Abstract Arginase 1 (ARG1), the enzyme catalyzing the conversion of arginine to ornithine and urea, is a hallmark of IL-10 producing immunosuppressive M2 macrophages, however ARG1 activity in T cells is disputed. Here we demonstrate that Arg1, but not Arg2, expression induction is a key feature of lung CD4 T cells during mouse in vivo influenza infection. Ablation of CD4 T cell-intrinsic Arg1 unexpectedly accelerated both the virus-specific Th1 effector response and its IL-10-associated contraction. Biologically, this led to efficient viral clearance, yet significantly reduced lung pathology. Surprisingly, loss of Arg1 in CD4 T cells did not result in disturbed intracellular ornithine or polyamine levels. Instead, by employing unbiased transcriptomic and metabolomic approaches, we found that Arg1 deficiency triggered altered glutamine metabolism, and rebalancing the glutamine flux normalized the Arg1 deficient T cell response. Further, the role of Arg1 in CD4 T cells was distinct from that of its’ isoenzyme Arg2, as ablation of CD4 T cell intrinsic Arg2 resulted in normal Th1 responses, and instead altered Th2 and Th17 responses. Finally, CD4 T cells from rare patients with a deficiency in ARG1, or from healthy donors with CRISPR-Cas9-mediated ARG1 deletion, recapitulated the mouse data, demonstrating that ARG1 also plays a CD4 T cell intrinsic role in human Th1 responses. Collectively, CD4 T cell-intrinsic ARG1, functions as an unexpected pace-keeper of human and mouse T helper 1 (Th1) responses with implications for Th1-associated tissue pathologies. Supported by grants from NIH (5K22HL125593 to M.K.) the Intramural Research Program of the NIH (NIDDK ZIA/DK075149 to B.A. and NHLBI ZIA/HL006223 to C.K.)
Citrullinemia is a urea cycle disorder caused by deficiency of argininosuccinate synthetase. Late onset forms can remain undiscovered until a decompensation that can resemble encephalitis. Herein, we report a 14-year old patient with suspected encephalitis with fluctuating episodes of confusion. EEG mainly showed bilateral slowing with some spikes plus spike waves; and was interpreted as suspicious for encephalitis. Brain MRI was normal. Leukocytes in CSF were slightly elevated. Treatment for a CNS infectious disease was begun. Symptoms did not resolve and there were several episodes of confusion, so a repeat lumbar puncture was performed according to a standardized protocol including an amino acid profile. An elevation of citrulline in CSF was found, which ultimately led to the diagnosis of a late onset citrullinemia. The establishment of this diagnosis will protect the patient from the sequelae of unrecognized and thus untreated episodes of hyperammonemia. Thus, following a standardized lumbar puncture protocol can be essential to detect patients with otherwise unrecognized underlying metabolic disorders that are not suspected because of clinical symptoms. In addition, it is important to stress that an ammonia concentration should be determined in any patient with neurological signs like confusion.
Case Study: Polymerase gamma (POLG) mutation leads to a mitochondrial disease, resulting in epilepsy, movement disorders, cognitive impairment, and liver dysfunction. Usually, clinical symptoms commence in early childhood, later manifestation is also possible. Here, we present a patient with POLG mutation and rapid progression.
Summary Progressive myoclonic epilepsy (PME) is a heterogeneous group of epilepsies characterized by myoclonus, seizures and progressive neurological symptoms. The index patient was a 6‐year old boy showing early‐onset therapy resistant PME and severe developmental delay. Genome‐wide linkage analysis identified several candidate regions. The potassium channel tetramerization domain containing 7 gene ( KCTD7 ) in the 7q11.21 linkage region emerged as a suitable candidate. Sequence analysis revealed a novel homozygous missense mutation (p.R94W) in a highly conserved segment of exon 2. This is the second family with PME caused by KCTD7 mutations, hence KCTD7 mutations might be a recurrent cause of PME.
Abstract Based on a patient encounter in which genetically confirmed Marfan's syndrome (MFS) underlay a spontaneously resolving subdural hygroma (SDHy) diagnosed in infancy, we review the literature of MFS clinically manifest in early life (early-onset MFS [EOMFS]) and of differential diagnoses of SDHy and subdural hemorrhage (SDHe) at this age. We found that rare instances of SDHy in the infant are associated with EOMFS. The most likely triggers are minimal trauma in daily life or spontaneous intracranial hypotension. The differential diagnosis of etiologies of SDHy include abusive and nonabusive head trauma, followed by perinatal events and infections. Incidental SDHy and benign enlargement of the subarachnoid spaces must further be kept in mind. SDHy exceptionally also may accompany orphan diseases. Thus, in the infant, EOMFS should be considered as a cause of SDHe and/or SDHy. Even in the absence of congestive heart failure, the combination of respiratory distress syndrome, muscular hypotonia, and joint hyperflexibility signals EOMFS. If EOMFS is suspected, monitoring is indicated for development of SDHe and SDHy with or without macrocephaly. Close follow-up is mandatory.
