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.

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.

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.

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.

An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms.

AIM: We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. METHOD: Retrospective review and brain MRI analysis of children enrolled in the International Collaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. RESULTS: Ten of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls. INTERPRETATION: It is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder.

Cerebral cavernous malformation: clinical report of two families with variable phenotype associated with KRIT1 mutation.

We report two families with a variable presentation in association with a KRIT1 mutation. The index patient in Family 1 was a 9-year old girl who presented with left hemi-dystonia and a cerebral cavernous malformation was identified in the right lentiform nucleus. The maternal grandmother presented with a spinal cavernoma, which was operated at 35-years of age. The mother presented with intractable temporal lobe epilepsy in childhood and underwent temporal lobe resection at 27-years of age. The second family has also presented variably with the youngest member of this family presenting with generalised tonic-clonic seizures at 18-months of age. We report both these families with variable presentation of an autosomal dominant condition and describe the phenotypic presentation in both these families in further detail and review the published literature on this condition.

Outcome of children with hyperventilation-induced high-amplitude rhythmic slow activity with altered awareness.

Hyperventilation-induced high-amplitude rhythmic slow activity with altered awareness (HIHARS) is increasingly being identified in children and is thought to be an age-related non-epileptic electrographic phenomenon. We retrospectively investigated the clinical outcome in 15 children (six males, nine females) with HIHARS (mean age 7y, SD 1y 11mo; range 4y 6mo-11y). The presenting feature in 11 cases was blank spells - two of these children also had generalized tonic-clonic seizures (GTCS) - and in one individual the main concern was deteriorating school performance. Three children had symptoms suggestive of focal motor seizures. Of the nine children presenting solely with blank spells, further follow-up (mean duration 18mo, SD 21mo) revealed full resolution of symptoms in six, but three had persistent symptoms. In our study, the symptoms of children with HIHARS presenting with blank spells in isolation appeared to resolve spontaneously and did not evolve into convulsive seizures or other paroxysmal events considered to be clearly epileptic. Children (with HIHARS) who presented with clinical features suggestive of GTCS or focal motor seizures (with or without blank spells) and/or had epileptiform discharges on interictal electroencephalography were subsequently diagnosed with epilepsy.

Unilateral periventricular leukomalacia in association with pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. A deficiency of PDH E1 alpha, a subunit of the PDH complex, is a prominent cause of congenital lactic acidosis. We describe a female infant born at term and delivered by emergency Caesarean section because of fetal distress. There was no parental consanguinity. She presented at 5 months of age with failure to thrive, microcephaly, hypertonia, and developmental impairment. Her plasma and cerebrospinal fluid lactate were raised. She had raised plasma pyruvate with a normal lactate-pyruvate ratio. Magnetic resonance imaging of the brain showed a focal dilatation of the right lateral ventricle with unilateral periventricular leukomalacia (PVL) with subependymal cyst. Skin fibroblast culture assay revealed PDH deficiency, confirmed by mutation analysis of the E1 alpha subunit. At 18 months of age, she has hypertonia and global impairment and is making slow progress. Denver II assessment showed delay in gross motor, fine motor, adaptive, personal, social, and language categories. She has been treated with dichloroacetate and a ketogenic diet since the age of 10 and 13 months respectively, without any side effects. To our knowledge, unilateral PVL as a neuroradiological feature has not been described in children with PDH deficiency. PDH deficiency should be considered as a differential diagnosis if PVL is unilateral and if the perinatal history is not typical of PVL.

Reversible parainfectious bilateral "striatal necrosis".

Bilateral striatal necrosis is usually associated with either endogenous or exogenous toxins, and with poor neurodevelopmental outcomes. We describe two patients with acute bilateral striatal clinical syndrome and magnetic resonance signal changes who made a complete clinical and radiologic recovery within 3 months. After an uneventful pregnancy, normal birth, and normal development, both boys presented at ages 3 and 5 years, respectively, after a viral illness with slurring of speech, bradykinesia, and an extrapyramidal movement disorder. On examination, both manifested bilateral cog wheel rigidity, with a broad-based gait and flexor plantar response. Cranial magnetic resonance imaging in both children indicated bilateral, symmetric, high signal changes in the lentiform nucleus, predominately in the putamen, with sparing of the globus pallidi bilaterally. The brain parenchyma was otherwise normal. Neurometabolic investigations produced normal results in both patients. The pathogenesis is uncertain, but could be immune-mediated. Both children, at 3-year and 1-year follow-ups, respectively, are doing well neurologically and academically. Our patients demonstrate that abnormal imaging findings during acute stages do not preclude good clinical and radiologic recovery.

Tigroid pattern of cerebral white matter involvement in chromosome 6p25 deletion syndrome with concomitant 5p15 duplication.

Sub-telomeric deletions of the short arm of chromosome 6 are a well-described clinical entity characterized by developmental impairment, hypotonia, eye abnormalities and defects in the heart and kidneys. Chromosome 5p terminal duplication is a rarer entity, associated with developmental impairment and facial dysmorphism. We report a 3-year-old patient with a chromosome 6p25.1pter deletion and chromosome 5p15.1pter duplication who had global developmental impairment and unusual cerebral white matter changes, with hypoplastic corpus callosum and cerebellar vermis on magnetic resonance imaging -brain scan. We discuss the differential diagnosis to consider in patients with this appearance on magnetic resonance imaging -brain scan and reiterate the need for chromosome analysis in patients with this pattern of developmental anomaly. Tigroid pattern of cerebral white matter involvement has not been reported in chromosomal deletion/duplication syndromes. With the increasing use of molecular karyotyping for patients with multiple congenital anomalies and developmental delay, it is important to consider the exact size and nature of chromosomal deletion/duplication, in order to provide families with prognostic information and recurrence risk. This in turn, will help provide valuable information regarding the natural history of rare chromosomal imbalances.

Intracranial calcification in early infantile Krabbe disease: nothing new under the sun.

We report the cases of three children, one male and two females, with a diagnosis of early infantile Krabbe disease demonstrating intracranial calcification on computed tomography (CT). The pattern of calcification was similar in all individuals and involved the internal capsule and cerebral white matter. The presence of calcification caused some diagnostic confusion in what was otherwise a typical clinical and radiological presentation. This finding is not new and has previously been described in publications from the 1980s and 1990s reporting the CT and magnetic resonance imaging appearances of Krabbe disease. With increasing use of magnetic resonance as the first imaging modality for investigation of neurological disorders, characteristic CT appearances may be forgotten. This report serves as a reminder that Krabbe disease should be included in the differential diagnosis of disorders causing intracranial calcification.

Encephalopathy in children: an approach to assessment and management.

Childhood encephalopathy is an uncommon but significant paediatric presentation and is associated with significant mortality and long-term morbidity in survivors. By definition it is a somewhat non-specific presentation with a wide differential diagnosis and long list of possible investigations. Choice of investigation, including neuroimaging modality, can be a daunting prospect for the clinician faced with the encephalopathic child and it is important to select appropriately for a high diagnostic yield. Initial management centres on good emergency care irrespective of cause. More specific therapies however vary enormously, and appropriate treatment is important and influences outcome. Evidence exists for management of many of the individual conditions causing encephalopathy. This review aims to outline a clinical approach to selecting investigations to identify a specific cause and provides an overview of the treatment for the commoner causes of encephalopathy that a general paediatrician may reasonably expect to be faced with.