Developmental Regression Research Articles

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital.

Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176T>C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993T>C and m.9176T>C), SURF1, and ALDH5A1 (≤50% 3year's survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year's survival). Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counseling, and to the design and monitoring of future clinical trials, the next frontier of LS research. ANN NEUROL 2022;91:466-482.

OP038: Novel whole methylome automated data analysis tool for investigation of unsolved diagnostic odyssey cases

The study of epigenetics has changed the lens in which we view both health and disease. Emerging tools in this field have brought new discoveries to the forefront of preventive, diagnostic and therapeutic markers. DNA methylation is an essential process that regulates chromatin structure and gene expression, and therefore affects many cellular functions including gene imprinting and cell differentiation. Using the power of molecular techniques and bioinformatics, we can now gain insight into methylation patterns at a single nucleotide level throughout the genome. In this study, we developed a methylation automated data analyzer to investigate putative multi-locus methylation defects in diagnostic odyssey cases, and to further appreciate differences in methylation patterns across the lifespan. Individual pathway analyses for genes DNMT3A, NLRP5, NLRP7, NPM2, PADI6 and ZFP42 were conducted. These genes were chosen because they are either known methyltransferases or may cause hypermethylation of H19 and/or hypomethylation of LIT1 . Additional genes from this analysis were chosen based on known direct interactions with the original input gene and co-expression with the input gene resulting in a final list of 15 genes of interest. Next, we filtered through the history of our exome sequencing (ES) cases from our clinical laboratory with high impact variants in these 15 genes of interest. Cases were chosen based on impact of the variant and allele frequency in gnomAD, which resulted in 11 cases, 10 of which were unsolved by ES. Methylation profiling was performed on all 11 cases using the Infinium MethylationEPIC 850K array. Using Python3.7, we developed our own unique Methylation Automation Data Analyzer (MADA). Using MADA, each case was analyzed and compared to either 74 female or 75 male healthy controls of various ages spanning from newborn to 81 years. Probes with a difference greater than or equal to 0.5 between the patient beta value and the mean beta value of the controls were selected. This final list of probes was investigated further based on genomic region, gene content, proximity to a CpG island and the individual patient’s phenotype. To investigate methylation patterns of various genomic regions across the lifespan, a separate algorithm within MADA was constructed. This analysis uses our cohort of healthy individuals (74 males and 75 females) and calculates the mean beta value for each age for each probe and thus allows for the observation of changes in methylation over time in healthy individuals from age newborn to 81 years. MADA provided insight into methylation of genomic regions that had otherwise been overlooked by conventional genetic testing in diagnostic odyssey cases. Here, we highlight three patients. Patient #1, a 13-year old male, had a de novo point variant in DNMT1 c.4636C>G; p.Pro1546Ala (NM_001130823.2) by ES. MADA produced a final list of 13 probes for which the genomic regions were all significantly hypermethylated compared to controls. This patient had additional clinical features that were atypical for the DNMT1 spectrum of phenotypes and MADA revealed other interesting findings that could potentially be contributing to the additional features. Patient #2, a 7-year old male, had a heterozygous maternally inherited variant in KHDC3L c.31_39dup9 p.Val11_Leu13dup (NM_001017361.3) by ES. MADA identified 11 probes of interest of which four regions covered by these probes were hypomethylated (including LARS2) and seven were hypermethylated as compared to the controls. This patient’s phenotype includes abnormal facial shape, autistic behavior delayed speech and language development, developmental regression, hyperpigmentation of the skin, intellectual disability, neurodevelopmental abnormality, and abnormal gait. Patient #3, a 10-year-old male with a paternally inherited variant NLRP7 c.2243_2249del7 (NM_001127255.1) identified through ES. The patient’s phenotype included absent speech, anxiety, aplasia cutis congenita of scalp, autistic behavior, brachycephaly, cortical dysplasia, dental crowding, intellectual disability, thin ear helix and progressive language deterioration. MADA identified 13 hits, including AFF2 and LARS2 both of which are hypomethylated in the patient compared to the controls. The second analysis investigated methylation patterns of various genomic regions across the lifespan. This tool allows for the input of any gene covered by the Illumina Infinium platform to be analyzed. We observed that there are critical points in an individual’s lifespan during which methylation of various genomic regions is altered that have not been previously described. These periods are related to important developmental stages such as infancy and puberty, among others. MADA can hence be used as a tool to further understand epigenomic changes during these critical periods throughout the lifespan, and the consequences of deviations from normal methylation patterns. There is growing evidence of “episignatures” or DNA methylation biomarkers for over 40 rare disorders in association with more than 60 genes. This study describes the development of a novel whole methylome automated data analysis tool, MADA, for the investigation of unsolved diagnostic odyssey cases. MADA offers an easy, streamlined approach for analysis of the methylome in undiagnosed ES cases and for uncovering potential episignatures in rare disorders.

EP025: Novel phenotype of aortic root dilatation and late onset of metabolic decompensation in patient with TMEM70 deficiency

TMEM70 deficiency causing mitochondrial complex V deficiency, nuclear type 2 [MIM: 614052] is the most common nuclear encoded defect affecting ATP synthase and has been well described in the literature as being characterized by neonatal/ infantile onset of poor feeding, hypotonia, lethargy, respiratory compromise, heart failure, lactic acidosis, hyperammonemia, and 3-methylglutaconic aciduria progressing to a phenotype of developmental delay, failure to thrive, short stature, non-progressive cardiomyopathy, microcephaly, facial dysmorphisms, hypospadias, persistent pulmonary hypertension of the newborn, and Wolff Parkinson White syndrome as well as metabolic crises followed by developmental regression.

X-linked adrenoleukodystrophy: A biochemical cause of developmental regression in a seemingly well child

This case report outlines the diagnostic journey of a child with X-linked adrenoleukodystrophy (X-ALD) and discusses the prevalence, investigation and treatment of the condition. X-ALD is a rare condition, with a combined prevalence of heterozygotes and hemizygotes of about 1 in 17,000 children.1 It causes a peroxisomal fatty acid oxidation disorder that leads to inflammatory disease in the cerebral white matter. Patients may present with developmental arrest or regression and language difficulties, though this may be misidentified as an attention deficit disorder.

Multi-omics approach characterises CRLS1 deficiency, a novel mitochondrial disorder

Introduction: The increasing integration of high-throughput genomic strategies, particularly whole exome (WES) and genome sequencing (WGS) has revolutionised mitochondrial diagnostics with the discovery of a growing list of novel disease genes. Application of ‘multi-omics’ technologies including proteomics, lipidomics and transcriptomics will improve the diagnostic gap. Case report: We present two individuals with progressive encephalopathy and biallelic variants identified on WES in the cardiolipin synthase 1 (CRLS1) gene. Additionally, the female infant had hypertrophic cardiomyopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus and died at 3.5 months. The 19-year-old male presented with neurodevelopmental regression, congenital nystagmus, sensorineural hearing loss and acquired microcephaly. Results: Respiratory chain enzyme analysis of skeletal muscle showed low Complex IV activity in the first patient. Mitochondrial morphology and biogenesis were impaired in her fibroblasts. Expression of wild-type CRLS1 restored her abnormal fibroblast morphology. Fibroblast proteomic profiling and mouse Crls1 knockout cell lines identified endoplasmic reticular, mitochondrial stress responses, and varying degrees of cardiolipin insufficiency. Lipid profiling in both demonstrated reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol. Collectively, these findings support that deleterious CRLS1 variants cause a novel mitochondrial disorder with multisystemic involvement. Conclusion: Innovative multi-omics approaches help establish novel diagnoses and provide insights into disease mechanisms.

EP020: Expanding the clinical spectrum of asparagine synthetase deficiency

Asparagine and glutamate are synthesized from aspartate and glutamine using the enzyme asparagine synthetase. A deficiency of this enzyme leads to asparagine synthetase deficiency (ASNSD). ASNSD is an autosomal recessive progressive neurological disorder classically characterized by congenital microcephaly, early onset epileptic encephalopathy, and developmental delay or regression. Seizures are typically present at birth but have been reported to start as late as 9 months of age. Asparagine levels may be low or normal in the serum but have been reported to be low or absent in the CSF.

Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease.

Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.

Regression in Early Childhood Development: An Unintended Outcome of Prolonged Hospitalization?

This brief review outlines a novel case study with targeted literature search. Patient X was a 21-month-old male who was receiving ongoing treatment for stage M MYCN-amplified high-risk neuroblastoma. Patient X's mother was considering refusal of further cancer-directed therapy because of the child's developmental regression noted during his prolonged hospitalization. Given the underlying malleability of the developing brain in early childhood, access to supportive services that facilitate ongoing neurodevelopment in hospitalized young children is of utmost importance; such services further reduce parental stress and likely enhances parental and medical team efficacy of care.

Progression of alternating hemiplegia of childhood‐related focal epilepsy to electrical status epilepticus in sleep with reversible encephalopathy

Mutations in the ATP1A3 gene (which encodes the main α subunit in neuronal Na+/K+-ATPases) cause various neurological syndromes including alternating hemiplegia of childhood. This rare disorder is characterized by paroxysmal episodes of hemiplegia, dystonia, oculomotor abnormalities, and occasionally developmental regression. Approximately 50% of alternating hemiplegia of childhood patients also have epilepsy, which is either focal or generalized. Seizures are often drug resistant. We report a 10-year-old girl with the D801N ATP1A3 mutation and alternating hemiplegia of childhood who manifested with drug-resistant focal seizures as an infant and throughout childhood. At the age of about10.5 years, her epilepsy evolved into electrical status epilepticus in sleep with generalized discharges. These changes coincided with developmental regression consistent with epileptic encephalopathy. Additionally, MRI and MR spectroscopy showed new cortical atrophy and markedly depressed N-acetyl aspartate peaks compared to previous normal studies. Electrical status epilepticus in sleep resolved after medication adjustments. She, now, only four months after her diagnosis of electrical status epilepticus in sleep, has regained most of the skills that were lost only a few months earlier. Our observations document that alternating hemiplegia of childhood can result in the above-described unique features; particularly, progression of focal epilepsy to electrical status epilepticus in sleep with generalized features and reversible epileptic encephalopathy.

Adrenocorticotropic Hormone (ACTH)-Induced Dyskinesias in Infantile Spasms: A Video Case Report

Case series Patients: Male, 10-month-old • Male, 8-month-old • Male, 5-month-old • Female, 4-month-old Final Diagnosis: ACTH-induced dyskinesias Symptoms: ACTH-induced dyskinesias Medication: — Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background:Infantile spasms is an age-specific epilepsy syndrome that occurs during infancy and is characterized by tonic and/or flexor-extensor spasms, hypsarrhythmia on electroencephalography (EEG), and neurodevelopmental regression. Adrenocorticotropic hormone (ACTH) is considered one of the main therapies for the treatment of infantile spasms, but despite its great efficacy, it is still associated with potential adverse effects.Case Reports:Four patients previously diagnosed with infantile spasms were treated with ACTH following the usual treatment regimen. All patients developed asymmetric, involuntary movements, with phenomenology characteristic of dyskinesia. The patients did not manifest loss of consciousness, and the EEG did not show epileptic activity during those episodes. In all cases, involuntary movements disappeared after the completion of the hormonal therapy.Conclusions:The adverse effect of hormonal therapy in infantile spasms is not well known in the literature and could be mistaken as seizures, leading to inappropriate management.

Predictors of language regression and its association with subsequent communication development in children with autism.

Language regression, broadly defined as the loss of acquired language skills in early childhood, is a distinctive feature of autism. Little is known about the factors underlying regression or the prognosis of children who exhibit regression. We examine potential predictors of language regression and test its association with language development in a prospective longitudinal sample of children with autism spectrum disorder (ASD) from diagnosis to age 10 years. We analysed data from Pathways in ASD, a prospective longitudinal study of 421 children enrolled around the time of an autism diagnosis between 2 and 5 years. Autism Diagnostic Interview-Revised data were available for 408 children, of whom 90 (22%) were classified as having language regression. Demographic and other health factors including caregiver education, family income, child sex, reported seizures, and age of enrolment did not differ between children with and without language regression. Children with language regression walked earlier and attained first words sooner than those without regression. However, both groups attained phrase speech at comparable ages. Those with regression exhibited greater delays in expressive and receptive communication over the follow-up period, although this effect was attenuated when accounting for baseline differences in motor and cognitive ability. Overall, those with language regression continued to exhibit expressive but not receptive communication delay compared to those without regression. Communication trajectories were heterogeneous to age 10 years, irrespective of regression status. Although language regression can be alarming, our findings confirm that its occurrence does not necessarily foreshadow worse developmental outcomes relative to those without regression. Although a discrepancy in age-equivalent communication skills may persist, this can be expected to be of less practical importance with rising average levels of skills. Future studies need to account for the significant variability in language trajectories by considering factors beyond developmental regression.

Missed Opportunities and the Impact of the Pandemic.

Benjamin is a 9-month-old, former 36-week gestation infant who presented to the high-risk infant follow-up clinic with parental concern for developmental regression. His mother reported that Benjamin seemed to be developing typically, but over the past 2 months, he has lost the ability to visually track objects, is not as engaged with her as he once was, and now only rarely makes babbling sounds. His mother also reported episodes of intermittent "bursts" of stiffening of his extremities and brief staring spells. Benjamin's mother described him as a "good, quiet baby." She commented that he used to laugh and cry more frequently but has recently been "very peaceful and calm." Benjamin's mother recently relayed her concerns for developmental regression to his pediatrician during an audio-only telehealth visit. Benjamin was referred to a pediatric neurologist, and the consultation visit is pending.His mother is a 28-year-old single parent whose pregnancy was complicated by pre-eclampsia, gestational diabetes, and anxiety. Benjamin required admission to the neonatal intensive care unit because of initial feeding difficulties. After 1 week, Benjamin was discharged to home and was referred for early intervention services. Owing to the pandemic, there were delays with initiating intervention, but bimonthly virtual interaction with a representative from the infant development program was eventually provided.Benjamin's mother expressed significant concerns regarding the potential of exposing him to a pandemic-related illness because of bringing her son to in-person medical visits. In fact, because of her concerns, she attended only virtual well-child pediatric visits over the past 6 months. A thorough social history revealed that she is a former dance studio instructor. The studio closed and she lost her primary source of income because of the pandemic. As a result, she decided to not send Benjamin to child care and maintained isolation from extended family members.On physical examination, pertinent findings included poor truncal tone, lack of orientation toward sounds, and limited eye contact. The Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) was administered, and the results indicated severe delays across all developmental areas, consistent with a diagnosis of global developmental delay.Benjamin's clinical presentation to the HRIF clinic and a history of developmental regression and intermittent body movements raised concerns for infantile spasms. He was transferred to the emergency department for evaluation and consideration for admission to the neurology service. An electroencephalogram confirmed epileptiform abnormalities consistent with infantile spasms, and he was immediately started on treatment.Impacts of the pandemic on the medical care of vulnerable/at-risk pediatric patients have included delayed receipt of early intervention services, parental fear regarding potential exposure to pandemic-related illness while seeking preventative care, increased use of virtual visit platforms for medical care and developmental intervention services, etc. What factors should be considered when providing support for these vulnerable/at-risk patients?

Whole-exome sequencing analysis to identify novel potential pathogenetic NPC1 mutations in two Chinese families with Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, affecting the nervous system and the internal organs. It is characterized by the presence of foam cells in bone marrow, liver, and spleen biopsies. Although many mutations in NPC1 have been identified to be related to disease onset, the relationship between genotype and phenotype remains unclear. To elucidate the genetic heterogeneity of NPC, we described the clinical manifestations and possible genetic pathogenesis of two patients from unrelated families with NPC. DNA was extracted from the peripheral blood of the two patients and their families and from healthy individuals. Whole-exome sequencing followed by Sanger sequencing was performed to verify the mutations identified in their families. We identified four mutations in NPC1 in the two patients from different families: c.1290delC (p.F431Lfs*18)/c.2807G > A(p.G936D) in family A and c.3604_3605insA (p.I1202Nfs*56)/c.881 + 3A > G in family B from their parents. Bioinformatics analysis predicted these mutations to be deleterious, suggesting that mutations in exons are highly conservative. The patient in family A presented with a developmental delay that was different from the typical symptoms of developmental regression in family B. Our study identified three novel mutations and one known mutation in NPC1 and evaluated their pathogenicity, enriching the NPC1 mutation and phenotype spectrum and providing a new basis for the genetic and prenatal diagnosis of this disease.

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log‐rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow‐up of affected individuals.

SSPE (SUBACUTE SCLEROSING PANENCEPHALITIS) - THE GREAT MASQUERADER

Background: SSPE is chronic progressive encephalitis affecting children and young adults which usually presents with cognitive decline and behavioural changes followed by periodic myoclonic jerks, seizures, vision loss and ataxia. High degree of suspicion is required as the presentation can be variable and can have many differentials. Aim: We aim to study various presentations of SSPE Methods and Material: Retrospective study was done to analyse various presentations in patients diagnosed with SSPE as per modied Dykens criteria from a tertairy care centre over a period of 2 years (1st January 2018-31st December 2020). Results: 6 cases of SSPE were identied. Case1 - 22 months old presented with subacute history of ataxia, multical myoclonus and developmental regression. Gradually myoclonus worsened to involve trunk and developed drop attacks. Case 2 - 17 years boy presented with single episode of seizure. Case 3- 25 years female with 5 months gestation presented with subacute vision loss followed by progressive cognitive decline, behavioural changes, Parkinsonism, Dystonia and stimulus sensitive myoclonus. Case4- 28 years female presented with rapidly progressive cognitive decline and behavioural changes. Case 5- 32 years male presented with history of myoclonic jerks and dropping of objects. Gradually developed progressive behavioural changes and cognitive decline and became vegetative. Case6 - 9 year old child presented with faciobrachial seizures (myoclonic jerks) and scholastic backwardness. Conclusions: SSPE can manifest with varied presenting complaints. Also, Results of EEG, MRI and CSF examination can change during the disease course. Therefore, high degree of suspicion is required for early diagnosis of this challenging entity.

Long-term outcome of patients with alpha-mannosidosis – A single center study

IntroductionAlpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study was to present the long-term follow-up of 12 Polish patients with AM, evaluate the clinical, biochemical, and molecular findings and progression of the disease. Material and methodsThe article presents a long-term (over 30 years) observational, retrospective, single-center study of patients with AM. ResultsThe hearing loss, as one of the first symptoms, was detected in childhood (mean age of 2 years and 6 months) in 10 patients. The other symptoms include: recurrent infections (all patients), inguinal hernias (6 patients), craniosynostosis (1 patient). The mean age at AM diagnosis was 6 years while median was 4 years (age range: 1 year and 8 months – 12 years). The most commonly identified variant in the MAN2B1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14years (range: 1 year – 26 years). Following birth, children with AM grow slowly, finally reaching the 3rd percentile (or values below the 3rd percentile). Hearing loss was not progressive while a gradual exacerbation of intellectual disability with no developmental regression was observed in all patients. Ataxia was diagnosed in 6 patients in the second decade of life (age range 15–20 years). ConclusionsOur study revealed the sensorineural hearing loss as one of the first noted symptom in AM which was congenital and non-progressive during the natural course of disease. A detailed anthropometric phenotype of AM patients was provided with observation of the growth decline during the long-term follow-up. Our study confirmed the existence of two distinguished clinical phenotypes of AM (mild and moderate), and also the lack of clear genotype-phenotype correlation.

A case of treatable encephalopathy, developmental regression, and proximal tremor

Tyrosine hydroxylase (TH) deficiency is an autosomal recessive condition first described as a progressive, early-onset hypokinetic-rigid and dystonic syndrome that was responsive to levodopa. Here we present a child with developmental regression, proximal tremor, and encephalopathy found to have tyrosine hydroxylase deficiency in whom treatment resulted in acquisition of developmental milestones.

Epilepsy features in ARID1B-related Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, caused by mutations in the ARID1B gene in over half of the cases. While the clinical characteristics of the syndrome have been increasingly described, a detailed evaluation of the epileptic phenotype in patients with ARID1B alterations and CSS has not been approached yet. We report seven patients with ARID1B-related CSS, focusing on epilepsy and its electroclinical features. The evolution of epilepsy and EEG findings of children with CSS are described and compared with patients previously reported in the literature. The patients described here reveal common features, consistent with those of patients previously described in the literature. The epilepsy phenotype of CSS due to ARID1B pathogenic variants may be described as focal epilepsy with seizures, variable in frequency, arising from motor areas, with onset in the first years of life and susceptibility to fever, and interictal perisylvian (centrotemporal) epileptiform abnormalities that are enhanced during sleep with possible evolution to an EEG pattern of continuous spike and wave during sleep (without documented developmental regression). Additional information emerging from other patients is needed to confirm this definition.

Experience in Diagnosing Neuronal Ceroid Lipofuscinosis Type-2

Introduction: Developmental regression is always an alarming symptom in children as it is an early sign of some genetic disorders, one of which is neuronal ceroid lipofuscinosis (NCL). NCL is a group of rare neurodegenerative disorder caused by accumulation of intracellular ceroid lipofuscin. Since 2017 an enzyme replacement therapy (ERT) has been approved by Food and Drug Administration (FDA) for this disease. The symptoms of NCL could be managed by ERT if detected early, and the child could live normally.Case: We present a case of a 6-year-and-5-month-old boy with developmental regression, speech delay, recurrent seizure, and visual impairment, who was diagnosed with NCL type 2 after genetic testing. Compound heterozygous mutations in tripeptidyl-peptidase 1 (TPP1) gene was revealed, consistent with very low level of TPP1 enzyme in this patient.Discussion: NCL is a fatal disease which is often misdiagnosed in early stage. Diagnostic delay of NCL often occurs due to lack of awareness which often leads to premature death.Conclusion: Knowledge regarding the disease is important for early detection and to slow down the disease progression.

Approach to Neurological Channelopathies and Neurometabolic Disorders in Newborns.

Ion channel disorders (channelopathies) can affect any organ system in newborns before 2 months of life, including the skeletal muscle and central nervous system. Channelopathies in newborns can manifest as seizure disorders, which is a critical issue as early onset seizures can mimic the presentation of neurometabolic disorders. Seizures in channelopathies can either be focal or generalized, and range in severity from benign to epileptic encephalopathies that may lead to developmental regression and eventually premature death. The presenting symptoms of channelopathies are challenging for clinicians to decipher, such that an extensive diagnostic survey through a precise step-by-step process is vital. Early diagnosis of a newborn’s disease, either as a channelopathy or neurometabolic disorder, is important for the long-term neurodevelopment of the child.