Explore the vast range of titles available.

Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids (“organic acids”) and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be “metabolically stable”. This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.

Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase-dependent (NOS-dependent) NO synthesis. Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. ASL deficiency (ASLD) is thus a model to study cell-autonomous, NOS-dependent NO deficiency. Here, we report that loss of ASL led to decreased NO production and impairment of osteoblast differentiation. Mechanistically, the bone phenotype was at least in part driven by the loss of NO-mediated activation of the glycolysis pathway in osteoblasts that led to decreased osteoblast differentiation and function. Heterozygous deletion of caveolin 1, a negative regulator of NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass in a hypomorphic mouse model of ASLD. The translational significance of these preclinical studies was further reiterated by studies conducted in induced pluripotent stem cells from an individual with ASLD. Taken together, our findings suggest that ASLD is a unique genetic model for studying NO-dependent osteoblast function and that the NO/glycolysis pathway may be a new target to modulate bone anabolism.

Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases. Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.

Objectives This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs. Methods Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping. Results Fifty-six patients were defined as early-onset ( n  = 23) if symptomatic < 28 days of age, late-onset ( n  = 23) if symptomatic later, or selectively screened perinatally due to a familial proband ( n  = 10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced ( n  = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients. Conclusions Our study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

A 39-year-old male was referred for treatment of hypertension. He had been treated for argininosuccinic aciduria since 8 months of age. Therapeutic drugs, including l-arginine, sodium phenylbutyrate, and antiepileptic drugs, had been prescribed. A detailed medical history revealed that he complained of chest discomfort under psychologic stress. A 12-lead electrocardiogram showed abnormal q waves in lead III and aVF. Transthoracic echocardiography showed hypokinesia of the left ventricular posterior wall. The patient was diagnosed with myocardial infarction because of coronary vasospastic angina by intracoronary acetylcholine provocation test. Argininosuccinic aciduria is a genetic disorder of the urea cycle caused by a deficiency of argininosuccinate lyase. Reduction of the enzymatic activity leads to a decrease in nitric oxide production, even if arginine is supplemented. Our case report supports the significance of endothelial function in the pathogenesis of coronary vasospasm.

Glutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid due to a defect in the glutaryl-CoA dehydrogenase enzyme involved in the catabolic pathways of l-lysine, l-hydroxylysine, and l-tryptophan. Glutaryl-CoA dehydrogenase is encoded by the GCDH gene (OMIM #608801), and several mutations in this gene are known to result in GA1. GA1 usually presents in the first 18–36 months of life with mild or severe acute encephalopathy, movement disorders, and striatal degeneration. Few cases of adult-onset GA1 have been described so far in the literature, often with non-specific and sometimes longstanding neurological symptoms. Since a preventive metabolic treatment is available, neurologists must be aware of this rare but likely underdiagnosed presentation, especially when typical neuroimaging features are identified. Here, we describe 35-year-old presenting with headache and subjective memory problems. There was no history of dystonic movement disorders. Neurological examination and neurocognitive tests were normal. Brain MRI scan revealed white matter abnormalities associated with subependymal nodules and mild frontotemporal hypoplasia suggestive of glutaric aciduria type 1 (GA1). Genetic testing confirmed the presence of homozygous c.1204C > T (p.R402W) variant in the GCDH gene, inherited from heterozygous parents.

Background The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. Aims/methods To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. Results We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). Conclusions The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

Background The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. Aims To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. Results Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QT c interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut 0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. Conclusions Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01–11, EudraCT-No. 2012–002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100-000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B 12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.