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Biomedical subjects

Guido Davidzon

Publications and source records attributed to Guido Davidzon.

6 recordsLinked to original sources
PubMed2006

Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene.

BACKGROUND: Mitochondrial DNA depletion syndrome is an autosomal recessive disorder characterized by decreased mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the beta-subunit of the adenosine diphosphate-forming succinyl coenzyme A synthetase ligase. OBJECTIVE: To highlight the variability in the clinical spectrum of TK2-related mitochondrial DNA depletion syndrome. DESIGN: Review of patients and the literature. SETTING: Tertiary care university. PATIENTS: Four patients with mitochondrial DNA depletion syndrome and mutations in the TK2 gene. MAIN OUTCOME MEASURES: Definition of clinical variability. RESULTS: Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. CONCLUSION: The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3-like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.

Adolescent↗
PubMed2006

Early-onset familial parkinsonism due to POLG mutations.

OBJECTIVE: To define the molecular etiology of early-onset parkinsonism and peripheral neuropathy. METHODS: Two sisters had early-onset parkinsonism (dystonic toe curling, action tremor, masked face, bradykinesia, stooped posture, and rigidity), together with clinical and electrophysiological signs of sensorimotor axonal peripheral neuropathy. RESULTS: No mutations were found in the genes for parkin or PINK1. Muscle biopsies showed ragged-red and cytochrome c oxidase-negative fibers, and biochemistry showed decreased activities of respiratory chain complexes containing mitochondrial DNA-encoded subunits. Multiple mitochondrial DNA deletions were seen by long polymerase chain reaction, and sequencing of the POLG gene showed that the patients were compound heterozygous for two patogenic mutations. INTERPRETATION: POLG mutations can cause early-onset parkinsonism in the absence of progressive external ophthalmoplegia.

Adult↗
PubMed2005

POLG mutations and Alpers syndrome.

Alpers-Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been associated with mitochondrial DNA (mtDNA) depletion and mutations in polymerase gamma gene (POLG). We have identified POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion.

Child, Preschool↗
PubMed2005

Mitochondrial DNA and disease.

The small circle of mitochondrial DNA (mtDNA) present in all human cells has proven to be a veritable Pandora's box of pathogenic mutations and rearrangements. In this review, we summarize the distinctive rules of mitochondrial genetics (maternal inheritance, mitotic segregation, heteroplasmy and threshold effect), stress the relatively high prevalence of mtDNA-related diseases, and consider recent additions to the already long list of pathogenic mutations (especially mutations affecting protein-coding genes). We then discuss more controversial issues, including the functional or pathological role of mtDNA haplotypes, the pathogenicity of homoplasmic mutations and the still largely obscure pathophysiology of mtDNA mutations.

DNA, Mitochondrial↗
PubMed2005

Hereditary ferritinopathy: a novel mutation, its cellular pathology, and pathogenetic insights.

We report a family of French Canadian and Dutch ancestry with hereditary ferritinopathy (neuroferritinopathy) and a novel mutation (C insertion at nt646-647 in exon 4) in the ferritin light chain gene, resulting in a longer than normal protein. Our failure to immunostain most of the abnormal ferritin deposits in the proband with a conformation-dependent monoclonal antibody to ferritin light chain supported a previously postulated conformational change of ferritin light chain in this disease. The posterior putamen and cerebellum were the primary pathologic loci in our proband, but asymptomatic hepatocytic intranuclear accumulations of iron and ferritin also were present. Both neurons and glia displayed highly distinctive, if not pathognomonic, swollen to vacuolated nuclei containing ferritin and iron. Hyaline deposits, again staining for both ferritin and iron, were additional morphologic features that may be unique to the ferritinopathies. The iron, at least in putamen where there was a nearly 40-fold increase, appeared to be both in the ferrous (Fe2+) and ferric (Fe3+) form; it was the most likely cause of the observed neuronal and glial apoptosis. We found morphologic evidence of both lipid peroxidation and abnormal nitration of proteins in putaminal neurons and glia, confirming the expected oxidative stress due to this excessive iron. Biochemical and immunohistochemical abnormalities in mitochondria also were demonstrated, probably due to an imbalance in iron homeostasis that had a deleterious effect on the respiratory chain.

Adult↗