NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.

Effect of carglumic acid with or without ammonia scavengers on hyperammonaemia in acute decompensation episodes of organic acidurias.

BACKGROUND: Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment. METHODS: A post-hoc analysis of two retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH3) scavengers compared with scavengers alone for reducing plasma NH3 levels in patients with OAs and hyperammonaemia (plasma NH3 > 60 µmol/L) during decompensation episodes. NH3 was analysed in 12-h periods at 0-48 h and 24-h periods at 48-120 h. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Of 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH3 scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH3 scavenger group. Median baseline NH3 level was: 199 µmol/L, carglumic acid; 122 µmol/L, NH3 scavengers; and 271 µmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3 scavengers' group; reductions were greatest in the combination group. Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was - 13, + 12% and - 27% at 0-12 h (p < 0.05 NH3 scavengers vs combination); - 47, - 22% and - 52% at 12-24 h (not significant); - 44, - 5% and - 61% at 24-48 h; and - 66, - 16% and - 76% at 48-72 h (p < 0.05 carglumic acid/combination groups vs NH3 scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition. CONCLUSIONS: Carglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH3 scavengers, the reduction in NH3 was greater than with NH3 scavengers alone in the first 72 h.

Angelman syndrome and isovaleric acidemia: What is the link?

We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice.

BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 µM) and NTBC-levels in the therapeutic range (20-40 µM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.