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.

We present the case of a patient who presented to the emergency department complaining of diffuse myalgias, severe jaw pain and chills. She met criteria for severe sepsis and received treatment including analgesia, antibiotics, intravenous fluids, and antipyretics. Workup revealed an elevated lactate and leukocytosis however, did not reveal any infectious source. The patient had a history of Crohn\'s disease and had received an infusion of infliximab ten days prior to the onset of her symptoms. After ruling out other potential causes of lactic acidemia, her final diagnosis was determined to be the rare presentation of an infliximab infusion reaction. On reviewing the literature, we could not find another documented case of a lactic acidemia caused by an infliximab infusion reaction. The key to the treatment of this patient was steroids, antihistamines, and supportive treatment. Emergency physicians do not often encounter infliximab infusion reactions because they occur so infrequently. Along with more common diagnoses such as sepsis, emergency physicians should include infliximab infusion reactions on the differential diagnosis in patients receiving this medication.

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.