Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

Prolonged respiratory failure responds to conventional therapy in isolated homocysteine remethylation defects.

Isolated remethylation defects are rare inherited diseases caused by a defective remethylation of homocysteine to methionine, preventing various essential methylation reactions to occur. Patients present with a systemic phenotype, which can especially affect the central and peripheral nervous systems leading to epileptic encephalopathy, developmental delay and peripheral neuropathy. Respiratory failure has been described in some cases, caused by both central and peripheral neurological involvement. In published cases, the genetic diagnosis and initiation of appropriate therapy were rapidly performed following respiratory failure and led to a rapid recovery of respiratory insufficiency within days. Here, we present two infantile-onset cases of isolated remethylation defects, cobalamine (Cbl)G and methylenetetrahydrofolate reductase (MTHFR) deficiencies, which were diagnosed after several months of respiratory failure. Disease modifying therapy based on hydroxocobalamin and betaine was initiated and shows a progressive improvement and enabled weaning off respiratory support after 21 and 17 months in CblG and MTHFR patients respectively. We show that prolonged respiratory failure responds to conventional therapy in isolated remethylation defects, but can require a sustained period of time before observing a full response to therapy.

Safety and efficacy of an engineered hepatotropic AAV gene therapy for ornithine transcarbamylase deficiency in cynomolgus monkeys.

X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD.

Brown Vialetto Van Laere syndrome: presenting with left ventricular non-compaction and mimicking mitochondrial disorders.

BACKGROUND: Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare, treatable neurodegenerative disorder with a variable clinical presentation, caused by mutations in three different riboflavin transporter genes. CASE: An 11-year-old-boy presented with respiratory insufficiency and a rapidly progressive muscle weakness. He was the fifth child of a consanguineous marriage with a medical history of hearing loss. He was peripherally week with a reduced muscle tone. Upper extremity muscles were effected more than lower limbs. He deteriorated rapidly and became quadriplegic. Brain magnetic resonance imaging and magnetic resonance spectroscopy were normal. Echocardiography revealed left ventricular non-compaction. A homozygous c.1088C > T (p.363L) missense mutation was identified in SLC52A2 gene. Significant clinical improvement was seen with high dose riboflavin. CONCLUSION: This is the first reported BVVLS case presented with left ventricle-non compaction which may be caused by a secondary respiratory chain deficiency. Riboflavin transporter deficiencies should be considered in the differential diagnosis of mitochondrial disorders and secondary respiratory chain deficiencies should be thought during the follow-up of BVVLS.

Gene therapy for inherited metabolic diseases.

Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a disease-changing therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best.

Improved metabolic control in tetrahydrobiopterin (BH4), responsive phenylketonuria with sapropterin administered in two divided doses vs. a single daily dose.

BACKGROUND: Phenylketonuria (PKU) often requires a lifelong phenylalanine (Phe)-restricted diet. Introduction of 6R-tetrahydrobiopterin (BH4) has made a huge difference in the diets of patients with PKU. BH4 is the co-factor of the enzyme phenylalanine hydroxylase (PAH) and improves PAH activity and, thus, Phe tolerance in the diet. A limited number of published studies suggest a pharmacodynamic profile of BH4 more suitable to be administered in divided daily doses. METHODS: After a 72-h BH4 loading test, sapropterin was initiated in 50 responsive patients. This case-control study was conducted by administering the same daily dose of sapropterin in group 1 (n=24) as a customary single dose or in two divided doses in group 2 (n=26) over 1 year. RESULTS: Mean daily consumption of Phe increased significantly after the first year of BH4 treatment in group 2 compared to group 1 (p<0.05). At the end of the first year of treatment with BH4, another dramatic difference observed between the two groups was the ability to transition to a Phe-free diet. Eight patients from group 2 and two from group 1 could quit dietary restriction. CONCLUSIONS: When given in two divided daily doses, BH4 was more efficacious than a single daily dose in increasing daily Phe consumption, Phe tolerance and the ability to transition to a Phe-unrestricted diet at the end of the first year of treatment.

An ignored cause of red urine in children: rhabdomyolysis due to carnitine palmitoyltransferase II (CPT-II) deficiency.

Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessively inherited disorder involving the ß-oxidation of long-chain fatty acids, which leads to rhabdomyolysis and subsequent acute renal failure. The clinical phenotype varies from a severe infantile form to a milder muscle form. Here, we report a 9-year-old boy referred to our hospital for the investigation of hematuria with a 2-day history of dark urine and malaise. As no erythrocytes in the microscopic examination of the urine and hemoglobinuria were present, myoglobinuria due to rhabdomyolysis was the most probable cause of dark urine. After excluding the other causes of rhabdomyolysis, with the help of metabolic investigations, the patient was suspected to have CPT-II deficiency, the most common cause of metabolic rhabdomyolysis. Our aim in presenting this case is to emphasize considering rhabdomyolysis in the differential diagnosis of dark urine in order to prevent recurrent rhabdomyolysis and renal injury.

Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B.

The autosomal co-dominant disorder familial hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, very low and low density lipoproteins. We describe an 11month-old child with failure to thrive, intestinal lipid malabsorption, hepatic steatosis and severe hypobetalipoproteinemia, suggesting the diagnosis of homozygous FHBL, abetalipoproteinemia (ABL) or chylomicron retention disease (CMRD). The analysis of candidate genes showed that patient was homozygous for a variant (c.1594 C>T) in the APOB gene causing arginine to tryptophan conversion at position 505 of mature apoB (Arg505Trp). No mutations were found in a panel of other potential candidate genes for hypobetalipoproteinemia. In vitro studies showed a reduced secretion of mutant apoB-48 with respect to the wild-type apoB-48 in transfected McA-RH7777 cells. The Arg505Trp substitution is located in the ßα1 domain of apoB involved in the lipidation of apoB mediated by microsomal triglyceride transfer protein (MTP), the first step in VLDL and chylomicron formation. The patient's condition improved in response to a low fat diet supplemented with fat-soluble vitamins. Homozygosity for a rare missense mutation in the ßα1 domain of apoB may be the cause of both severe hypobetalipoproteinemia and intestinal lipid malabsorption.

Primary systemic carnitine deficiency: a Turkish case with a novel homozygous SLC22A5 mutation and 14 years follow-up.

Systemic primary carnitine deficiency is an autosomal recessive disorder caused by the deficiency of carnitine transporter. Main features are cardiomyopathy, myopathy and hypoglycemic encephalopathy. We report a Turkish case with a novel SLC22A5 gene mutation presented with a pure cardiac phenotype. During the 14-year follow-up study, cardiac functions were remained within a normal range with oral L-carnitine supplementation.

An asymptomatic mother diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency after newborn screening.

BACKGROUND: 3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an autosomal recessively inherited disease of leucine catabolism. It is the most commonly observed organic acidemia where tandem mass spectrometry can be performed in newborn screening. The clinical phenotypes may differ from neurological involvement in newborns to asymptomatic adults. Diagnosis is made by increased 3-hydroxyisovaleric acid in blood and 3-methylcrotonylglycine in urine. CASE REPORT: We would like to present an interesting case of a 32-year-old asymptomatic mother, who was investigated metabolically and diagnosed with 3-MCC deficiency, after a 7-day-old healthy baby referred to our unit with the preliminary diagnosis of organic academia during her extended newborn screening. RESULTS: All of the metabolic findings of the baby were normal except for very low carnitine levels. Her mother's total and free carnitine levels were also extremely low. Urine organic acid analysis revealed excessively increased 3-methylcrotonylglycine and 3-hydroxyisovaleric acid. Acylcarnitine profile showed markedly elevated C5 hydroxy 3 hydroxyisovalerylcarnitine and decreased C2 acetylcarnitine. In order to confirm the diagnosis of 3-methylcrotonylglycinuria, molecular analysis was done, and IVS3-1G>C/p.T556I compound heterozygote mutation was detected. p.T556I is a novel mutation. CONCLUSION: We would like to emphasize performing extended metabolic investigations in case of suspicion of metabolic disease in order to diagnose metabolic diseases both in babies and in asymptomatic mothers.

Two novel missense mutations in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (OMIM no. 605899) is an autosomal recessively inherited glycine encephalopathy, caused by a deficiency in the mitochondrial glycine cleavage system. Here we report 2 neonates who were admitted to the hospital with complaints of respiratory failure and myoclonic seizures with an elevated cerebrospinal fluid/plasma glycine ratio and diagnosed as nonketotic hyperglycinemia. We report these cases as 2 novel homozygous mutations; a missense mutation c.593A>T (p.D198 V) in the glycine decarboxylase gene and a splicing mutation c.339G>A (Q113Q) in the aminomethyltransferase gene were detected. We would like to emphasize the genetic difference of our region in inherited metabolic diseases once again.

Symptomatic and asymptomatic candidiasis in a pediatric intensive care unit.

INTRODUCTION: This study aimed to examine the incidence, epidemiology, and clinical characteristics of symptomatic and asymptomatic candidiasis in a pediatric intensive care unit (PICU), and to determine the risk factors associated with symptomatic candidiasis. METHODS: This retrospective study included 67 patients from a 7-bed PICU in a tertiary care hospital that had Candida-positive cultures between April 2007 and July 2009. Demographic and clinical characteristics of the patients, Candida isolates, antimicrobial and antifungal treatments, and previously identified risk factors for symptomatic candidiasis were recorded, and symptomatic and asymptomatic patients were compared. RESULTS: In all, 36 (53.7%) of the patients with Candida-positive cultures had asymptomatic candidiasis and 31 (46.3%) had symptomatic candidiasis. Candida albicans was the most common Candida sp. in the asymptomatic patients (n = 20, 55.6%), versus Candida parapsilosis in the symptomatic patients (n = 15, 48.4%). The incidence of central venous catheter indwelling, blood transfusion, parenteral nutrition, and surgery was higher in the symptomatic patient group than in the asymptomatic patient group (P < 0.5). Surgery was the only independent predictor of symptomatic candidiasis according to forward stepwise multivariate logistic regression analysis (OR: 6.1; 95% CI: 1.798-20.692). CONCLUSION: Surgery was the only risk factor significantly associated with symptomatic candidiasis and non-albicans Candida species were more common among the patients with symptomatic candidiasis. While treating symptomatic candidiasis in any PICU an increase in the incidence of non-albicans candidiasis should be considered.