Femur Fractures in 5 Individuals With Pantothenate Kinase-associated Neurodegeneration: The Role of Dystonia and Suggested Management.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, neurodegenerative disorder that manifests with progressive loss of ambulation and refractory dystonia, especially in the early-onset classic form. This leads to osteopenia and stress on long bones, which pose an increased risk of atraumatic femur fractures. The purpose of this study is to describe the unique challenges in managing femur fractures in PKAN and the effect of disease manifestations on surgical outcomes. METHODS: A retrospective case review was conducted on 5 patients (ages 10 to 20 y) with PKAN with a femur fracture requiring surgical intervention. Data regarding initial presentation, surgical treatment, complications, and outcomes were obtained. RESULTS: All patients were non-ambulatory, with 4 of 5 patients sustaining an atraumatic femur fracture in the setting of dystonia episode. One patient had an additional contralateral acetabular fracture. Postoperatively, 4 of the 5 patients sustained orthopaedic complications requiring surgical revision, with 3 of these secondary to dystonia. Overall, 4 required prolonged hospitalization in the setting of refractory dystonia. CONCLUSION: Femur fractures in PKAN present distinct challenges for successful outcomes. A rigid intramedullary rod with proximal and distal interlocking screws is most protective against surgical complications associated with refractory dystonia occurring during the postoperative period. Multidisciplinary planning for postoperative care is essential and may include aggressive sedation and pain management to decrease the risk of subsequent injuries or complications. LEVEL OF EVIDENCE: Level IV.

The Phenotypic Continuum of ATP1A3-Related Disorders.

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021. RESULTS: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. DISCUSSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms.

Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene <i>DNM1L</i>, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.

Movement disorders in MCT8 deficiency/Allan-Herndon-Dudley Syndrome.

BACKGROUND AND OBJECTIVES: MCT8 deficiency is a rare genetic leukoencephalopathy caused by a defect of thyroid hormone transport across cell membranes, particularly through blood brain barrier and into neural cells. It is characterized by a complex neurological presentation, signs of peripheral thyrotoxicosis and cerebral hypothyroidism. Movement disorders (MDs) have been frequently mentioned in this condition, but not systematically studied. METHODS: Each patient recruited was video-recorded during a routine outpatient visit according to a predefined protocol. The presence and the type of MDs were evaluated. The type of MD was blindly scored by two child neurologists experts in inherited white matter diseases and in MD. Dystonia was scored according to Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). When more than one MD was present, the predominant one was scored. RESULTS: 27 patients were included through a multicenter collaboration. In many cases we saw a combination of different MDs. Hypokinesia was present in 25/27 patients and was the predominant MD in 19. It was often associated with hypomimia and global hypotonia. Dystonia was observed in 25/27 patients, however, in a minority of cases (5) it was deemed the predominant MD. In eleven patients, exaggerated startle reactions and/or other paroxysmal non-epileptic events were observed. CONCLUSION: MDs are frequent clinical features of MCT8 deficiency, possibly related to the important role of thyroid hormones in brain development and functioning of normal dopaminergic circuits of the basal ganglia. Dystonia is common, but usually mild to moderate in severity, while hypokinesia was the predominant MD in the majority of patients.

Intrathecal baclofen pumps in the management of hypertonia in childhood: a UK and Ireland wide survey.

BACKGROUND: Intrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland. METHODS: An electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset. RESULTS: 176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%). CONCLUSIONS: ITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.

Celiac Plexus Block to Treat Refractory Feed Induced Dystonia in Children with Severe Neurodisability: A Single Center Case Series.

This observational study describes the procedure technique, safety outcomes, and patient responses to celiac plexus blockade (CPB) in children with severe neurodisability with refractory feed intolerance, feed induced pain or feed induced dystonia (FID). Method: A review of the pathophysiological response to feeding in children with significant neurodisability and the effect on the neuroenteric system. A 2-stage CT-guided temporary celiac plexus blockade followed by neurolysis technique is described. We compile a case series of 5 patients with life limiting conditions and significant disability undergoing CPB in a single tertiary pediatric hospital. Results: A total of 10 separate procedures in 5 children were completed. A positive outcome was observed in 3 out of 4 cases of pediatric FID. Two of the three patients on parenteral nutrition had improved feed tolerance postprocedure. All children tolerated the procedure well, no postprocedure complications were documented. Conclusions: In selected cases, children with life-threatening feed induced dystonia or effective intestinal failure can be safely treated with celiac plexus blockade when other therapies have failed.

Pharmacological management of abnormal tone and movement in cerebral palsy.

BACKGROUND: The evidence base to guide the pharmacological management of tone and abnormal movements in cerebral palsy (CP) is limited, as is an understanding of routine clinical practice in the UK. We aimed to establish details of motor phenotype and current pharmacological management of a representative cohort across a network of UK tertiary centres. METHODS: Prospective multicentre review of specialist motor disorder clinics at nine UK centres, collecting data on clinical features and pharmacological management of children and young people (CYP) with CP over a single calendar month. RESULTS: Data were collected from 275 CYP with CP reviewed over the calendar month of October 2017. Isolated dystonia or spasticity was infrequently seen, with a mixed picture of dystonia and spasticity ± choreoathetosis identified in 194/275 (70.5%) of CYP. A comorbid diagnosis of epilepsy was present in 103/275 (37.4%). The most commonly used medications for abnormal tone/movement were baclofen, trihexyphenidyl, gabapentin, diazepam and clonidine. Medication use appeared to be influenced separately by the presence of dystonia or spasticity. Botulinum toxin use was common (62.2%). A smaller proportion of children (12.4%) had undergone a previous neurosurgical procedure for tone/movement management. CONCLUSIONS: CYP with CP frequently present with a complex movement phenotype and comorbid epilepsy. They have multiple therapy, medical and surgical management regimens. Future trials of therapeutic, pharmacological or surgical interventions in this population must adequately encompass this complexity in order to be translatable to clinical practice.

KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect.

OBJECTIVE: Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. METHODS: Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. RESULTS: Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. INTERPRETATION: Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774-788.

Home video telemetry in children: A comparison to inpatient video telemetry.

PURPOSE: Home Video Telemetry (HVT) combines ambulatory EEG with simultaneous video recording. No previous reports have compared HVT and inpatient video telemetry (IVT) in a purely paediatric population. This study compares HVT and IVT in this group in terms of diagnostic efficacy, recording quality and acceptability to parents/carers. METHODS: 33 HVT and 29 IVT patients aged 1-17 years were included. Information regarding patient demographics, ictal capture, diagnostic utility, recording quality (e.g. video clarity, EEG artefacts) and parent/carer preferences was documented. Difficulties using HVT equipment were recorded. RESULTS: 62% of IVT patients and 64% of HVT patients had typical attacks during the recording. 59% of IVT and 70% of HVT recordings were considered to have answered the referral question. Study quality was similar in both groups. In HVT studies the rate of equipment difficulties was 52%; problems included camera positioning and failure to turn on the infrared button at night. Diagnostic information was lost in 15% of patients. 76% of parents/carers of HVT patients would choose this investigation again. CONCLUSIONS: The diagnostic efficacy and study quality of HVT and IVT are similar in paediatric patients. HVT is acceptable to most parents/carers. User error may compromise the investigation in a minority of cases but did not impact on diagnostic utility. Adoption of HVT investigation could provide an accessible and economic alternative to IVT.

Feed-induced Dystonias in Children With Severe Central Nervous System Disorders.

Dystonias can arise from any painful stimuli in neurologically disabled children. Classically, feed-induced dystonias from mediastinal pain due to severe gastroesophageal reflux disease are described as Sandifer spasm. We report a case series of 12 severely neurologically impaired children with enteral feed-induced dystonias. Intestinal dysmotility was demonstrated in several. Improvements are seen with jejunal feeds or gut rest with total parenteral nutrition. Use of parenteral nutrition in children with severe neurodisability requires thorough discussion with patient groups and commissioners to give clinicians guidelines to standardize care.

Pneumatosis Coli in Complex Neurodisability: An Increasingly Problematic Disease Spectrum and Proposed Management.

This case series describes our experience in managing 4 children with complex neurodisability, feed intolerance, and pneumatosis coli. In all of the 4 patients, symptoms and feed tolerance were substantially improved by the formation of a laparoscopically assisted defunctioning ileostomy. We describe our present management strategy and believe this is a promising treatment for those patients who can reduce long-term dependence on parenteral nutrition, although we acknowledge that there is a long-term risk of disuse colitits in the defunctioned bowel.

Fifteen-minute consultation: Approach to the child with an acute confusional state.

Acute confusional state (ACS) refers to sudden impairment of cognitive function and represents a major medical emergency. The impairment may be global or confined specifically to a particular faculty of higher mental function, such as memory. This review highlights the importance of relevant medical history and clinical signs and symptoms in reaching the correct diagnosis. In this review, we have presented a diagnostic approach to a child presenting with ACS and described commonly encountered causes, their treatments and outcomes. We have also presented an algorithm for the diagnostic approach to the child with ACS.

Fifteen minute consultation: tics and Tourette syndrome.

Tic disorders including Tourette syndrome (TS) are neuropsychiatric disorders that are common referrals to paediatricians, paediatric neurologists and child psychiatrists. Although differentiating tics and TS from other movement disorders is not difficult, it is essential to detect comorbid conditions and their contribution to TS.

Nonketotic hyperglycinemia case series.

UNLABELLED: To present three cases who presented with neonatal hiccups and who were later diagnosed with nonketotic hyperglycinemia (NKH). CASE SERIES: We present three babies who presented in neonatal life with hiccups who later were diagnosed with NKH. Two babies presented on the 2(nd) day of life with hypotonia, poor feeding, and abnormal movements including jitteriness, hiccups, and twitching. The third baby only had transient hiccups lasting for a couple of days in the 1(st) week of life but later presented at 3 months of age with poor feeding, drowsiness, and jerky movements. All three cases needed extensive investigations before reaching the diagnosis including metabolic screen, lumbar puncture, electroencephalography, and computed tomography/magnetic resonance imaging. The first two babies needed intubation on their 2(nd) day of life because of apneas in whom later, the care was withdrawn after reaching the diagnosis of NKH because of poor prognosis. The third baby was discharged home on oral dextromethorphan and ketogenic diet. We discuss the importance of early recognition of symptoms (frequent hiccups) and investigation needed to reach the diagnosis early as it helps in making decision to either carry on treatment or withdraw care because of poor prognosis. It also helps in genetic counseling and prenatal diagnosis can be offered at the subsequent pregnancy.

Neonatal hypertonia - a diagnostic challenge.

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested.

The value of long term EEG monitoring in children: a comparison of ambulatory EEG and video telemetry.

PURPOSE: Outpatient ambulatory EEG may be followed by inpatient video telemetry EEG when investigating children for possible seizures and for classification of epilepsy. We investigated the value of ambulatory EEG and subsequent video telemetry recording in our centre. METHOD: The departmental EEG database was interrogated retrospectively for children undergoing ambulatory recording followed by inpatient video telemetry within an 18-month period. RESULTS: 30 patients fitted these criteria, 21 females, 9 males, age range 3-16 years. The mean interval between studies was 9 months. For ambulatory recordings 93% of studies were undertaken to ascertain if behaviours were epileptic. 66% of ambulatory recordings studies captured an event of interest and 63% were able to answer the question asked of the test. In video telemetry recording 80% of studies were aimed at ascertaining if events were epileptic or not, 20% were undertaken for classification of seizure type. 70% of recordings captured an ictus and were considered helpful in addressing the clinical question. Pooled together 90% of patients had a paroxysmal event captured and the clinical question answered by the recording techniques. In patients for whom ambulatory recording failed to capture an attack or answer the clinical question, 70% went on to have a successful video telemetry recording. CONCLUSION: Both ambulatory EEG and inpatient video telemetry are effective tools for diagnosis of seizures. The majority of patients with failed ambulatory recordings go on to have successful video telemetry. Combining the two resources provides useful clinical information in nearly all instances.