Converging Role for REEP1/SPG31 in Oxidative Stress.

Mutations in the receptor expression-enhancing protein 1 gene are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in , suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear.

CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis.

Organelle biogenesis requires proper transport of proteins from their site of synthesis to their target subcellular compartment. Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and traffic through the Golgi complex before being transferred to the endolysosomal system, but how they are transferred from the ER to the Golgi is unknown. Here, we show that ER-to-Golgi transfer of lysosomal enzymes requires CLN8, an ER-associated membrane protein whose loss of function leads to the lysosomal storage disorder, neuronal ceroid lipofuscinosis 8 (a type of Batten disease).

Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28.

Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts.

Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy.

We describe the case of a woman in whom combination of a mitochondrial (MT-CYB) and a nuclear (SDHB) mutation was associated with clinical and metabolic features suggestive of a mitochondrial disorder. The mutations impaired overall energy metabolism in the patient's muscle and fibroblasts and increased cellular susceptibility to oxidative stress. To clarify the contribution of each mutation to the phenotype, mutant yeast strains were generated.

Novel MTCYB mutation in a young patient with recurrent stroke-like episodes and status epilepticus.

The acronym "MELAS" (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) denotes patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Here we report on a girl with repeated stroke-like episodes and status epilepticus, who was diagnosed with MELAS due to a novel mitochondrial cytochrome b gene (MTCYB) mutation (m.15092G>A, which predicts p.

A novel SUCLA2 mutation in a Portuguese child associated with "mild" methylmalonic aciduria.

Succinyl-coenzyme A synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) from succinyl-coenzyme A and adenosine diphosphate (ADP) in the tricarboxylic acid cycle. This enzyme is made up of α and β subunits encoded by SUCLG1 and SUCLA2, respectively. We present a child with severe muscular hypotonia, dystonia, failure to thrive, sensorineural deafness, and dysmorphism.

Dopamine-agonist responsive Parkinsonism in a patient with the SANDO syndrome caused by POLG mutation.

Background: Disorders of oxidative phosphorylation affects 1/5000 individuals and present heterogeneous involvement of tissues highly dependent upon ATP production.

Case Presentation: Here we present the case of a 48-year-old woman carrying a homozygous mutation (p.A899T) in mitochondrial polymerase gamma (POLG) and manifesting with a complex neurological phenotype including Dopamine-agonist responsive Parkinsonism.

Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency.

Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex.

TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis.

Mammalian complex V (F1F0-ATP synthase or ATPase) uses the proton gradient to generate ATP during oxidative phosphorylation and requires several helper proteins, including TMEM70, to form the holoenzyme in a stepwise process in which nuclear DNA is combined with mitochondrial DNA-encoded subunits. We report the clinical and molecular findings in three patients presenting lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy. All three showed an isolated defect of fully assembled ATP synthase in association with a "common" (c.

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures.

TRPV4 mutations in children with congenital distal spinal muscular atrophy.

Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.

Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine.

Δ(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia).

Cardiolipin content in mitochondria from cultured skin fibroblasts harboring mutations in the mitochondrial ATP6 gene.

The role of phospholipids in normal assembly and organization of the membrane proteins has been well documented. Cardiolipin, a unique tetra-acyl phospholipid localized in the inner mitochondrial membrane, is implicated in the stability of many inner-membrane protein complexes. Loss of cardiolipin content, alterations in its acyl chain composition and/or cardiolipin peroxidation have been associated with dysfunction in multiple tissues in a variety of pathological conditions.

Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1.

We present clinical, neuroimaging, and molecular data on the identification of a new homozygous c.1783A>G (p.Thr595Ala) mutation in NDUFS1 in two inbred siblings with isolated complex I deficiency associated to a progressive cavitating leukoencephalopathy, a clinical and neuroradiological entity originally related to unknown defects of the mitochondrial energy metabolism.

Assaying ATP synthesis in cultured cells: a valuable tool for the diagnosis of patients with mitochondrial disorders.

Mitochondrial ATP synthase plays a central role in cell function by synthesising most of the ATP in human tissues. In different cells, active regulation of mitochondrial ATP synthase in response to cellular energy demand has been demonstrated, as well as its alteration under several pathological conditions affecting oxidative phosphorylation (OXPHOS). Traditionally, detection of OXPHOS defects is based on the spectrophotometric measurement of respiratory chain complex activities in muscle biopsies.

Cellular and functional analysis of four mutations located in the mitochondrial ATPase6 gene.

The smallest rotary motor of living cells, F0F1-ATP synthase, couples proton flow-generated by the OXPHOS system-from the intermembrane space back to the matrix with the conversion of ADP to ATP. While all mutations affecting the multisubunit complexes of the OXPHOS system probably impact on the cell's output of ATP, only mutations in complex V can be considered to affect this output directly. So far, most of the F0F1-ATP synthase variations have been detected in the mitochondrial ATPase6 gene.

Urine acylcarnitine analysis by ESI-MS/MS: a new tool for the diagnosis of peroxisomal biogenesis disorders.

Background: Patients with peroxisomal biogenesis disorders (PBDs) have an abnormal profile of circulating acylcarnitines (i.e. elevated C16:0-DC-, C18:0-DC-, C24:0-, C26:0-carnitine).

Infantile mitochondrial disorders.

Mitochondrial disorders encompass any medical specialty and affect patients at any age. Likewise, the spectrum of clinical and genetic signatures of these disorders is ample, making a precise diagnosis difficult. We will report some of the major clinical phenotypes observed in infancy, their underlining molecular features, and will propose an approach to reach a more complete diagnosis.

SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness.

One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families.

A new method for analysis of mitochondrial DNA point mutations and assess levels of heteroplasmy.

Determination of mitochondrial DNA (mtDNA) heteroplasmy for the diagnosis of patients with mitochondrial disorders is a difficult task due to the coexistence of wild-type and mutant genomes. We have developed a new method for genotyping and quantification of heteroplasmic point mutations in mtDNA based on the SNaPshot technology. We compared the data of this method with the widely used "last hot-cycle" PCR-RFLP method by studying 15 patients carrying mtDNA mutations.