Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD.

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.

Efficacy of BNT162b2 and CoronaVac in patients diagnosed with COVID-19.

This retrospective observational study is aimed to determine the efficacy of BNT162b2 (Pfizer-BioNTech) and CoronaVac (Sinovac) vaccines against symptomatic or severe disease in COVID-19-diagnosed patients. The secondary aim was to define the differences between vaccinated and un-vaccinated patients in terms of age, comorbidities and course of the disease, and to determine the survival rates. Of the 1463 PCR-positive patients, 55.3 % were vaccinated, and 44.7 % were unvaccinated. While 959 patients had mild-moderate symptoms, 504 patients had severe-critical symptoms and were treated in the intensive care unit. There was a statistically significant difference in the distribution of the type and doses of vaccines between the patient groups (p = 0.021). The rate of receiving 2 doses of Biontech was 18.9 % in the mild-moderate patient group but lower in the severe patient group (12.6 %). The rate of two doses of Sinovac and two doses of Biontech vaccine (four doses of vaccine) was 5 % in the mild-moderate patient group and 1.9 % in the severe patient group. The mortality rates were statistically significantly different (p < 0.001) between the patient groups: 65.3 % in the severe patient group and 1 % in the mild-moderate patient group. The multivariate model showed that the mortality risk of the unvaccinated patients was 1.5 times higher than the vaccinated ones (p = 0.042). In addition to being unvaccinated, advanced age, coronary artery disease (CAD), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and obesity were found to be associated with higher mortality risk. Besides, the reduction in mortality rate was more evident in individuals vaccinated with at least 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine than in CoronaVac group.

Expanding the phenotypic landscape of Gaucher disease type 3c with a novel entity - Transient neonatal cholestasis.

Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions.

Targeting the liver to treat the eye.

Over the last two decades, gene therapy has given hope of potential cure for many rare diseases. In the simplest form, gene therapy is the transfer or editing of a genetic material to cure a disease via nonviral or viral vehicles. Gene therapy can be performed either in vivo by injecting a vector carrying the gene or tools for gene editing directly into a tissue or into the systemic circulation, or ex vivo when patient cells are genetically modified outside of the body and then introduced back into the patient (Yilmaz et al, 2022). Adeno-associated viral vectors (AAV) have been the vectors of choice for in vivo gene therapy. There has been a lot of promising research on the development of novel tissue and cell-specific serotypes in order to improve efficacy and safety for clinical applications (Kuzmin et al, 2021). In this issue of EMBO Molecular Medicine, Boffa and colleagues present a novel AAV-based liver-directed gene therapy for ornithine aminotransferase deficiency.

[Evaluation of the Effects of Tocilizumab Use on Oxygen Parameters, Inflammatory Markers and Survival in Patients Diagnosed with COVID-19 in Intensive Care Unit]. / Yogun Bakimda COVID-19 Tanili Hastalarda Tosilizumab Kullaniminin Oksijen Parametreleri, Enflamatuvar Belirteçler ve Sagkalim Üzerine Etkilerinin Degerlendirilmesi.

Inflammation plays a key role in the progression of COVID-19 infection from acute viral disease to organ failure and death. Tocilizumab maintains its current place as a frequently preferred agent in hyperinflammatory syndrome in COVID-19 infection. This study was aimed to evaluate changes in oxygen parameters and inflammatory markers before and after treatment, to define survival rates and complications in the patients who have been followed up in the tertiary intensive care unit of our hospital with the diagnosis of COVID-19 and who have been administered tocilizumab for hyperinflammatory syndrome in the follow-up. This study was planned as a retrospective observational study. A total of 132 patients were included in the study. The patient's data; age, comorbidities, sequential organ failure assessment (SOFA) and acute physiologic assessment and chronic health evaluation II (APACHE II) scores, duration of stay on a mechanical ventilator, duration of stay in the intensive care unit, positivity of real-time polymerase chain reaction (Rt-PCR), the presence of lung tomography findings specific to SARS-CoV-2 pneumonia, survival data, laboratory parameters, lactate mmol/L, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PCO2), oxygen saturation % (SpO2) and partial pressure of oxygen/inspired oxygen (PaO2/FiO2) values on hospitalization date, tocilizumab administration date and post-administration days one, three, five, and seven; treatments administered and drug complications were recorded. IBM SPSS Version 25.0 statistical package program was used for statistical analysis. Of the 132 patients, 36 were female and 96 were male (p= 0.972). The mean age was 61.9 ± 1.07 years, the mean APACHE 2 score ± standard deviation (SD) was 14.89 ± 5.22 and mortality was 41.7%. The mean duration on a mechanical ventilator was 9.54 ± 15.63 days and the mean length of stay in the intensive care unit was 20.50 ± 15.48 days. A statistically significant difference was found between the PaO2, SpO2, and the PaO2/FiO2 values on the day of hospitalization and days one, three, five, and seven after tocilizumab administration, and also between the day of tocilizumab administration and days following the administration (p<0.001). There was a significant decrease in ferritin, D-dimer, and C-reactive protein levels, and a significant increase in the lymphocyte count (p<0.05). Elevated transaminases (n= 36), acute renal injury (n= 25), atrial fibrillation (n= 10), pneumothorax (n= 10), and pneumomediastinum (n= 6) were the most common complications during the disease. In our study, a significant improvement was observed in inflammatory parameters and oxygen parameters from the first day after tocilizumab administration. In the first seven days patient mortality was zero with improvement in the P/F ratios. These data supported the opinion that tocilizumab might be an effective treatment option for COVID-19 infection. In addition to the potential benefits of tocilizumab in critical COVID-19 patients, it is essential that the side effects related to the use of the drug be closely monitored, and early identification of and intervention in thromboembolic events increases survival.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

[Investigation of Factors Affecting Viral Clearance Time by Real-Time Polymerase Chain Reaction Method in Nasopharyngeal Swab Samples of COVID-19 Patients]. / COVID-19 Hastalarinin Nazofarengeal Sürüntü Örneklerinde Gerçek Zamanli Polimeraz Zincir Reaksiyonu ile Yöntemiyle Viral Klirens Süresine Etki Eden Faktörlerin Arastirilmasi.

The coronavirus disease-2019 (COVID-19) pandemic continues to threaten the lives of millions of people. Viral shedding through the respiratory tract is the main risk factor for the transmission of the severe acute respiratory syndrome-2 (SARS-CoV-2) virus from sick individuals to healthy individuals. In this study, we aimed to investigate the viral clearance (VC) time in PCR tests of COVID-19 patients and the possible factors affecting this time. Seventy patients older than 18 years of age whose presence of SARS-CoV-2 virus was proven by real-time polymerase chain reaction (Rt-PCR) in nasopharyngeal swab samples were included in the study. The presence of SARS-CoV-2 RNA was investigated by RT-PCR in nasopharyngeal swab samples at 48-72 hour intervals, five days after the initial diagnosis. Demographic , physical examination, laboratory test, computed tomography (CT) results, concomitant diseases, and duration of VC were recorded. Of the cases, 41 were female and 29 were male. The mean age was 45.8 ± 19.2 years. According to the CT results, in the group with no involvement, local involvement and widespread involvement, the duration of VC was 9.66 ± 5.91 days, 9.99 ± 4.68 days, and 10.94 ± 5.34 days, respectively (p> 0.05). While the duration of VC was determined as 8.93 ± 4.33 days in the group without comorbidity, this period was found to be 12.26 ± 5.69 days (p= 0.025) in the group with the comorbidity. It was determined that the duration of VC was 9.55 ± 6.37 days in women and 9.20 ± 7.22 days in men (p= 0.040). The duration of VC was found to be 10.18 ± 7.1 days in patients over 50 years of age and 8.87 ± 5.15 days under 50 years of age (p= 0.03). A significant correlation was found between the laboratory test lactate dehydrogenase level and VC duration (p= 0.007). However, a significant relationship could not be established between other laboratory test results and the duration of VC. In this retrospective observational study, the relationship between viral clearance duration in Rt-PCR and gender, age, CT results, comorbidities and laboratory results in nasopharyngeal swab samples was investigated and it was determined that the duration of VC was significantly prolonged in case of female gender, being over 50 years old and having a comorbid disease. The results obtained may contribute to predict the isolation times of the patients and to reveal the factors that may affect viral shedding.

Evaluation of bone health in patients with mucopolysaccharidosis.

INTRODUCTION: This study aimed to evaluate the relationship between clinical findings, height and weight standard deviation scores, 25-hydroxyvitamin D3 (25(OH)D3) level, and dual-energy X-ray absorptiometry (DXA) results in patients diagnosed with mucopolysaccharidosis (MPS), where effective current treatments such as enzyme replacement therapy (ERT) can be accessed. MATERIALS AND METHODS: 25(OH)D3 level was measured in 126 patients with MPS (17 with MPS I, 14 with MPS II, 18 with MPS III, 33 with MPS IVA, and 44 with MPS VI; 24-524 months). DXA was performed in 45 of these patients (8 with MPS I, 4 with MPS II, 4 with MPS III, 12 with MPS IVA, and 17 with MPS VI; 62-197 months; all patients were under 18 when DXA was performed) to assess bone mineral density (BMD) of the lumbar spine. RESULTS: In total, 67.5% patients had a short stature, and 50% of them were underweight for their age. Of the patients, 13.5% were immobile, 28.6% had 25(OH)D3 deficiency, and 30.2% had an insufficient level of 25(OH)D3. BMD z score of 45 patients was - 2.5 ± 1.7. In 40% patients, it was < - 2. However, after correction for height-for-age z score (HAZ), HAZ-adjusted BMD z score was - 0.1 ± 0.9. In 2.2% patients, it was < - 2. CONCLUSION: The low BMD z score prevalence reported with DXA was misleadingly higher in children with MPS and short stature. To prevent exposure to unnecessary antiresorptive treatments in these children, the effect of severe short stature and bone geometry on DXA measurements should be considered; further studies on bone health are warranted.

Niemann-Pick type C disease with a novel intronic mutation: three Turkish cases from the same family.

OBJECTIVES: Niemann-Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. CASE PRESENTATION: Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. CONCLUSIONS: When combined with the filipin staining and the patients' clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.

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.

The outcome of 41 Late-Diagnosed Turkish GA-1 Patients: A Candidate for the Turkish NBS.

BACKGROUND: Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. METHOD: This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. RESULTS: The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. CONCLUSION: All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Background/aim: Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut­ enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods: The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations. Results: While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion: We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.

Novel therapies for mucopolysaccharidosis type III.

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease.

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0-24) and 7.5 (0-24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

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.

Clinical features of 27 Turkish Propionic acidemia patients with 12 novel mutations.

Kör D, Seker-Yilmaz B, Bulut FD, Kilavuz S, Öktem M, Ceylaner S, Yildizdas D, Önenli-Mungan N. Clinical features of 27 Turkish Propionic acidemia patients with 12 novel mutations. Turk J Pediatr 2019; 61: 330-336. Propionic acidemia (PA) is an inherited metabolic disease caused by the deficiency of one of the four biotin-dependent enzymes propionyl-CoA carboxylase (PCC), and is characterized by coma and death in unrecognized patients, additionally late diagnosis leads to severe developmental delay and neurological sequels. Manifestations of PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. Mutations in PCCA-PCCB genes cause the clinically heterogeneous disease of PA. In this study, we investigate the mutation spectrum of PCCAPCCB genes and phenotypic features of 27 Turkish patients with PA from the South and Southeast parts of Turkey. We report 12 novel PA mutations, five affecting the PCCA gene and 7 affecting the PCCB gene.