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

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

Wilson and Jungner Revisited: Are Screening Criteria Fit for the 21st Century?

Driven by technological innovations, newborn screening (NBS) panels have been expanded and the development of genomic NBS pilot programs is rapidly progressing. Decisions on disease selection for NBS are still based on the Wilson and Jungner (WJ) criteria published in 1968. Despite this uniform reference, interpretation of the WJ criteria and actual disease selection for NBS programs are highly variable. A systematic literature search [PubMED search “Wilson” AND “Jungner”; last search 16.07.22] was performed to evaluate the applicability of the WJ criteria for current and future NBS programs and the need for adaptation. By at least two reviewers, 105 publications (systematic literature search, N = 77; manual search, N = 28) were screened for relevant content and, finally, 38 publications were evaluated. Limited by the study design of qualitative text analysis, no statistical evaluation was performed, but a structured collection of reported aspects of criticism and proposed improvements was instead collated. This revealed a set of general limitations of the WJ criteria, such as imprecise terminology, lack of measurability and objectivity, missing pediatric focus, and absent guidance on program management. Furthermore, it unraveled specific aspects of criticism on clinical, diagnostic, therapeutic, and economical aspects. A major obstacle was found to be the incompletely understood natural history and phenotypic diversity of rare diseases prior to NBS implementation, resulting in uncertainty about case definition, risk stratification, and indications for treatment. This gap could be closed through the systematic collection and evaluation of real-world evidence on the quality, safety, and (cost-)effectiveness of NBS, as well as the long-term benefits experienced by screened individuals. An integrated NBS public health program that is designed to continuously learn would fulfil these requirements, and a multi-dimensional framework for future NBS programs integrating medical, ethical, legal, and societal perspectives is overdue

Die intrazerebrale Gentherapie des Aromatischen-L-Aminosäure-Decarboxylase-Mangels mit Eladocagene exuparvovec : Eine Stellungnahme der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Deutschen Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ)

Background The autosomal recessive defect of aromatic L‑amino acid decarboxylase (AADC) causes a severe combined deficiency of dopamine, serotonin and catecholamines. The clinical picture is characterized by truncal hypotonia, delayed or absent achievement of motor milestones, and oculogyric crises from infancy onwards. The response to conventional drug treatment is very limited, especially in severe cases. The intracerebral application of eladocagene exuparvovec, an AAV2-based gene therapy, which is expected to be approved in mid-2021, is the first available causal therapeutic approach. Aim In collaboration with the German Society of Neuropediatrics (GNP), the Working Group of Pediatric Metabolic Disorders (APS), the German Society of Neurosurgery (DGNC) and the German Society of Pediatrics and Adolescent Medicine (DGKJ), the structural requirements and practical aspects in the preparation, implementation and follow-up of the treatment with eladocagene exuparvovec were elaborated. Discussion The present statement compiles the necessary framework conditions for a quality-assured administration of eladocagene exuparvovec. The treatment requires prehospital, inpatient and posthospital care by a multiprofessional team in a specialized and qualified treatment center. Patient follow-up is intended to contribute to knowledge-generating care. Due to lack of data on the therapeutic (long-term) effect as well as on advantages and disadvantages of the different stereotactic approaches, a structured follow-up plan and documentation in an appropriate, industry-independent registry are necessary.Hintergrund Der autosomal-rezessiv vererbte Defekt der aromatischen L‑Aminosäure-Decarboxylase (AADC) führt zu einem ausgeprägten, kombinierten Mangel an Dopamin, Serotonin und Katecholaminen. Das klinische Bild ist charakterisiert durch eine rumpfbetonte, muskuläre Hypotonie, verzögertes oder fehlendes Erreichen der motorischen Meilensteine und okulogyre Krisen ab dem Säuglingsalter. Der Erfolg der konventionellen, medikamentösen Behandlung ist besonders bei schweren Verläufen sehr limitiert. Mit der intrazerebralen Applikation von Eladocagene exuparvovec (Upstaza®), einer AAV2-basierten Gentherapie, deren Zulassung für Mitte 2021 erwartet wird, steht erstmals ein kausaler Therapieansatz zur Verfügung. Ziel In Zusammenarbeit mit der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ) wurden die Strukturvoraussetzungen und die praktischen Aspekte in der Vorbereitung, Durchführung und Nachsorge der Therapie mit Eladocagene exuparvovec erarbeitet. Diskussion Die vorliegende Stellungnahme stellt die notwendigen Rahmenbedingungen für eine qualitätsgesicherte Anwendung von Eladocagene exuparvovec zusammen. Die Behandlung erfordert eine prästationäre, stationäre und poststationäre Betreuung durch ein multiprofessionelles Team in einem spezialisierten und qualifizierten Therapiezentrum. Die Nachsorge der Patienten soll zu einer wissensgenerierenden Versorgung beitragen. Aufgrund von fehlenden Daten zur therapeutischen (Langzeit‑)Wirkung sowie zu Vor- und Nachteilen der verschiedenen stereotaktischen Prozeduren sind ein strukturierter Nachsorgeplan und die Erfassung in einem geeigneten, industrieunabhängigen Register notwendig

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke

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.Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg

Unmet Needs of Parents of Children with Urea Cycle Disorders

(1) Background: Phenotypic diversity and long-term health outcomes of individuals with urea cycle disorders (UCDs) have been described in detail. However, there is limited information on the burden on affected families. (2) Methods: To evaluate the family burden in parents with children suffering from UCDs, we used validated questionnaires. Socio-demographic characteristics were evaluated, and an adapted version of the Parental Need Scale for Rare Diseases questionnaire was used. The survey was conducted in families of UCD patients cared for at the University Children&rsquo;s Hospital Heidelberg. (3) Results: From April to November 2021, 59 participants were interviewed (mothers n = 34, fathers n = 25). The affected patients most frequently suffered from ornithine transcarbamylase deficiency (OTC-D) (female n = 12, male n = 12), followed by argininosuccinate synthetase deficiency (ASS-D, n = 13) and argininosuccinate lyase deficiency (ASL-D, n = 8). About one-third of the participants were &ldquo;dissatisfied&rdquo; or &ldquo;extremely dissatisfied&rdquo; with health professionals&rsquo; disease knowledge. In addition, 30% of the participants reported a medium or high need for &ldquo;additional information on the development of their children&rdquo;, and 44% reported a medium or high need &ldquo;for information on available services&rdquo;. A majority of 68% reported a need for additional support regarding services such as support groups (42%) or psychological counseling (29%). (4) Conclusions: Our study indicates that there is an unmet need for sufficient information about the development of children with UCDs, as well as for information about available support services for families with UCD patients. Furthermore, the results highlight the importance of establishing or improving family-centered care approaches. This pilot study may serve as a template for the assessment of the family burden associated with other inherited metabolic diseases

Compound heterozygosis in AADC deficiency: A complex phenotype dissected through comparison among heterodimeric and homodimeric AADC proteins

Compound heterozygosis is the most diffuse and hardly to tackle condition in aromatic amino acid decarboxylase(AADC) deficiency, a genetic disease leading to severe neurological impairment. Here, by using an appropriatevector, we succeeded in obtaining high yields of AADC protein and characterizing two new heterodimers,T69M/S147R and C281W/M362T, detected in two AADC deficiency patients. We performed an extensive bio-chemical characterization of the heterodimeric recombinant proteins and of the related homodimers, by a com-bination of dichroic andfluorescence spectroscopy and activity assays together with bioinformatic analyses. Wefound that T69M/S147R exhibits negative complementation in terms of activity but it is more stable than the av-erage of the homodimeric counterparts. The heterodimer C281W/M362T retains a nearly good catalytic effi-ciency, whereas M362T homodimer is less affected and C281W homodimer is recovered as insoluble. Theseresults, which are consistent with the related phenotypes, and the data emerging from previous studies, suggestthat the severity of AADC deficiency is not directly explained by positive or negative complementation phenom-ena, but rather depends on: i) the integrity of one or both active sites; ii) the structural and functional propertiesof the entire pool of AADC proteins expressed. Overall, this integrated and cross-sectional approach enablesproper characterization and depicts the functional result of subunit interactions in the dimeric structure andwill help to elucidate the physio-pathological mechanisms in AADC deficiency

Die intrazerebrale Gentherapie des Aromatischen-L-Aminosäure-Decarboxylase-Mangels mit Eladocagene exuparvovec

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Hintergrund&lt;/jats:title&gt; &lt;jats:p&gt;Der autosomal-rezessiv vererbte Defekt der aromatischen L‑Aminosäure-Decarboxylase (AADC) führt zu einem ausgeprägten, kombinierten Mangel an Dopamin, Serotonin und Katecholaminen. Das klinische Bild ist charakterisiert durch eine rumpfbetonte, muskuläre Hypotonie, verzögertes oder fehlendes Erreichen der motorischen Meilensteine und okulogyre Krisen ab dem Säuglingsalter. Der Erfolg der konventionellen, medikamentösen Behandlung ist besonders bei schweren Verläufen sehr limitiert. Mit der intrazerebralen Applikation von Eladocagene exuparvovec (Upstaza®), einer AAV2-basierten Gentherapie, deren Zulassung für Mitte 2021 erwartet wird, steht erstmals ein kausaler Therapieansatz zur Verfügung.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Ziel&lt;/jats:title&gt; &lt;jats:p&gt;In Zusammenarbeit mit der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ) wurden die Strukturvoraussetzungen und die praktischen Aspekte in der Vorbereitung, Durchführung und Nachsorge der Therapie mit Eladocagene exuparvovec erarbeitet.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Diskussion&lt;/jats:title&gt; &lt;jats:p&gt;Die vorliegende Stellungnahme stellt die notwendigen Rahmenbedingungen für eine qualitätsgesicherte Anwendung von Eladocagene exuparvovec zusammen. Die Behandlung erfordert eine prästationäre, stationäre und poststationäre Betreuung durch ein multiprofessionelles Team in einem spezialisierten und qualifizierten Therapiezentrum. Die Nachsorge der Patienten soll zu einer wissensgenerierenden Versorgung beitragen. Aufgrund von fehlenden Daten zur therapeutischen (Langzeit‑)Wirkung sowie zu Vor- und Nachteilen der verschiedenen stereotaktischen Prozeduren sind ein strukturierter Nachsorgeplan und die Erfassung in einem geeigneten, industrieunabhängigen Register notwendig.&lt;/jats:p&gt; &lt;/jats:sec&gt