Neurometabolic Disorder Research Articles

Comparison of Phenytoin, Valproate and Levetiracetam in Pediatric Convulsive Status Epilepticus: A Randomized Double-blind Controlled Clinical Trial

To compare the efficacy of phenytoin, valproate, and levetiracetam in the management of pediatric convulsive status epilepticus. Randomized double-blind controlled clinical trial. Pediatric critical care division in a tertiary care institute from June, 2016 to December, 2018. 110 children aged three month to 12 year with convulsive status epilepticus. Patients not responding to 0.1 mg/kg intravenous lorazepam were randomly assigned (1:1:1) to receive 20 mg/kg of phenytoin (n=35) or valproate (n=35) or levetiracetam (n=32) over 20 minutes. Patients with nonconvulsive status epilepticus, recent hemorrhage, platelet count less than 50,000 or International normalized ratio (INR) more than 2, head injury or neurosurgery in the past one-month, liver or kidney disease, suspected or known neurometabolic or mitochondrial disorders or structural malformations, and allergy to study drugs; and those who were already on any one of the study drugs for more than one month or had received one of the study drugs for current episode, were excluded. The primary outcome was the proportion of patients that achieved control of convulsive status epilepticus at the end of 15 minutes after completion of the study drug infusion. Secondary outcomes were time to control of seizure, rate of adverse events, and the requirement of additional drugs to control seizure, length of ventilation, hospital stay, and functional status after three months (Glasgow Outcome Scale). The study was stopped after the planned mid-interim analysis for futility. Intention to treat analysis was done. There was no difference in primary outcome in phenytoin (31/35, 89%), valproate (29/35, 83%), and levetiracetam (30/32, 94%) (P=0.38) groups. There were no differences between the groups for secondary outcomes. One patient in the phenytoin group had a fluid-responsive shock, and one patient in the valproate group died due to encephalopathy and refractory shock. Phenytoin, valproate, and levetiracetam were equally effective in controlling pediatric convulsive status epilepticus.

Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase-deficient mice.

Ventriculomegaly and hydrocephalus are associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans suffering from non-ketotic hyperglycinemia (NKH), a neurometabolic disorder characterized by accumulation of excess glycine. Here, we showed that ventriculomegaly in Gldc-deficient mice is preceded by stenosis of the Sylvian aqueduct and malformation or absence of the subcommissural organ and pineal gland. Gldc functions in the glycine cleavage system, a mitochondrial component of folate metabolism, whose malfunction results in accumulation of glycine and diminished supply of glycine-derived 1-carbon units to the folate cycle. We showed that inadequate 1-carbon supply, as opposed to excess glycine, is the cause of hydrocephalus associated with loss of function of the glycine cleavage system. Maternal supplementation with formate prevented both ventriculomegaly, as assessed at prenatal stages, and postnatal development of hydrocephalus in Gldc-deficient mice. Furthermore, ventriculomegaly was rescued by genetic ablation of 5,10-methylene tetrahydrofolate reductase (Mthfr), which results in retention of 1-carbon groups in the folate cycle at the expense of transfer to the methylation cycle. In conclusion, a defect in folate metabolism can lead to prenatal aqueduct stenosis and resultant hydrocephalus. These defects are preventable by maternal supplementation with formate, which acts as a 1-carbon donor.

The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy

Adrenoleukodystrophy is a neurometabolic disorder caused by a defective peroxisomal ABCD1 transporter of very long-chain fatty acids (VLCFAs). Its pathogenesis is incompletely understood. Here we characterize a nematode model of X-ALD with loss of the pmp-4 gene, the worm orthologue of ABCD1. These mutants recapitulate the hallmarks of X-ALD: i) VLCFAs accumulation and impaired mitochondrial redox homeostasis and ii) axonal damage coupled to locomotor dysfunction. Furthermore, we identify a novel role for PMP-4 in modulating lipid droplet dynamics. Importantly, we show that the mitochondria targeted antioxidant MitoQ normalizes lipid droplets size, and prevents axonal degeneration and locomotor disability, highlighting its therapeutic potential. Moreover, PMP-4 acting solely in the hypodermis rescues axonal and locomotion abnormalities, suggesting a myelin-like role for the hypodermis in providing essential peroxisomal functions for the nematode nervous system.

Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

BackgroundAromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants in the dopa decarboxylase (DDC) gene. Consensus guidelines recommend dopamine agonists, monoamine oxidase inhibitors, and other symptomatic treatments, but most patients have an unrelenting disease course with no response to these therapies.Case presentationWe describe 2 African American siblings with AADC deficiency and identify 2 DDC gene variants not previously associated with the disorder. The patients were evaluated for cognitive and neurologic impairments. Diagnosis of AADC deficiency was initially based on evaluation of urine and plasma metabolites, followed by targeted DDC gene sequencing. The first patient, a firstborn African American female, had moderate elevations of vanillactic and vanilpyruvic acids, and slight elevation of N-acetylvanilalanine in urine. The second patient, an African American female and younger sibling of the first patient, had low AADC enzyme activity and elevated 3-O-methyldopa levels in plasma. Genetic testing confirmed that both siblings possessed the same 2 DDC gene variants, which were identified as NM_000790.3: c.48C > A (p.Tyr16Ter) and NM_000790.3: c.116G > C (p.Arg39Pro).ConclusionsThis report describes 2 previously unknown patients with AADC deficiency and confirmed the presence of 2 DDC gene variants not previously associated with this disorder. Further research is needed to identify disease-modifying treatments for this devastating neurometabolic disorder. Gene therapy with a recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) is currently in clinical development.

Amyotrophic onset in GCH1 dopa-responsive dystonia

Dopa-responsive dystonia (DRD) belongs to combined dystonia syndrome (dystonia-plus syndrome)1 which encompasses non-degenerative and neurometabolic disorders characterized by combination of dystonia as the prominent sign, with another movement manifestation. Parkinsonism and myoclonus are the main disturbances accompany dystonia in the combined dystonia syndrome. Dystonia with parkinsonism includes DRD [DYT5, tyrosine hydroxylase (TH), and sepiapterin reductase (SPR)], dopamine agonist-responsive dystonia, rapid-onset dystonia parkinsonism (DYT12), and early-onset dystonia with parkinsonism (DYT16). However, dystonia combined with myoclonus is just classified as myoclonus dystonia (DYT11).2 DRD can be inherited in either autosomal dominant or autosomal recessive patterns. The autosomal dominant inheritance results in the typical phenotype of DRD, known as DYT5 or Segawa disease, which is caused by heterozygous mutations of guanosine triphosphate (GTP) cyclohydrolase I gene (GCH1). Mutations of the TH and SPR genes are responsible for autosomal recessive types of DRD.3 DYT5 is represented as progressive lower limbs dystonia with childhood-onset at the common age of 2-5 years. It shows diurnal fluctuations, which are aggravated toward the evening and alleviated by sleeping. Excellent and sustained response to the low dose of levodopa is the marked feature of DYT5 disease. Additional parkinsonism and spasticity may present later in life.4 Moreover, hemiatrophy of the brain, body, or both has been reported in patients with DRD, associated with a biochemical lesion located in basal ganglia.5 However, focal atrophy and muscle weakness rarely accompanies DRD. Interestingly, we aimed to introduce weakness and focal muscle atrophy as the onset manifestations of DRD in an elderly man misdiagnosed for about 70 years.

Utility of Seizure Pattern and Related Clinical Features in the Diagnosis of Neurometabolic Disorders.

The current study aimed at identifying the role of seizure types and related clinical features in differentiation between neurometabolic disorders and other causes of seizure. The current cross sectional study was conducted at two referral children hospitals in Tehran, Iran, from 2011 to 2018. The study population included 120 patients presenting with seizure due to neurometabolic disorders and 120 cases due to other causes. The types of seizure and related clinical findings were assessed in both groups. There was a significant difference in the frequency of seizure types in the two groups. Tonic and myoclonic seizures as well as infantile spasm were observed more commonly in the patients with neurometabolic disorders, while atonic, partial and generalized tonic-clonic seizures were more common in the control group. In addition, frequency of refractory seizure, age at onset of seizure, and pattern of involvement in brain imaging were helpful for differentiation. The pattern of seizure and related findings varied in patients with metabolic disorders, and was helpful for diagnosis. Thus, these factors can contribute to early diagnosis and treatment.

Neuroendocrine and metabolic impairments in patients with Parkinson's disease

Neuroendocrine and neurometabolic disorders, although occasionally noted in Parkinson's disease (PD), existed in the shadow of motor and non-motor symptoms (hypokinesia, rigidity, tremor, depression, constipation, etc.). In recent years, they are increasingly being diagnosed and are the subject of special research. These include, in particular, disorders of carbohydrate metabolism, changes in body weight, metabolic disorders in bone tissue, secretion, as well as the secretion of neurohormones, such as melatonin. They are associated with other non-motor symptoms, negatively affect patients' general condition and quality of life, but can be treatable. At the same time, treatment of neuroendocrine and neurometabolic disorders can favorably influence the rate of progression of the disease as a whole. This review discusses the pathophysiological mechanisms, clinical consequences, as well as pharmacological and non-pharmacological approaches to the treatment of neuroendocrine and neurometabolic disorders arising in PD, which have been relatively rarely covered in literature.Нейроэндокринные и нейрометаболические нарушения хотя эпизодически и отмечались при болезни Паркинсона (БП), но они существовали в тени более типичных для этого заболевания моторных и немоторных симптомов (гипокинезии, ригидности, тремора, депрессии, запоров и т.д.). Однако в последние годы они все чаще диагностируются и служат предметом специальных исследований. К ним, в частности, относятся: нарушения углеводного метаболизма, изменения массы тела, нарушения обмена веществ в костной ткани секреции, а также секреции нейрогормонов, например, мелатонина. Они связаны с другими немоторными симптомами, негативно влияют на общее состояние пациентов и качество их жизни, но могут поддаваться лечению. При этом коррекция нейроэндокринных и нейрометаболических нарушений может благоприятно влиять на темп прогрессирования болезни в целом. В данном обзоре обсуждаются патофизиологические механизмы, клинические последствия, а также фармакологические и нефармакологические подходы к терапии тех нейроэндокринных и нейрометаболических нарушений, возникающих при БП, которые недостаточно освещены в литературе.

Prevalence of neurometabolic diseases in Saudi Arabia

Neurometabolic disorders are most often seen in newborns and infants and have come to be recognized as an important group of disorders. Understanding diagnostic and therapeutic developments in neurometabolic disorders requires a concrete understanding of the classical principles of inborn errors of metabolism in order to provide key constructs for a fundamental understanding of this interesting category of disorders. The Saudi Arabian population has a comparatively high incidence of neurometabolic disorders, primarily due to consanguinity (with a high inbreeding coefficient factor) and large family sizes. The most frequently occurring group of disorders are lysosomal storage diseases, followed by organic acidemias; intellectual disability and cerebral palsy are the most commonly presented neurological features among Saudi Arabian children. This review summarizes the reports and studies of neurometabolic disorders prevalent in Saudi Arabia. It presents an overview of the types of disorders, current screening and diagnostic strategies, and prevalence of disease conditions in Saudi Arabia.

An Approach to Neurometabolic Epilepsy in Children with an Underlying Neurometabolic Disorder.

Inborn errors of metabolism (IEM) are rare conditions, with an overall incidence of 1 per 1000 births. Approximately 40-60% of IEM cases present with epilepsy as one of the main clinical presentations of the disease. A substantial number of these patients require timely and accurate diagnosis, besides specific treatment to prevent the irreversible outcomes. In this two-year retrospective study, a total of 128 patients with documented neurometabolic disorders were selected and evaluated in Mofid Children Hospital of Tehran, Iran, using a questionnaire to investigate the prevalence of epilepsy and seizure phenotypes. The collected data were evaluated in SPSS version 23. Seizure was reported in 49% (63/128) of the patients. A single episode of seizure occurred in 7 (7%) patients. The prevalence of epilepsy was estimated at 42% (54/128). The most common seizure types were generalized tonic-clonic (43%), tonic (22%), and myoclonic (10%), respectively. Epilepsy was refractory in 30% (16/54) of the patients, and the mean number of administered anti-seizure drugs for refractory cases was 3.2. Overall, 50% of refractory cases had mixed-type seizures, and 25% had generalized tonic-clonic and myoclonic seizures. Neurometabolic disorders are rare, but treatable causes of epilepsy. A considerable number of patients (42%) in the current study presented with epilepsy as a clinical feature of IEM.

Succinate Dehydrogenase Deficiency: A Treatable Neurometabolic Disorder.

Succinate dehydrogenase (SDH) deficiency is a rare autosomal recessive neurometabolic disorder that causes brain insult, neurodevelopmental delay, exercise intolerance, and cardiomyopathy. A 25-month-old boy was referred to our neurometabolic center due to developmental regression after injecting the influenza vaccine when he was 10 months old. Magnetic resonance imaging (MRI) showed high signal changes in the brain white matter, and magnetic resonance spectroscopy (MRS) detected a high succinate peak at 2.4 parts per million (ppm). The evaluation of urine organic acids showed a significant elevated succinic acid and whole exome sequencing, confirming SDH. Treatment with a mitochondrial cocktail was initiated, and remarkable improvement was observed. SDH deficiency as a treatable neurometabolic disorder should be considered in any patients with developmental disorders, accompanied by hyperintensity in white matter (as similar to leukodystrophia). Further evaluation is recommended since outcomes depend on early diagnosis and treatment.

Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome.

Introduction:Whole Exome Sequencing (WES) has been increasingly utilized in genetic determinants of various inherited diseases.Methods:We applied WES for a patient presenting 3-Methylglutaconic Aciduria (MEG), Deafness (D), Encephalopathy (E), and Leigh-like (L) syndrome. Then Sanger sequencing was used for the detected variant validation.Results:We found an insertion, rs797045105 (chr6, 158571484, C>CCATG), in the SERAC1 gene with homozygous genotype in the patient and heterozygous genotype in her unaffected parents. Notably, bioinformatics analysis using mutation taster (prob>0.99) and DDIGin (prob=86.51) predicted this mutation as disease-causing. Also, the variant was not present in our database, including 700 exome files.Conclusion:These findings emphasize the pathogenicity of rs797045105 for MEGDEL syndrome. On the other hand, our data shed light on the significance of WES application as a genetic test to identify and characterize the comprehensive spectrum of genetic variation and classification for patients with neurometabolic disorders.

Evaluation of clinical, neuroradiologic, and genotypic features of patients with L-2-hydroxyglutaric aciduria.

Aim:L-2-hydroxyglutaric aciduria is a slowly progressive neurometabolic disorder caused by an enzymatic deficiency of L-2-hydroxyglutarate dehydrogenase. Here, we aimed to evaluate the clinical, neuroradiologic, and genotypic characteristics of patients with L-2-hydroxyglutaric aciduria who were followed in our outpatient clinic.Material and Methods:Twenty-five patients with L-2-hydroxyglutaric aciduria were enrolled in the study. Data regarding demographic, clinical, and neuroradiologic findings and molecular analysis were evaluated retrospectively.Results:The mean age of patients at the time of diagnosis was 12.09±8.02 years, whereas the mean age at the time of the first symptoms was 39.47±29.96 months. Diagnostic delay was found as 9.95±7.78 years. Developmental delay, decrease in school success, and seizures were the most common initial symptoms; however, behavioral problems and seizures became more prominent in the disease course. At the time of diagnosis, mental retardation and at least one pathologic cerebellar finding were detected in all symptomatic patients. Three patients developed brain tumors. The most common neuroimaging findings were subcortical white matter changes and cerebellar dentate nucleus involvement. In one patient, there was only isolated basal ganglia involvement without white matter lesions. Patients with similar genotypic features exhibited different clinical and radiologic findings.Conclusion:Although clinical symptoms appear early in L-2-hydroxyglutaric aciduria, there is approximately a ten-year delay in diagnosis. In subjects in whom brain tumor is detected in early childhood, L-2-hydroxyglutaric aciduria should be considered in the differential diagnosis in the presence of mental retardation accompanied by developmental delay, cerebellar and pyramidal findings, and behavior disorders in a wide spectrum ranging from autism spectrum disorder to psychosis. In patients with L-2-hydroxyglutaric aciduria, incipient headache, tinnitus, altered consciousness, and seizures can be indicative of brain tumors.

Human iPSC-Derived Cerebral Organoids Model Features of Leigh Syndrome and Reveal Abnormal Corticogenesis

Leigh syndrome (LS) is a rare, inherited neuro-metabolic disorder that presents with bilateral brain lesions, caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated iPSCs from three available LS fibroblast lines and identified, through whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS derived cell lines were viable and able to differentiate into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS-derived cerebral organoids showed defects in neural epithelial bud generation, reduced size and loss of cortical architecture at 100 days. The MT-ATP6/PDH line produced organoid neural progenitor cells with an abnormal mitochondrial morphology characterized by fragmentation and disorganization, and demonstrated increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that could be used as LS model systems.

Why should a neuropaediatrician always measure head circumference - a case report of Glucose transporter 1 deficiency syndrome (Glut1-DS)

Introduction. The deficit of the type 1 glucose transporter (Glut1-DS) belongs to the neurometabolic disorders that can be effectively treated, in this case with ketogenic diet. By limiting glucose supply to the brain the deficit of glucose transporter 1 leads to cerebral energy deficiency. Glut1-DS manifests with a wide range of neurological symptoms that usually start in early childhood, including cognitive impairment, epilepsy and permanent and/or paroxysmal motor disorders, often provoked by physical activity, fasting or hyperthermale. Aim. We present the case of a 6,5-year-old patient with Glut1- -DS who, despite presenting typical symptoms, remained undiagnosed for years. Family history was positive of intellectual disability in first degree relative. The child suffered from psychomotor development delay, motor coordination difficulties, motor disorders and epilepsy with focal and absence seizures of early onset. However, the significant symptom of secondary microcephaly remained unnoticed for years. Conclusion. Secondary microcephaly is a valuable symptom which can guide towards the diagnosis. The early diagnosis of Glut1 deficiency syndrome enables prompt introduction of the ketogenic diet crucial for the child’s development and improvement of both the patients and their families’ quality of life.

A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations.

Leigh syndrome (also called Leigh disease or subacute necrotizing encephalomyelopathy) is a rare inherited neurometabolic disorder, which affects the central nervous system. This meta-study systematically analyzed clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations.Literature was searched for publications in MEDLINE, EMBASE, and the China National Knowledge Infrastructure database for meta-analyses of the incidence of clinical symptoms, laboratory assessments, imaging data, muscle biopsy histochemical staining, activity of the mitochondrial respiratory chain enzyme complex, gene mutations, and the association between age at disease onset and type of gene mutations.This study included 5 studies with 385 Leigh syndrome patients. The most common clinical features of Leigh syndrome included elevated blood and/or cerebrospinal fluid (CSF) levels of lactate (72%), developmental retardation (57%), hypotonia (42%), followed by respiratory dysfunction (34%), epileptic seizures (33%), poor feeding (29%), and weakness (27%). Approximately 80% of the patients had deficiencies of the respiratory chain enzyme complex or isolated complex I deficiency (35%), 32% had mitochondrial DNA (mtDNA) mutations, and 38% had nuclear DNA (nDNA) mutations. Patients with nDNA mutations were younger than those with mtDNA mutations (8.82 ± 13.88 vs 26.20 ± 41.11 years, P = .007).The data from the current meta-analysis demonstrated a variety of clinical and molecular manifestations of Leigh syndrome, with upregulated lactate levels in the blood or CSF being the most common feature. Diagnosis of Leigh syndrome could be confirmed using combined enzymatic and genetic analyses.

Inborn errors of metabolism leading to neuronal migration defects.

The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non-protein-coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer-specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß-oxidation defects and congenital disorders of O-glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non-metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.

Изучение морфофункциональных параметров кардиомиоцитов в условиях алкогольной кардиомиопатии на фоне применения комбинированного лекарственного средства

В последнее время в связи с распространением алкогольной кардиомиопатии среди трудоспособного населения промышленно развитых стран актуальной необходимостью является поиск новых лекарственных препаратов строго направленного действия, с учетом комплекса механизмов повреждающего действия этилового алкоголя на миокард. В этом отношении интерес представляет комбинированное средство L-аргинина c тиотриазолином (разработка НПО «Фарматрон»), а также Милдронат, Мексидол и Тиотриазолин. Экспериментально доказано, что по силе кардиопротективного эффекта (влияние на показатели площади и плотности ядер кардиомиоцитов; концентрацию РНК в ядрах и в цитоплазме кардиомиоцитов, ядерно-цитоплазматический коэффициент) комбинированное средство L-аргинин/тиотриазолин достоверно превосходит референс-препараты Милдронат, Мексидол и Тиотриазолин.

A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia

We describe a case of 5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency characterized by microcephaly, global developmental delay, epilepsy, and cerebral hypomyelination. Whole exome sequencing (WES) demonstrated homozygosity for the R74X mutation in the MTHFS gene. The patient had the unexpected finding of elevated cerebrospinal fluid (CSF) neopterin. The novel finding of macrocytic anemia in this patient may provide a clue to the diagnosis of this rare neurometabolic disorder.

Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment.

Neurometabolic disorders are often inherited and complex disorders that result from abnormalities of enzymes important for development and function of the nervous system. Recently, biallelic mutations in NAXE (APOA1BP) were found in patients with an infantile, lethal, neurometabolic disease. Here, exome sequencing was performed in two affected sisters and their healthy parents. The best candidate, NAXE, was tested for replication in exome sequencing data from 4351 patients with neurodevelopmental disorders. Quantitative RT-PCR, western blot and form factor analysis were performed to assess NAXE expression, protein levels and to analyze mitochondrial morphology in fibroblasts. Vitamin B3 was administered to one patient. Compound heterozygous missense (c.757G>A: p.Gly253Ser) and splicing (c.665-1G>A) variants in NAXE were identified in both affected sisters. In contrast to the previously reported patients with biallelic NAXE variants, our patients showed a milder phenotype with disease onset in early adulthood with psychosis, cognitive impairment, seizures, cerebellar ataxia and spasticity. The symptoms fluctuated. Additional screening of NAXE identified three novel homozygous missense variants (p.Lys245Gln, p.Asp218Asn, p.Ile214Val) in three patients with overlapping phenotype (fluctuating disease course, respiratory insufficiency, movement disorder). Lastly, patients with the c.665-1G>A splicing variant showed a significant reduction of NAXE expression compared to control fibroblasts and undetectable NAXE protein levels compared to control fibroblasts. Based on the metabolic pathway, vitamin B3 and coenzyme Q treatment was introduced in one patient in addition to antiepileptic treatment. This combination and avoidance of triggers was associated with continuous motor and cognitive improvement. The NAXE variants identified in this study suggest a loss-of-function mechanism leading to an insufficient NAD(P)HX repair system. Importantly, symptoms of patients with NAXE variants may improve with vitamin B3/coenzyme Q administration.

Expected future developments in child neurology

We stand on the shoulders of giants on the threshold of many new exciting developments in the field of child neurology due to innovations in clinical approach, diagnostic technologies and treatment strategies. There are many exciting new technologies, but we must never forget the power of clinical medicine which allows us to interpret and use these tools with precision and with clinical wisdom. Strong collaborations continue to be needed: between clinicians for the meticulous clinical phenotyping, expansion of the range of phenotypic expression, and the entry of patients into international RCTs (randomised controlled trials); between the biochemists for the biochemical phenotyping and understanding of the basic pathophysiology of the underlying dysregulations and disease mechanisms arising from the protein dysfunctions and the development of robust biomarkers, to evaluate disease severity and response to therapies; and between the geneticists for the understanding of the impact of the exonic or intronic mutations, roles of other regulatory genes on the affected pathway, and epigenetic factors. These collaborations in the aggregate will lead the field forward in terms of increased insight into disease pathophysiology for the development of targeted precision medicine treatment strategies and effective preventative measures. This review is meant to highlight certain selected areas of future development and is not meant to be a comprehensive survey beyond the scope of this review. The subspecialty areas which will be highlighted will include intellectual disability, epilepsy, neuroprotection, neonatal and fetal neurology, CNS infections, headache, autoimmune/inflammatory disorders, demyelinating disorders, stroke, movement disorders, neurotransmitter defects, neuromuscular diseases, neurometabolic disorders, neurogenetic diseases, neuropsychiatry/autism, and neurooncology. In each subspecialty area, I will endeavor to identify emerging diseases, new specific diagnostic technologies and novel therapeutic approaches, but will need to be selective. This review is the culmination of a literature survey for current developments, discussions with leaders in each of the subspecialty fields, who I will acknowledge at the end, and certain personal projections.