Marzio Bellan

POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness

The authors identified two novel heterozygous missense transitions in the gene for the mitochondrial polymerase gammaA subunit (POLG) in a family with an autosomal recessive syndrome comprising progressive external ophthalmoplegia (PEO), polyneuropathy, ataxia, sensorineural hearing loss, and affective disorders. These mutations were not detected in 120 healthy control subjects.

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudo-obstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall.

Mitochondrial DNA nucleotide changes C14482G and C14482A in the ND6 gene are pathogenic for Leber's hereditary optic neuropathy

A novel mitochondrial DNA nucleotide transversion, C14482A (M64I), different from the previously reported C14482G (M64I), was found to cause Lebers hereditary optic neuropathy with visual recovery in an Italian family. These equivalent changes are the fifth pathogenic mutation for pure Lebers hereditary optic neuropathy. This confirms that the ND6 gene of complex I is a mutational hot spot and suggests that different amino acid substitutions at residue 64, as induced by C14482G or C14482A (M64I) and the common T14484C (M64V) mutations, are associated with visual recovery.

Myelin, mitochondria, and autoimmunity What's the connection?

Mitochondrial optic neuropathies are inherited nonsyndromic disorders characterized by selective degeneration of retinal ganglion cells leading to visual loss and optic nerve atrophy.1 The two most common are the maternally inherited Leber hereditary optic neuropathy (LHON, OMIM#535000) and the autosomal dominant optic atrophy (DOA, OMIM#165500). LHON, the first disease to be associated with a mitochondrial DNA (mtDNA) point mutation, is due in most cases to one of three mutations at positions 11778/ND4, 3460/ND1, and 14484/ND6 affecting complex I subunit genes. As a consequence there is a well documented defect of mitochondrial respiration, chronic increase in oxidative stress, and cell predisposition to apoptosis.1 As regards DOA, a large subset of patients present with a heterozygous mutation in OPA1 , a nuclear gene encoding a dynamin-related GTPase targeted to mitochondria and involved in mitochondrial fusion, cristae organization, and control of apoptosis. There is mounting evidence that there is defective mitochondrial respiration also in OPA1-related patients with DOA.2,3 Despite being a nonsyndromic optic neuropathy …

Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report

PurposeTo describe the ocular features of a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) due to a homozygous G1443A mutation in the thymidine-phosphorylase gene.MethodsA case report with extensive ophthalmological investigation over a 9-year period, until death at age 38 years. Measures used included standard ophthalmological examination, visual field examination and optical coherence tomography (OCT).ResultsPtosis and external ophthalmoplegia progressively worsened during the follow-up, as did the neurological and general status. Corneal and optic disc alterations were also observed at the last visit. Glaucomatous changes of the optic disc were confirmed by the visual field examination and OCT.ConclusionIn addition to previously described alterations such as ptosis and external ophthalmoplegia, MNGIE may be associated with glaucomatous-like optic neuropathy.