RESUMEN
We describe two novel missense variants in CACNA1A segregating in a family with variable severity of ataxia/oculomotor dysfunction, neurobehavioral impairments, and epilepsy. The most severe outcome occurred in a compound heterozygous proband, which could represent variable expression of the paternal allele or biallelic modulation of calcium channel function. Acetazolamide and lamotrigine were effective for seizure control.
Asunto(s)
Ataxia Cerebelosa , Epilepsia , Anticonvulsivantes/uso terapéutico , Ataxia , Canales de Calcio/genética , Humanos , Mutación MissenseRESUMEN
The purpose of this study was to determine the effect of age upon hepatic gluconeogenesis (HGN) from lactate in the presence of various concentrations of alcohol from young (3 months) and old (24 months) male rats. After a 24-hour fast, livers were perfused with collagenase and the hepatocytes were isolated. Aliquots of the cell suspension were placed in Krebs-Henseleit buffer and incubated with lactate, [U-(14)C]lactate, and nine different concentrations of ethanol (EtOH) for 30 min. Dose-effect curves were generated for the determination of maximal and half-maximal alcohol-induced inhibition on gluconeogenesis. There were no significant differences in basal HGN (lactate only and no EtOH) between young and old hepatocytes, 86.9+/-6.3 nmol/mg protein/30 min. The addition of ethanol significantly reduced HGN from lactate in both groups. At the highest ethanol concentration (15 mM), the glucose production was inhibited more from old, 46.1+/-1.2 nmol/mg protein/30 min, compared to young hepatocytes, 56.0+/-1.6 nmol/mg protein/30 min. The greater age-related reduction in HGN was confirmed by the minimal glycogenolysis, and the concomitant decline in [U-(14)C]glucose production, lactate uptake, and [U-(14)C]lactate uptake. The results suggest that alcohol elicits a greater inhibition upon HGN from lactate in old compared to young liver cells.
Asunto(s)
Envejecimiento/metabolismo , Etanol/farmacología , Gluconeogénesis/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Ácido Láctico/metabolismo , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hepatocitos/metabolismo , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
Hepatic gluconeogenic capacity was studied in young (4 months of age) and old (24 months of age) male Fischer 344 rats fasted for 24 hours using the isolated hepatocyte technique. Following the isolation of liver cells, the following precursors were added to the cell suspensions and incubated for 30 minutes: lactate (5 mmol/L), pyruvate (5 mmol/L), alanine (5 mmol/L), glutamine (5 mmol/L), oxaloacetate (5 mmol/L), glycerol (5 mmol/L), dihydroxyacetone (10 mmol/L), fructose (10 mmol/L), or saline (no precursor addition). To confirm that glucose production reflects gluconeogenic capacity, there was significant depletion of hepatic glycogen after the 24-hour fast and minimal alterations in glycogen content once substrates were added. Adjusting the gluconeogenic rates to reflect 100% cell viability resulted in no difference between young and old animals for any substrate used with the sole exception of fructose. The hepatic glucose production from fructose was 34% greater for young versus old animals. The results suggest that following a period of starvation the basal glucose production rates from hepatocytes, incubated with precursors entering the gluconeogenic pathway prior to fructose-6-phosphate, are equivalent in young and old rats.