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

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders

INTRODUCTION: Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. METHODS AND RESULTS: The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. CONCLUSION: The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches

Succinic semialdehyde dehydrogenase deficiency: in vitro and in silico characterization of a novel pathogenic missense variant and analysis of the mutational spectrum of ALDH5A1

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter \u3b3-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including \u3b3-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T &gt; C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary

The effect of temperature on angiogenesis in chicken embryos

Anjiyogenez embriyonik dönemde yeni damarların oluşumunda önemli bir rol oynar. Bu çalışmanın amacı, Koryoallantoik Membran (KAM) modeli kullanılarak 37.50C ve 39.00C olacak şekilde iki farklı kuluçka sıcaklığına maruz bırakılan tavuk embriyolarında anjiyogenez sürecindeki olası farklılıkları belirlemektir. Çalışmada her birinde 16’şar adet döllü tavuk yumurtasının analiz edildiği deney ve kontrol grubu olmak üzere iki grup yer aldı. Yumurtalar inkübasyonun 7. gününde penset ve cerrahi makas yardımıyla embriyoya zarar vermeden açıldı. Fotoğrafları çekilen embriyoların tepe-kıç ve occipitofrontal uzunlukları ile KAM’daki damar kalınlıkları, damar yoğunluğu ve damar dal sayıları ImageJ programı kullanılarak ölçüldü. Verilerin istatistiksel analizi SPSS programı aracılığıyla yapıldı. Sıcaklığa bağlı olarak 39.00C’de inkübe edilen yumurtalardan elde edilen embriyoların tepe-kıç uzunluklarının değerlerinde istatistiksel olarak anlamlı olmasa da bir azalma mevcuttu. Bununla birlikte occipito-frontal uzunluk değerlerinin arttığı, kafatasının daha büyük bir görünüme sahip olduğu ve bu artışın istatistiksel olarak anlamlı olduğu tespit edildi (p<0.05). 37.50C’de inkübe edilen yumurtalardan elde edilen embriyoların damar yoğunluğu ortalaması 1.58±0.57 iken, 39.00C’de inkübe edilen yumurtalardan elde edilen embriyoların ortalama damar yoğunluğu 1.46±0.61 olarak tespit edildi. Ortalama damar yoğunluğu değerleri arasında istatistiksel olarak gruplar arasında bir fark gözlenmedi (p>0.05). Her iki grubun karşılaştırılmasında artan sıcaklığa bağlı olarak damar dal sayısında bir azalma (37.50C’de 35.44±10.97, 39.00C’de 24.94±6.97) olduğu görüldü. Bu azalmanın istatistiksel olarak anlamlı olduğu tespit edildi (p<0.05). Genel anlamda sıcaklık artışının tavuk embriyolarında KAM’da damar yoğunluğu, kalınlığı ve dal sayısında bir azalmaya sebep olduğu gözlendi. Sonuç olarak embriyolarda büyüme ve gelişmenin olumsuz yönde etkilendiği belirlendi.Angiogenesis plays an important role in the formation of new vessels in the embryonic period. The aim of this study is to determine possible differences in angiogenesis process in chicken embryos exposed to two different incubation temperatures of 37.50C and 39.00C using Chorioallantoic Membrane (CAM) model. The study included two groups, each with an experimental and control group, in which 16 fertilized chicken eggs were analyzed. The eggs were opened on the 7th day of incubation with the aid of forceps and surgical scissors without damaging the embryo. Head-stern, occipito-frontal length, vessel thickness, density and number of each embryo on CAM were measured by ImageJ. Statistical analysis of the data was performed by SPSS program. Depending on the temperature, there was a decrease, although not statistically significant, in the values of head-stern lengths of the embryos obtained from the eggs incubated at 39.00C. However, it was determined that occipito-frontal length values increased, the skull had a larger appearance and this increase was statistically significant (p<0.05). The mean density of embryos obtained from eggs incubated at 37.50C was 1.58±0.57, while the mean vessel density of embryos obtained from eggs incubated at 39.00C was 1.46±0.61. There was no statistically difference between mean vessel density values (p>0.05). A comparison of both groups showed a decrease in the number of vascular branches (35.44±10.97 at 37.50C, 24.94±6.97 at 39.00C) due to the increasing temperature. This decrease was found to be statistically significant (p<0.05). In general, it was observed that the increase in temperature caused a decrease in vessel density, thickness and number of branches in chicken embryos on CAM. As a result, it was determined that growth and development were negatively affected in embryos

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

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

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic