Polymerase gamma 1 mutations: clinical correlations.
ABSTRACT Mitochondrial disorders result from primary defects in the mitochondrial DNA (mtDNA) or from defects in nuclear genes which cause disease by affecting the mtDNA. POLG1 is a nuclear gene which encodes for the catalytic subunit of the mtDNA polymerase gamma, essential for mtDNA replication. Less than a decade ago, POLG1 mutations were discovered in patients with progressive external ophthalmoplegia. Since then, it has emerged that POLG1 mutations can result in a spectrum of clinical manifestations, resulting in autosomal recessive or dominant mitochondrial diseases.
Here we summarize the common clinical phenotypes associated with POLG1 mutations. Alpers syndrome, progressive external ophthalmoplegia with or without limb myopathy, ataxia-neuropathy syndrome, and epilepsy are frequent clinical manifestations of the POLG1-related disease. Childhood progressive encephalopathy, Parkinsonism, stroke-like events, and isolated exercise intolerance can occur in association with POLG1 mutations. Muscle biopsy can show signs of mitochondrial dysfunction by histologic and biochemical studies or it can be unrevealing. mtDNA analysis of affected tissues can reveal depletion, multiple deletions or point mutations, but it can be occasionally noninformative by routine analysis.
: POLG1 mutations result in extremely heterogenous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes. The lack of signs of mitochondrial dysfunction in the muscle biopsy does not exclude a POLG1-related disease. Analysis of mtDNA of clinically affected tissues is often informative, but not always. Molecular analysis of POLG1 is essential when POLG1-related disease is suspected. Sodium valproate should be avoided because of the risk of liver failure.
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- "Onset in early to mid childhood Creatine deficiency syndromes DD, sz, MRS+, AE autism SLC6A8, GAMT, GATM Oral creatine (GAMT, AGAT) Inherited: GAMT/GATM (AR), SLC6A8 (X- linked)  Autosomal dominant nocturnal frontal lobe epilepsy Seizures arising from sleep, prominent motor manifestations CHRNA4, CHRNB2, CHRNA2 NS Inherited (AD)  Alpers-Huttenlocher syndrome Progressive encephalopathy, refractory sz, hepatic failure, poliodystrophy POLG1 Avoid VPA (liver failure) Inherited (AR)   "
ABSTRACT: The contributions of genetic influences in both rare and common epilepsies are rapidly being elucidated, and neurologists routinely consider genetic testing in the workup of numerous epilepsy syndromes. Trends in patient attitudes and developments in clinical molecular diagnostics will increase interest in, and the availability of genetic tests for, genetic evaluations of epilepsies. We review recent and planned developments in clinical genetic testing platforms, including their indications, strengths, and limitations. We discuss genome-wide microarray methods (i.e., methods to detect copy number variations), karyotypes, and sequence-based testing. We outline the general approach to genetic evaluations of epilepsy, emphasizing the importance of clinical evaluations, and provide online clinical resources. Finally, we present potential social, legal, and financial barriers to genetic evaluations, and discuss concerns regarding clinical utility and recurrence risk. This review provides a practical overview of molecular diagnostics for the neurologist in the genetic evaluation of epilepsies in 2011.Pediatric Neurology 05/2011; 44(5):317-27. DOI:10.1016/j.pediatrneurol.2011.01.017 · 1.50 Impact Factor
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ABSTRACT: The feasibility of applying automatic phoneme analysis to articulation testing of motor-impaired speech has been investigated. An articulation test consisting of twenty-four monosyllabic words has been established. After the subject is prompted to say each word, the acoustic speech waveform is digitized and stored. Features are then extracted to facilitate segmentation of each word into individual phonemes. The phoneme sequence uttered by the subject is then compared to the expected sequence to determine the errors that have occurred.< >Engineering in Medicine and Biology Society, 1988. Proceedings of the Annual International Conference of the IEEE; 12/1988
Conference Paper: A new class of digital filters for medical imaging[Show abstract] [Hide abstract]
ABSTRACT: A class of digital filters based on the Cohen orthogonal polynomial is described. From this general polynomial, three-pole and five-pole filters can be derived that subsequently can produce low-pass, high-pass, or bandpass filters. The methodology for producing these filters is briefly outlined, followed by some representative results.< >Engineering in Medicine and Biology Society, 1988. Proceedings of the Annual International Conference of the IEEE; 12/1988