A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.

Carbonic anhydrase VA (CA-VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition.

Recurrent hyperammonaemia in a patient with carbonic anhydrase VA deficiency.

Carbonic anhydrase VA deficiency is a recently described inherited cause of paediatric hyperammonaemia. Most published cases describe patients with only one episode of hyperammonaemia whilst others report patients who had up to three metabolic crises with the first invariably being the most severe. We describe a patient with carbonic anhydrase VA deficiency who experienced 7 hyperammonemic episodes over a 3-year period, up to age 5 years 9 months. These episodes did not clearly decrease in severity over time. This report expands the clinical phenotype and the age window for metabolic crises associated with this condition.

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice.

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca2+ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30-100 mg/kg, per os - p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.

Mitochondrial carbonic anhydrase VA deficiency in three Indian infants manifesting early metabolic crisis.

BACKGROUND: Hyperammonemia and hyperlactatemia in neonates and young children with non-specific biochemical markers poses a diagnostic challenge. An accurate diagnosis is essential for effective management. CASE REPORTS: We present three infants from unrelated families, one with infantile and two with neonatal hyperammonemic encephalopathy, hypoglycaemia, and hyperlactatemia. The underlying cause was confirmed following whole exome sequencing as biochemical markers were not conclusive of a definite diagnosis. CONCLUSION: The combination of hyperammonemic encephalopathy, hyperlactatemia and hypoglycemia in neonates and infants should prompt physicians to suspect Carbonic anhydrase VA deficiency. Majority of these children can have a favourable long-term outcome with symptomatic treatment.

Topiramate Protects Pericytes from Glucotoxicity: Role for Mitochondrial CA VA in Cerebromicrovascular Disease in Diabetes.

Hyperglycemia in diabetes mellitus causes oxidative stress and pericyte depletion from the microvasculature of the brain thus leading to the Blood-Brain Barrier (BBB) disruption. The compromised BBB exposes the brain to circulating substances, resulting in neurotoxicity and neuronal cell death. The decline in pericyte numbers in diabetic mouse brain and pericyte apoptosis in high glucose cultures are caused by excess superoxide produced during enhanced respiration (mitochondrial oxidative metabolism of glucose). Superoxide is precursor to all Reactive Oxygen Species (ROS) which, in turn, cause oxidative stress. The rate of respiration and thus the ROS production is regulated by mitochondrial carbonic anhydrases (mCA) VA and VB, the two isoforms expressed in the mitochondria. Inhibition of both mCA: decreases the oxidative stress and restores the pericyte numbers in diabetic brain; and reduces high glucose-induced respiration, ROS, oxidative stress, and apoptosis in cultured brain pericytes. However, the individual role of the two isoforms has not been established. To investigate the contribution of mCA VA in ROS production and apoptosis, a mCA VA overexpressing brain pericyte cell line was engineered. These cells were exposed to high glucose and analyzed for the changes in ROS and apoptosis. Overexpression of mCA VA significantly increased pericyte ROS and apoptosis. Inhibition of mCA VA with topiramate prevented increases both in glucose-induced ROS and pericyte death. These results demonstrate, for the first time, that mCA VA regulates the rate of pericyte respiration. These findings identify mCA VA as a novel and specific therapeutic target to protect the cerebromicrovascular bed in diabetes.