Tetrahydrobiopterin (BH
) 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 BH
biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH
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 BH
deficiencies.
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 BH
deficient patients.
Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly ...recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan‐Herndon‐Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain‐thyroid’ disorders.
What this paper adds
An overview of the neurological manifestations of thyroid dysfunction.
Detailed characterization of the genetic ‘brain‐thyroid’ disorders.
OBJECTIVETo characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy.
METHODSWe identified a cohort of 31 ...patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system.
RESULTSWe identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.
CONCLUSIONSGain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
Aim
Using Niemann–Pick type C disease (NPC) as a paradigm, we aimed to improve biomarker discovery in patients with neurometabolic disorders.
Method
Using a multiplexed liquid chromatography tandem ...mass spectrometry dried bloodspot assay, we developed a selective intelligent biomarker panel to monitor known biomarkers N‐palmitoyl‐O‐phosphocholineserine and 3β,5α,6β‐trihydroxy‐cholanoyl‐glycine as well as compounds predicted to be affected in NPC pathology. We applied this panel to a clinically relevant paediatric patient cohort (n = 75; 35 males, 40 females; mean age 7 years 6 months, range 4 days–19 years 8 months) presenting with neurodevelopmental and/or neurodegenerative pathology, similar to that observed in NPC.
Results
The panel had a far superior performance compared with individual biomarkers. Namely, NPC‐related established biomarkers used individually had 91% to 97% specificity but the combined panel had 100% specificity. Moreover, multivariate analysis revealed long‐chain isoforms of glucosylceramide were elevated and very specific for patients with NPC.
Interpretation
Despite advancements in next‐generation sequencing and precision medicine, neurological non‐enzymatic disorders remain difficult to diagnose and lack robust biomarkers or routine functional testing for genetic variants of unknown significance. Biomarker panels may have better diagnostic accuracy than individual biomarkers in neurometabolic disorders, hence they can facilitate more prompt disease identification and implementation of emerging targeted, disease‐specific therapies.
What this paper adds
Intelligent biomarker panel design can help expedite diagnosis in neurometabolic disorders.
In Niemann–Pick type C disease, such a panel performed better than individual biomarkers.
Biomarker panels are easy to implement and widely applicable to neurometabolic conditions.
What this paper adds
Intelligent biomarker panel design can help expedite diagnosis in neurometabolic disorders.
In Niemann–Pick type C disease, such a panel performed better than individual biomarkers.
Biomarker panels are easy to implement and widely applicable to neurometabolic conditions.
Improved time to diagnosis for neurometabolic disorders, with Niemann Pick C (NPC) as an example, using a multiplex assay panel. Top panel displays the current scenario with diagnostic confirmation taking months and often requiring lengthy biochemical testing, especially in cases of genetic variants of unknown significance. Improved diagnosis using a bloodspot assay can achieve biochemical confirmation in 2 to 6 weeks and reduce need for subsequent biochemical confirmation after genetic diagnosis. Abbreviations: CE, clinical exome; CDH, ceramide dihexoside; DBS, dried blood spot; GlcCer, glucosylceramide; NPC, Niemann‐Pick type C; PPCS, N‐palmitoyl‐O‐phosphocholineserine; SM, sphingomyelin; WES, whole exome sequencing; WGS, whole genome sequencing.
This original article is commented on by Pearl on pages 1441–1442 of this issue.
Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and ...serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty‐three patients (60% female; ages 6 months‐36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0‐12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non‐motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose‐limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.
To explore the phenotypic spectrum of
-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features ...of 11 affected individuals.
Individuals with
-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.
Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of
, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in
, these events were reported later only in
mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients.
Although heterozygous
mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC.
testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for
mutations.
Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders characterized by the presence of radiologically discernible high brain iron, particularly within the ...basal ganglia. A number of childhood NBIA syndromes are described, of which two of the major subtypes are pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN). PKAN and PLAN are autosomal recessive NBIA disorders due to mutations in PANK2 and PLA2G6, respectively. Presentation is usually in childhood, with features of neurological regression and motor dysfunction. In both PKAN and PLAN, a number of classical and atypical phenotypes are reported. In this chapter, we describe the clinical, radiological, and genetic features of these two disorders and also discuss the pathophysiological mechanisms postulated to play a role in disease pathogenesis.
This review provides recommendations for the evaluation and management of individuals with beta‐propeller protein‐associated neurodegeneration (BPAN). BPAN is one of several neurodegenerative ...disorders with brain iron accumulation along with pantothenate kinase‐associated neurodegeneration, PLA2G6‐associated neurodegeneration, mitochondrial membrane protein‐associated neurodegeneration, fatty acid hydroxylase‐associated neurodegeneration, and COASY protein‐associated neurodegeneration. BPAN typically presents with global developmental delay and epilepsy in childhood, which is followed by the onset of dystonia and parkinsonism in mid‐adolescence or adulthood. BPAN is an X‐linked dominant disorder caused by pathogenic variants in WDR45, resulting in a broad clinical phenotype and imaging spectrum. This review, informed by an evaluation of the literature and expert opinion, discusses the clinical phenotype and progression of the disease, imaging findings, epilepsy features, and genetics, and proposes an approach to the initial evaluation and management of disease manifestations across the life span in individuals with BPAN.
What this paper adds
The complex epilepsy profile of beta‐propeller protein‐associated neurodegeneration (BPAN) often resolves in adolescence.
The treatment for an individual with BPAN is supportive, with attention to sleep disorders, complex epilepsy, and behavioral problems.
Individuals with BPAN have shifting needs throughout their life span requiring multidisciplinary care.
What this paper adds
The complex epilepsy profile of beta‐propeller protein‐associated neurodegeneration (BPAN) often resolves in adolescence.
The treatment for an individual with BPAN is supportive, with attention to sleep disorders, complex epilepsy, and behavioral problems.
Individuals with BPAN have shifting needs throughout their life span requiring multidisciplinary care.
podcast : (https://youtu.be/NUF4DJXVlWw)
High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of ...cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as “cerebral palsy.” This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.
PDF
