The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.

Correction to: DNAJC12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8.

Recommendations on phenylketonuria in Turkey.

BACKGROUND: Phenylketonuria (PKU), is an autosomal recessive disease leading to the conversion defect of phenylalanine (Phe) into tyrosine. Severe neurocognitive and behavioral outcomes are observed in untreated cases. The present paper aims to review clinical experiences and expert recommendations in diagnosis, treatment, and follow-up of pediatric PKU patients in Turkey. METHODS: Two advisory board meetings were held in the year 2016 and 2017 with contributions of four leading experts in this field, and an online update meeting was held for final decisions about statements, and conclusions in January 2021. Considering management gaps in diagnosis, treatment, and follow-up of PKU, discussion points are defined. The Committee members then reviewed the Turkish and general literature and the final statements were formulated. RESULTS: The diagnostic cut-off for dried blood spots should remain at 2 mg/dl. Treatment cut-off value is acceptable at 6 mg/dl. Compliance with an ideal follow-up list is strongly recommended. Total protein intake should not be limited. Age-related safe levels of protein intake should be encouraged with an additional 40% from L-amino acids supplements, a 20% compensatory factor to account for the digestibility and utilization of amino acids from the supplement, and a further 20% compensation to optimize Phe control. Cognitive impairment and intelligence quotient evaluations should be performed at least twice before 3 years of age. In pregnant women, the target Phe level should be < 5 mg/dl, and they should be followed-up weekly in the first trimester, then every 2 weeks after organogenesis. Novel pharmacological treatments are promising, but some of them have limitations for our country. CONCLUSIONS: Early diagnosis and treatment initiation; determination and standardization of diagnostic and treatment thresholds; treatment modalities and follow-up parameters are significant steps in treating PKU in the long term. PKU follow-up is a dynamic process with uncertainties and differences in clinical practice.

Hyperinsulinism May Be Underreported in Hypoglycemic Patients with Phosphomannomutase 2 Deficiency

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.

Increased ocular wall thickness and decreased globe volume in children with mucopolysaccharidosis type VI.

PURPOSE lthough clinical ophthalmologic findings have been reported, no study documented magnetic resonance imaging (MRI) findings in mucopolysaccharidosis (MPS) type VI. The aim of this study was to determine the ophthalmologic imaging findings of MPS type VI in the pediatric age group retrospectively. METHODS Brain MRIs of 10 patients with MPS type VI and 49 healthy children were evaluated independently by two pediatric radiologists for the following characteristics: globe volume, ocular wall thickness, and optic nerve sheath diameter for each orbit. The means of the measurement of each group were compared by using an independent t-test. Agreement and bias between reviewers were assessed by intra-class correlation coefficients (ICC). RESULTS A total of 59 children [32 girls (54.23%), 27 boys (45.77%); age range, 4-16 years; mean age, 10.37 ± 3.73 years] were included in the study. Statistical analysis revealed smaller eyeballs and thicker ocular walls of patients with MPS type VI (P < .001 and P < .001, respectively). However, there was no statistically significant difference in terms of optic nerve sheath diameter between the two groups (P=.648). CONCLUSION Patients with MPS type VI displayed reduced globe volumes and increased ocular wall thicknesses compared to the healthy children. Therefore, we recommend that ophthalmologic imaging findings might prove to be an auxiliary tool in the diagnosis of MPS patients.

Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)

Home visits in phenylketonuria: a 12-month longitudinal study.

This study aimed to evaluate the effect of dietary education given to the caregivers of children with phenylketonuria (PKU) in their home environment on children's blood phenylalanine (Phe) levels. Thirty-six children with PKU, aged 2-12 years, were recruited. Each caregiver was visited on three separate occasions and given a detailed dietary education. Fasting morning skin puncture blood samples were collected on Newborn Screening Blood Test filter paper for Phe analysis at baseline and 1, 4, 12, 24, and 48 weeks after the home visits. The mean baseline blood Phe level (365 +/- 232 micromol/L) significantly decreased with home visits at the 1st week (314 +/- 226 micromol/L) (p < 0.05). Four weeks after the home visits, the median blood Phe level was still lower than baseline, but the difference was not statistically significant (p > 0.05). The mean blood Phe levels significantly increased at the end of the 12th, 24th and 48th weeks (329 +/- 230 micromol/L; 447 +/- 189 micromol/L and 486 +/- 261 micromol/L, respectively) (p < 0.05). A well-controlled blood Phe level can be achieved with intense, regular and continuing education programs, which include regular home visits.

Difficulties Associated with Enzyme Replacement Therapy for Mucopolysaccharidoses.

BACKGROUND: Mucopolysaccharidoses are extremely rare, progressive, often severe multisystem disorders, some of which are managed by weekly intravenous enzyme replacement therapy. This study aimed to determine the difficulties faced by the patients with mucopolysaccharidosis and their families due to enzyme replacement therapy. METHODS: A questionnaire about demographics, enzyme replacement therapy-related characteristics, and specific enzyme replacement therapy-related difficulties was conducted over the telephone with mucopolysaccharidosis patients (or their parents) followed at a referral center in Turkey, who have been on enzyme replacement therapy for ≥12 months. The responses were analyzed with chi-square, Mann-Whitney U, Kruskal-Wallis tests, Spearman's rank correlation, and binary logistic regression. RESULTS: A total of 54 patients (median age: 13 years) participated, who had been receiving enzyme replacemnt therapy for a median of 5.02 years, 83.3% of whom had mucopolysaccharidosis- IVA or -VI. About 72.2% went to school or work, 64.1% of whom missed a full day every week due to enzyme replacement therapy. About 63% missed at least 1 dose in the past 6 months, mostly due to not being able to obtain doses or having intercurrent infections. Significantly more enzyme replacement therapy doses were missed or unobtained in Central (non-Ankara) and Eastern Anatolia, but enzyme replacement therapy-related disruption to family life was more severe in families living in Ankara. CONCLUSIONS: We provide the first Turkish data about mucopolysaccharidosis patients' subjective enzyme replacement therapy experience, which is influenced by actionable inequalities and hurdles, partially related to geographical factors. Access to the drugs can be facilitated, and the clash of enzyme replacement therapy infusions with school and work should be avoided. Multi-center studies using more objective data sources are needed.

Complicated peripartum course in a patient with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency.

Very long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency is an autosomal recessive fatty acid oxidation disorder characterized by rhabdomyolysis, hypoglycemia and cardiomyopathy. The general treatment approach in adult patients is based on the prevention of catabolism. High carbohydrate, low fat diet and supplementation of medium-chain triglycerides are essential in the treatment. There is little experience with pregnancy follow-up in this patient group. We present a complicated peripartum course and successful management in a patient with VLCAD deficiency. Although high-dose glucose infusion was initiated, creatine kinase levels significantly increased in the immediate postpartum period, but the patient remained asymptomatic and rhabdomyolysis resolved rapidly after increasing the glucose infusion rate.

COVID-19-related anxiety in phenylketonuria patients.

BACKGROUND: Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism, the treatment of which often requires a special diet to prevent adverse neuropsychiatric outcomes. In the COVID-19 pandemic, which has had a substantial effect on the whole world since the beginning of 2020, PKU patients represent a vulnerable population because they may be dependent on special nutritional products, have limited access to routine care and display increased levels of anxiety. METHODS: For this reason, an online questionnaire assessing the anxiety levels and various personal opinions and practices regarding the pandemic was sent to the PKU patients managed at our clinic, who were 12 years of age or older. Ninety-eight patients responded to the questionnaire. Median age of the participants was 19 years. RESULTS: Most patients were compliant with the hygiene and social distancing recommendations regarding the spread of COVID-19. Of the patients, 61.2% felt more anxious since the pandemic. The most common concern was the possibility of not being able to obtain special nutritional products (58.2%). Anxiety level was significantly higher in females. CONCLUSIONS: These data suggest that food security is an important issue of concern in PKU patients. In line with the changing world after the pandemic, different strategies should be considered in the management of patients with inborn errors of metabolism, including PKU.

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials.

INTRODUCTION: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. MATERIALS AND METHODS: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 µmol/L, 600-1200 µmol/L, and >1200 µmol/L). RESULTS: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. CONCLUSION: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.

INTRODUCTION: Glutaric aciduria type 1 (GA1) is a rare and inherited autosomal-recessive metabolic disorder that occurs in the deficiency of glutaryl-co-enzyme A dehydrogenase (GCDH) enzyme encoded by GCDH gene. In this study, we aim to retrospectively investigate the clinical, biochemical, and neuroradiological parameters and examine the spectrum of GCDH gene variants in Turkish patients with glutaric aciduria type 1. METHODS: This is a descriptive cross-sectional study. The study was conducted in fifty-three patients from 39 unrelated Turkish families who were diagnosed with GA1 based on their clinical presentation, neuroimaging, and biochemical measurements, at the department of pediatric metabolism of a university hospital between June 1998 and August 2019. Pathogenic variants screening of GCDH gene was performed by direct DNA sequence analysis in forty-six patients with GA1. Pathogenicity of the novel variants was predicted via computational programs. RESULTS: A total of 53 patients were diagnosed with GA1. Of those, 32 (60.3%) had encephalopathic crisis and 33 (62.3%) had macrocephaly. Twenty different pathogenic variants were detected, 7 of which are novel (p.Glu57Lys, p.Ser145Profs*79, p.Ser246Glyfs*96 p.Ala293Val, p.His348Gln, p.His417Tyr, p.Asp418Val). The p.Arg402Trp, p.Pro248Leu and p.Leu340Phe variants were the most common in Turkish patients, with a frequency of 21.2%, 18.2% and 12.1% respectively. CONCLUSION: This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the GCDH gene. The identification of common variants and hot spot regions of the GCDH gene is important for genetic counselling and the prenatal diagnosis of Turkish patients with GA1.

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies.

BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients.

Correction to: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies.

An amendment to this paper has been published and can be accessed via the original article.

Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency.

The pyruvate dehydrogenase (PDH) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. We report four novel PDHA1 mutations in patients with pyruvate dehydrogenase deficiency. Analysis of PDH activity showed decreased activity in fibroblasts from all four patients, around 16-52% of mean control, similar to what has been found in previous studies. Two of the mutations were missense mutations: c.616G>A (p.Glu206Lys) and c.457A>G (p.Met153Val), one was a 3 bp in-frame deletion: c.429_431delAGG (p.Gly143del), and one was a 65 bp duplication: c.900-6_958dup65. cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication. The small amount of normal transcript likely explains the survival of the patient, who was a boy. The duplication and one of the missense mutations were associated with decreased amounts of E(1)α And E(1)ß protein on western blot analysis, whereas the other two mutations were associated with normal amounts. This study adds four novel mutations to the around 90 reported mutations in PDHA1 (HGMD PDHA1 mutation database). The phenotypes of patients with PDH deficiency have been divided into three groups: a neonatal form with severe lactic acidosis, a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia, and an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor retardation, in some cases Leigh-like lesions and mild to moderate hyperlactataemia. The four patients reported here all belong to the latter group, which is the largest.