Peer reviewe

Loss-of-function mutations in <em>MGME1</em> impair mtDNA replication and cause multisystemic mitochondrial disease.

Known disease mechanisms in mitochondria! DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2)(1-3) or the biosynthesis pathways of deoxyribonucleoside 5&#39;-triphosphates for mtDNA synthesis(4-11). However, in many of these disorders, the underlying genetic defect has yet to be discovered. Here, we identify homozygous nonsense and missense mutations in the orphan gene C20orf72 in three families with a mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure. Muscle biopsies showed mtDNA depletion and multiple mtDNA deletions. C20orf72, hereafter MGME1 (mitochondrial genome maintenance exonuclease 1), encodes a mitochondria! RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. We show that MGME1 cleaves single-stranded DNA and processes DNA flap substrates. Fibroblasts from affected individuals do not repopulate after chemically induced mtDNA depletion. They also accumulate intermediates of stalled replication and show increased levels of 7S DNA, as do MGME1-depleted cells. Thus, we show that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance