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This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l ‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno‐associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l ‐DOPA into dopamine in Parkinson’s patients. Graphical Abstract This Commentary provides an overview of putamen‐targeted gene therapies for treating aromatic l ‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease.

Background Data on clinical manifestations of neurofibromatosis-Noonan syndrome (NF-NS) remain heterogeneous, with limited validated descriptions. Methods This study aims to better define the clinical and molecular features of NF-NS and compare them with existing literature. Secondary objectives include evaluating inter-rater diagnostic agreement among experienced clinicians and assessing the utility of deep-learning algorithms (Face2Gene ® [F2G]). Additionally, we assess the prevalence of congenital heart malformations (CHM) in NF-NS compared to ‘classic’ neurofibromatosis type 1 (NF1). A 9-year, prospective, monocentric study was conducted, involving patients with NF1 pathogenic variants (PVs) and Noonan syndrome-like facial phenotype (NSLFP). Results Twenty-six patients were enrolled. NSLFP was categorized as ‘suggestive’ in 69% of cases and ‘typical’ in 31%. The presence of at least two facial abnormalities (e.g., low-set ears, downslanted palpebral fissures, hypertelorism, and ptosis) was consistently observed in ‘typical’ cases. Inter-rater concordance was substantial (0.65 [95% CI = 0.56; 0.74]), while concordance between clinicians and F2G was almost perfect at (0.821 [CI 95% = 0.625; 1.000]). Missense NF1 PVs were observed in 38.5% of cases. Apart from NSLP and a high frequency of pectus excavatum (62.5%), no significant differences in anthropometric, dermatological, neurological, skeletal, or ocular clinical features were observed between NF-NS and ‘classic’ NF1. CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present in 7.7%. Conclusion NF-NS is a distinct phenotypic variant of NF1, marked by NSLP with consistent facial features -, and frequent pectus excavatum. F2G demonstrated high diagnostic concordance, reinforcing its clinical utility. Given the elevated risk of CHM, especially pulmonic stenosis, proactive cardiovascular assessment similar to other RASopathies is recommended for NS-NF patients, regardless of NF1 PV type.

Purpose Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. Methods We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Results We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. Conclusion A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.

Background Tenfold or more overdose of a drug or preparation is a dreadful adverse event in neonatology, often due to an error in programming the infusion pump flow rate. Lipid overdose is exceptional in this context and has never been reported during the administration of a composite intravenous lipid emulsion (ILE). Case presentation Twenty-four hours after birth, a 30 weeks’ gestation infant with a birthweight of 930 g inadvertently received 28 ml of a composite ILE over 4 h. The ILE contained 50% medium-chain triglycerides and 50% soybean oil, corresponding to 6 g/kg of lipids (25 mg/kg/min). The patient developed acute respiratory distress with echocardiographic markers of pulmonary hypertension and was treated with inhaled nitric oxide and high-frequency oscillatory ventilation. Serum triglyceride level peaked at 51.4 g/L, 17 h after the lipid overload. Triple-volume exchange transfusion was performed twice, decreasing the triglyceride concentration to < 10 g/L. The infant’s condition remained critical, with persistent bleeding and shock despite supportive treatment and peritoneal dialysis. Death occurred 69 h after the overdose in a context of refractory lactic acidosis. Conclusions Massive ILE overdose is life-threatening in the early neonatal period, particularly in premature and hypotrophic infants. This case highlights the vigilance required when ILEs are administered separately from other parenteral intakes. Exchange transfusion should be considered at the first signs of clinical or biological worsening to avoid progression to multiple organ failure.

Background Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality. Methods In response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment. Conclusion Suggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

IntroductionWolfram syndrome (WFS1-Spectrum Disorder) is an ultra-rare monogenic form of progressive neurodegeneration and diabetes mellitus. In common with most rare diseases, there are no therapies to slow or stop disease progression. Sodium valproate, an anticonvulsant with neuroprotective properties, is anticipated to mediate its effect via alteration of cell cycle kinetics, increases in p21cip1 expression levels and reduction in apoptosis and increase in Wolframin protein expression. To date, there have been no multicentre randomised controlled trials investigating the efficacy of treatments for neurodegeneration in patients with Wolfram syndrome.Methods and analysisTREATWOLFRAM is an international, multicentre, double-blind, placebo-controlled, randomised clinical trial designed to investigate whether 36-month treatment with up to 40 mg/kg/day of sodium valproate will slow the rate of loss of visual acuity as a biomarker for neurodegeneration in patients with Wolfram syndrome. Patients who satisfied the eligibility criteria were randomly assigned (2:1) to receive two times per day oral gastro-resistant sodium valproate tablets up to a maximum dose of 800 mg 12 hourly or sodium valproate-matched placebo. Using hierarchical repeated measures analyses with a 5% significance level, 80% power and accounting for an estimated 15% missing data rate, a sample size of 70 was set. The primary outcome measure, visual acuity, will be centrally reviewed and analysed on an intention-to-treat population.Ethics and disseminationThe protocol was approved by the National Research Ethics Service (West of Scotland; 18/WS/0020) and by the Medicines and Healthcare products Regulatory Agency. Recruitment into TREATWOLFRAM started in January 2019 and ended in November 2021. The treatment follow-up of TREATWOLFRAM participants is ongoing and due to finish in November 2024. Updates on trial progress are disseminated via Wolfram Syndrome UK quarterly newsletters and at family conferences for patient support groups. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.Trial registration numberNCT03717909.

We report four patients from two families who presented attacks of childhood‐onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14‐mutation‐related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14‐related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9.

GNAO1‐associated disorders have a large spectrum of neurological symptoms, from early‐onset developmental and epileptic encephalopathies (DEE) to late‐onset movement disorders. First reported in 2013 and now identified in around 400 cases worldwide, this disease is caused by dominant, mostly de novo missense mutations in GNAO1, the gene encoding the major neuronal G protein Gαo. Being the immediate transducer of a number of neuronal G protein‐coupled receptors, Gαo plays crucial functions in brain development and physiology. Here, we discover a novel mutation site in GNAO1, Cys225 mutated to Tyr or Arg in pediatric individuals from France and China (p.(Cys225Tyr) and p.(Cys225Arg), respectively), leading to severe early‐onset DEE. Molecular investigations characterize the novel pathogenic variants as deficient in the interactions with guanine nucleotides and physiological cellular partners of Gαo, with reduced stability and plasma membrane localization and a strong neomorphic interaction with the chaperone Ric8A. Salts of zinc, emerging as a promising targeted therapy for GNAO1‐associated disorders, impose a previously unseen effect on the mutant Gαo, accelerating the loss of its ability to interact with guanine nucleotides. Our study, combining clinical, cellular, molecular, and modeling approaches, describes deep insights into molecular etiology and treatment perspectives of the novel form of GNAO1‐associated disorders. The major neuronal G protein Gαo (structural model on the left) is mutated in position Cys225 to Tyr or Arg in a severe form of pediatric encephalopathy. These pathogenic variants produce the protein deficient in physiological cellular interactions, cellular stability, and plasma membrane localization.

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We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, failure to thrive. He progressively developed dystonia‐parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2‐WI hyperintensities and brain atrophy. Molecular analysis was performed post‐mortem following the diagnosis of dentatorubral–pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile‐onset DRPLA.