Developmental Skills and Neurorehabilitation for Children With Batten Disease: A Retrospective Chart Review of a Comprehensive Batten Clinic.

BACKGROUND: Batten disease is a rare, progressive neurogenetic disorder composed of 13 genotypes that often presents in childhood. Children present with seizures, vision loss, and developmental regression. Neurorehabilitation services (i.e., physical therapy, occupational therapy, and speech-language therapy) can help improve the quality of life for children and their families. Owing to the rarity of Batten disease, there are no standardized clinical recommendations or outcome assessments. To describe developmental profiles, current dose of neurorehabilitation, and outcome assessments used clinically for children diagnosed with Batten disease. METHODS: Electronic medical records of 70 children with Batten disease (subtypes n = 5 CLN1; n = 25 CLN2; n = 23 CLN3; n = 17 CLN6) were reviewed (7.0 ± 3.4 years). Descriptive statistics were used to describe clinical features, developmental skills, dose of neurorehabilitation, and outcome assessment use. RESULTS: Across CLN subtypes, most children experienced vision impairments (61%) and seizures (68%). Most children demonstrated delays in fine motor (65%), gross motor (80%), cognitive (63%), and language skills (83%). The most common frequency of neurorehabilitation was weekly (42% to 43%). Two standardized outcome assessments were used to track developmental outcomes: Peabody Developmental Motor Scales, second edition (30% of children completed this assessment) and Preschool Language Scales, fifth edition (27.4% of children completed this assessment). CONCLUSIONS: Neurorehabilitation professionals should understand the clinical features and prognosis for children with Batten disease. The child's clinical features and family preferences should guide the rehabilitation plan of care. Future work needs to be completed to define dosing parameters and validate outcome assessments for neurorehabilitation services.

Editorial commentary on "Gait phenotype in Batten disease: A marker of disease progression".

Batten disease, also known as neuronal ceroid lipofuscinosis, refers to a diverse group of 13 hereditary inborn errors of metabolism resulting in the abnormal accumulation of autofluorescent storage material in lysosomes leading to neurodegeneration, typically with associated intractable epilepsy, behavioral dysregulation, cognitive, motor, language and visual decline, as well as a shortened life expectancy [1]. Assessment of disease progression within this population is fraught with difficulty because individuals may have limited attention or cooperation affecting compliance with requested tasks, or have visual impairment reducing options for methods of assessment. Further, language and cognitive assessments have been designed to assess typically developing individuals based on specific age limits, which then fail to capture low developmental functioning once the mental age of the individual drops below the basal age of the assessment tool. Yet, metrics to measure disease progression are essential to inform therapeutic decision-making, prognostication, and clinical trial outcomes.

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients.

BACKGROUND: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. METHODS: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. RESULTS: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). CONCLUSION: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.

Language Regression in an Atypical SLC6A1 Mutation.

Recent technological advances in exome sequencing or targeted gene sequencing with epilepsy panels have allowed clinicians to better understand the pathogenesis and clinical presentation of children with epilepsy. We present a child with a SLC6A1 mutation with language delay and autistic spectrum disorder and remind the reader that the identification of specific mutations in these conditions increase the likelihood of identification of potential therapeutic targets.

Unique Characteristics of the Photoparoxysmal Response in Patients With Neuronal Ceroid Lipofuscinosis Type 2: Can EEG Be a Biomarker?

OBJECTIVE: The objective was to identify unique features of the photoparoxysmal response seen in patients with neuronal ceroid lipofuscinosis type 2 as compared to patients with a photoparoxysmal response associated with other epilepsy syndromes. METHODS: Electroencephalograms from patients with neuronal ceroid lipofuscinosis type 2 seen at the authors' institution in the past 10 years as well as electroencephalograms (EEGs) reported to have a photoparoxysmal response during a single year were reviewed. RESULTS: A photoparoxysmal response was seen in 60% of the patients with neuronal ceroid lipofuscinosis type 2. This was most commonly seen with low frequency intermittent photic stimulation (76%) which often occurred in a time-locked fashion (63%) and was seen on the patient's initial EEG (78%). A unique pattern the authors called "sentinel" discharge was identified in 30% of EEGs in patients with neuronal ceroid lipofuscinosis. CONCLUSIONS: Photoparoxysmal responses in patients with neuronal ceroid lipofuscinosis type 2 have features which are distinguishing from photoparoxysmal responses seen in other epilepsies.

Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease.

INTRODUCTION: X-linked Charcot-Marie-Tooth (CMT1X) disease is caused by mutations in the GJB1 gene. We describe a young man who presented with recurrent central nervous symptoms and transient white matter changes in the setting of a novel mutation in the GJB1 gene. METHODS: Evaluation included clinical examination, neuroimaging, electrophysiological, and molecular genetic studies. RESULTS: Clinical examination on 2 admissions 5 years apart demonstrated hemiparesis with findings of underlying peripheral neuropathy. Electrophysiologic studies revealed a sensorimotor polyneuropathy. MRI studies from both admissions revealed white matter changes, with improvement on an intervening study. Mutation analysis showed a novel mutation (c.98T>A; p.Ile33Asn) in the GJB1 gene. CONCLUSIONS: Mutations in GJB1 can result in recurrent central nervous system symptoms with transient white matter signal changes on MRI. In patients presenting with hemiparesis, the presence of signs of a peripheral neuropathy may facilitate identification of CMT1X, and is likely to affect clinical management.

Safety and pharmacokinetics of ribavirin for the treatment of la crosse encephalitis.

BACKGROUND: La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development. METHODS: In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days). RESULTS: In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 µM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications. CONCLUSIONS: Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication.

Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders.

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.

Phenotypic variations in 3 children with POLG1 mutations.

Autosomal inherited mitochondrial diseases have been of increasing interest among clinicians and mitochondrial research groups because these diseases are caused through a secondary effect on the mitochondrial DNA. It was thought that the genetic stability of mitochondrial DNA relies on the accuracy of DNA polymerase gamma. Mutations of DNA polymerase gamma 1 gene (MIM# 174763) have been shown to be a cause of mitochondrial disorders associated with Mendelian disorders characterized by multiple mitochondrial DNA deletions or depletions. To date, several clinical phenotypes associated with polymerase gamma mutation have been reported presenting in both adults and children. We present 3 children in whom were found to have reported pathogenic DNA polymerase gamma 1 mutations: heterozygous p.G517V in 2 half siblings and heterozygous p.T251I and p.P587L in the other. The aim of this communication is to report 3 pediatric cases associated with DNA polymerase gamma 1 mutations to augment the expanding clinical phenotype that has been previously reported.

Danon disease: an unusual presentation of autism.

Danon disease is an X-linked cardioskeletal myopathy, originally reported as "lysosomal glycogen storage disease with normal acid maltase," resulting from a primary deficiency of lysosome-associated membrane protein-2 because of mutations in the lysosome-associated membrane protein-2 gene. Classic clinical features in males include cardiomyopathy (100%, eventually), myopathy (90%), and mental retardation (70%), but mostly of a mild degree. We report on an unusual presentation in a patient with autism, motor delay, and a normal cardiac evaluation. The presence of multiorgan involvement, including elevated liver enzymes, abnormal cranial magnetic resonance imaging, and diffuse hypotonia with swallowing difficulties, prompted a muscle biopsy. A quadriceps muscle biopsy was performed, and the findings were most suspicious for a glycogen storage-type disease. Subsequently, a pathogenic lysosome-associated membrane protein-2 mutation was found. To our knowledge, there are no previous clinical reports of autism in children with Danon disease.

Periodic lateralized epileptiform discharges in La Crosse encephalitis, a worrisome subgroup: clinical presentation, electroencephalogram (EEG) patterns, and long-term neurologic outcome.

La Crosse virus encephalitis is the most common mosquito-borne virus in children in the United States. La Crosse virus encephalitis has emerged as a significant health concern due to its potential for acute morbidity, including seizures, alterations in mental status, and, in rare cases, death, as well as the potential for chronic morbidity, including, epilepsy and cognitive and behavioral disorders. The aim of this study is to provide a clinical description of the largest series of children reported with periodic lateralizing epileptiform discharges (PLEDS) associated with La Cross virus encephalitis with reference to their clinical course, seizure type, electroencephalogram (EEG) patterns, and 2- and 10-year long-term neurologic outcome. In addition, to evaluate whether this subset of children may indeed have more severe disease than children with La Crosse virus encephalitis without PLEDS, comparisons are made between the 2 groups on specific variables. All patients presented with fever and disorientation; 6 of the 9 (66%) presented with seizures. PLEDS localized to the temporal lobe in 7 patients (77%). The children with PLEDS had longer intensive care unit stays (6.5 +/- 2.4 vs 3.2 +/- 1.9; P < .0001), a higher rate of intubation (88% vs 20%; P < .001), and a higher rate of cerebral herniation (1%; P < .05) than children with La Crosse virus encephalitis without PLEDS. Follow-up data on the subset with PLEDS also suggest a relatively high rate of epilepsy and behavioral difficulties with hyperactivity symptoms, memory deficits, and school difficulties. The implications for recognition, management, and follow-up of this worrisome subset of patients with La Crosse virus encephalitis are discussed.

Levetiracetam in the treatment of Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is an epileptic encephalopathy characterized by multiple seizure types, mental retardation, and a slow spike-and-wave pattern on electroencephalography. Medical intractability is common. We identified a case series of six patients diagnosed with Lennox-Gastaut syndrome in which levetiracetam was initiated as add-on therapy for the management of seizures. At follow-up, four patients experienced 100% reduction of their myoclonic seizures; two patients had greater than 50% reduction of their atonic seizures, and four patients experienced 100% reduction in their generalized tonic-clonic seizures. Tonic seizures were not responsive to treatment. The most common side effect was irritability; the most positive change involved alertness. In this small sample, levetiracetam appeared effective in reducing seizures in Lennox-Gastaut syndrome. This preliminary study is limited by its retrospective design and small number of patients, but positive findings warrant a larger scale, multicenter study.