Clinical course of 63 patients with neonatal onset urea cycle disorders in the years 2001-2013.

BACKGROUND: Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS). METHODS AND RESULTS: Data of 63 patients were collected (27 patients with ASS deficiency, 23 patients with OTC deficiency, and 12 patients with CPS1 deficiency, one patient definite diagnosis not documented). The majority of patients (43/63, 68 %) had an initial ammonia concentration exceeding 500 µmol/L (normal < 100), of which most (26/43, 60.5 %) were also encephalopathic and were treated with hemodialysis. In patients surviving the initial crisis, recurrence of hyperammonemic events within the first 1.5 years of life occurred frequently (mean 3.6 events, range 0-20). Of all patients, 16 (25.4 %) died during or immediately after the neonatal period. CONCLUSION: We observed in this cohort of neonatal onset UCD patients a high rate of initial life-threatening hyperammonemia and a high risk of recurrence of severe hyperammonemic crises. These corresponded to a high mortality rate during the entire study period (30.2 %) despite the fact that patients were treated in leading European metabolic centers. This underlines the need to critically re-evaluate the current treatment strategies in these patients.

Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis.

PURPOSE: Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB). Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates. This study aimed to test for CAVA or CAVB deficiencies in a group of 96 patients with early-onset hyperammonemia and to prove the disease-causing role of the CAVA variants found. METHODS: We performed CA5A and CA5B sequencing in the described cohort and developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues. RESULTS: In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B. Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect. CONCLUSION: CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs. It seems to be more common than other rare metabolic diseases, and early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae.Genet Med 18 10, 991-1000.

Sellar and parasellar lesions - clinical outcome in 61 children.

OBJECTIVE: To evaluate clinical outcome in a 10-year consecutive series of children operated for sellar and parasellar tumors with special focus on neuropsychology and endocrinology. PATIENTS AND METHODS: We analyzed 61 children (30 female) under 18 years of age (mean age 9.9, range 1 month-17 years) operated between 2000 and 2010. Medical records were evaluated retrospectively; postoperative histologic diagnoses included 20 craniopharyngiomas, 17 gliomas, 6 pituitary adenomas and 18 rare tumor entities. RESULTS: Of 61 patients, 58 (95%) were still alive at last follow-up. Three patients died, all due to progression of malignant rhabdoid tumors. Postoperative clinical morbidity consisted of endocrinological (66%), visual (60.7%) and other neurological deficits (55.9%) after a mean follow-up of 44 months. When compared to all other tumor entities in this series, craniopharyngiomas were associated with high rates of gross-total resection (p=0.008), frequent progression of residual tumor (p=0.005) scotomas (p=0.013), persistent diabetes insipidus (p<0.001), and panhypopituitarism (p<0.001). Surgically treated gliomas showed higher rates of motor weakness (p=0.004), double vision (p<0.001), and milder forms of endocrinopathy (single hormone deficits, p=0.02). In general, deterioration in school performance was associated with multiple surgeries (p=0.018) and radiotherapy (p=0.021). CONCLUSION: Excellent overall survival in these patients is possible, however malignant rhabdoid tumors have a poor prognosis. Aggressive treatment is associated with significant morbidity. Children operated for craniopharyngioma showed an expected high rate of endocrine deterioration, whereas glioma patients had higher incidences of motor weakness and double vision. The treating physicians should be well aware of all these considerable postoperative deficits, especially when facing interdisciplinary management decisions, and for the informed consent discussions with the patient and the parents.