Diagnosis and management of glutaric aciduria type I – revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline

Spurious sea ice formation caused by oscillatory ocean tracer advection schemes

Tracer advection schemes used by ocean models are susceptible to artificial oscillations: a form of numerical error whereby the advected field alternates between overshooting and undershooting the exact solution, producing false extrema. Here we show that these oscillations have undesirable interactions with a coupled sea ice model. When oscillations cause the near-surface ocean temperature to fall below the freezing point, sea ice forms for no reason other than numerical error. This spurious sea ice formation has significant and wide-ranging impacts on Southern Ocean simulations, including the disappearance of coastal polynyas, stratification of the water column, erosion of Winter Water, and upwelling of warm Circumpolar Deep Water. This significantly limits the model’s suitability for coupled ocean-ice and climate studies. Using the terrain-following-coordinate ocean model ROMS (Regional Ocean Modelling System) coupled to the sea ice model CICE (Community Ice CodE) on a circumpolar Antarctic domain, we compare the performance of three different tracer advection schemes, as well as two levels of parameterised diffusion and the addition of flux limiters to prevent numerical oscillations. The upwind third-order advection scheme performs better than the centered fourth-order and Akima fourth-order advection schemes, with far fewer incidents of spurious sea ice formation. The latter two schemes are less problematic with higher parameterised diffusion, although some supercooling artifacts persist. Spurious supercooling was eliminated by adding flux limiters to the upwind third-order scheme. We present this comparison as evidence of the problematic nature of oscillatory advection schemes in sea ice formation regions, and urge other ocean/sea-ice modellers to exercise caution when using such schemes

Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals