Emily de los Reyes

Profound Infantile Neuroretinal Dysfunction in a Heterozygote for the CLN3 Genetic Defect

The neuronal ceroid-lipofuscinoses are a group of diseases that are characterized by progressive neuroretinal symptomatology, progressive accumulation of autofluorescing waxy lipopigments (ceroid-lipofuscin) within the brain and other tissues, and cerebral atrophy. Juvenile neuronal ceroid-lipofuscinosis, or Batten disease, is a form of neuronal ceroid-lipofuscinosis that is characterized by onset of neuroretinal symptoms between 4 and 10 years. Juvenile neuronal ceroid-lipofuscinosis is the most common type of neuronal ceroid-lipofuscinosis in the United States and Europe and is inherited as an autosomal recessive genetic disorder. Research in the last decade has led to the identification of the responsible gene for juvenile neuronal ceroid-lipofuscinosis, which is designated as CLN3. CLN3 is located on chromosome 16p11.2-12.1. The major mutation is a 1.02 kb deletion, which removes exons 7 and 8. Both homozygotic and heterozygotic deletions at the CLN3 gene site have been associated with the clinical syndromes of juvenile neuronal ceroid-lipofuscinosis. We report a possible atypical case of neuronal ceroid-lipofuscinosis, an infant, who presented at 5 months of age with a lack of developmental milestones, poor vision, severe retinopathy, intractable seizures, and progressive cerebral atrophy. Extensive laboratory investigations, including thorough metabolic evaluations, were unremarkable except for neuroimaging studies, electroencephalography, and electroretinography, all of which showed abnormalities confirming both cerebral and retinal degeneration. Although skin and conjunctival biopsies did not show classic fingerprint cytosomes by electron microscopic study, which characterize juvenile neuronal ceroid-lipofuscinosis, a diagnosis of an atypical form of juvenile neuronal ceroid-lipofuscinosis was suspected on the basis of the clinical picture. The retinal abnormalities, surprisingly, were those believed to be diagnostic of juvenile-onset neuronal ceroid-lipofuscinosis, or Batten disease. Subsequently, a heterozygous mutation for the common 1.02 kb deletion characteristic of juvenile neuronal ceroid-lipofuscinosis was established. (J Child Neurol 2004;19:42—46).

Study of Intraventricular Cerliponase Alfa for CLN2 Disease

Background Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme‐replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children. Methods In a multicenter, open‐label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300‐mg dose for at least 96 weeks. The primary outcome was the time until a 2‐point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the rate of decline in 42 historical controls. We also compared the rate of decline in the motor–language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow‐up (in units of 48 weeks). Results Twenty‐four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2‐point decline in the motor–language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor–language score per 48‐week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. Conclusions Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device‐related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899.)

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.

Child Neurology: Diagnosis of Lambert-Eaton myasthenic syndrome in children

Objective: To report a case of Lambert-Eaton myasthenic syndrome (LEMS) in a child and review the existing literature of LEMS in children. Methods: We report a pediatric case of LEMS with the classic clinical triad of proximal weakness, autonomic dysfunction, and areflexia; the characteristic increment in compound motor action potential on high-frequency repetitive nerve stimulation; and positive serum P/Q-type voltage-gated calcium channel antibodies. Only 11 pediatric cases of LEMS have been reported in the literature. Results: The patients presentation with LEMS led to the diagnosis of occult neuroblastoma. Based on review of the existing pediatric literature, no consistent clinical or electrodiagnostic criteria exist to diagnose LEMS in children. Conclusions: There exists a need for consistent clinical criteria and electrodiagnostic testing for prompt diagnosis of LEMS in children. Prompt identification of LEMS will alert the physician to search for malignancy or another immune-mediated process.

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.

In Memoriam: Paul Richard Dyken, MD (1934-2017)*

Paul Richard Dyken, the consummate physician artist, passed away after a courageous battle with cancer on September 11, 2017. He was survived by his wife of 56 years, Linda Dyken, 3 children (Shelli, Jason, and Jill), and 5 grandchildren. He was a passionate teacher and a loyal friend. Although he was well known as an outstanding clinician, teacher, and physician, his love for life was in full evidence by his passion for family, travel, and art. His pioneering work with rare diseases such as myotonic dystrophy, Batten disease, and subacute sclerosing panencephalitis continue to affect our understanding of these disorders. Although Paul may have been known as a southern gentleman, he was born in Casper, Wyoming, in 1934. He went to Indiana University for his undergraduate and medical degrees and then completed an internship at Philadelphia General Hospital. He met his wife, Linda, on a blind date, and they married the following year in 1961, after which they moved to Indiana University to finish his residency. He added a year of neurophysiology training at Washington University in St Louis, then spent another year at the University of Chicago with Douglas Buchanan to sharpen his skills in pediatric neurology. He spent 4 years as a faculty member at Indiana University with his brother, Mark Dyken, before becoming the Director of Pediatric Neurology at Milwaukee Children’s Hospital (now Children’s Hospital of Wisconsin) and Chairman of the Neurology Department of the Medical College of Wisconsin. In 1972, Paul was lured to the Medical College of Georgia in Augusta, where he headed pediatric neurology for 13 years. He was chaired the Department of Neurology at the University of Southern Alabama in Mobile, Alabama, for 10 years prior to his retirement in 1994. Paul completed a sabbatical at Harvard University to learn electron microscopy, an essential technique for the diagnosis and classification of Batten disease. Dr Dyken was a founding member of the Child Neurology Society and served as the Society’s ninth president from 1980 to 1981. One of his enduring legacies will be the founding in 1975 of the Southern Pediatric Neurology Society (SPNS), where many neurologists forged their path of research presentations in a nonthreatening and relaxed manner. His mantra of “There is no such thing as a bad abstract” is followed to this day by the SPNS. As a testament to his humorous nature, his wry alternative name for SPNS was the Organization of Li’l Neurologists. He organized numerous conferences, most in New Orleans, Louisiana. The previous executive director, Dr Jean Teasley relates that he vigorously supported the conference from a personal standpoint, sometimes using his own resources to make the meeting successful. This conference allowed physicians to discuss both typical and rare diseases. Dr Dyken was found to have a meningioma in 1984 by serendipity. As a testament to his curious mind, he volunteered

Low-level expression of EPG5 leads to an attenuated Vici syndrome phenotype

Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8‐year‐old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well‐controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099‐6C > G). Reverse transcription‐polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17—which maintains an open reading frame—in 77% of the transcript, along with 23% expression of wild‐type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild‐type mRNA may result in a significantly attenuated Vici syndrome phenotype.