A novel variant in NEUROD2 in a patient with Rett-like phenotype points to Glu130 codon as a mutational hotspot

BackgroundNEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay.Case reportWe describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients.ConclusionsOur results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.     

Case report of a rare purine synthesis disorder due to 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR) deficiency

BackgroundAICA (5-aminoimidazole-4-carboxamide) ribosiduria is an inborn error in purine biosynthesis caused due to biallelic pathogenic variants in the 5-aminoimidazole-4-carboxamide ribonucleotide-formyltransferase/imp cyclohydrolase (ATIC) gene located on chromosome 2q35. ATIC codes for a bifunctional enzyme, AICAR transformylase and inosine monophosphate (IMP) cyclohydrolase, which catalyse the last two steps of de novo purine synthesis. This disorder has been previously reported in only 4 cases worldwide, and herein, we report the first from India.Case ReportThe proband presented with global developmental delay, developmental hip dysplasia (DDH), acyanotic heart disease and nystagmoid eye movements. Whole exome sequencing (WES) identified compound heterozygous pathogenic variants in the ATIC. A novel splice site variant; c.1321-2A > G and a previously reported missense variant; c.1277A > G (p.Lys426Arg) were identified. Segregation analysis of parents showed the father to be a heterozygous carrier for the splice site variant and the mother, a heterozygous carrier for the missense variant.ConclusionThis case of a rare genetic disorder of purine biosynthesis of ATIC deficiency is the first case reported from India. Early diagnosis lead to early interventional therapy and genetic counselling.     

The eldest case of MICPCH with CASK mutation exhibiting gross motor regression

BackgroundMICPCH is manifested as microcephaly associated with pontocerebellar hypoplasia and global developmental delay but developmental regression has never been reported. We describe the detailed clinical history of a woman with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) with a CASK mutation who exhibited gross motor regression after adolescence.Case: The patient experienced severe motor and intellectual developmental delay with microcephaly from infancy. The initial diagnosis was Rett syndrome based on her clinical features, including hand stereotypes and the absence of structural abnormality on magnetic resonance imaging (MRI) performed at the age of 5 years. Although gross motor abilities developed slowly and she could walk independently, she never acquired speech or understanding of languages. After adolescence, her motor ability gradually regressed so that she was unable to stand without support and moved with a wheelchair. At the age of 31 years, because of her atypical clinical course for Rett syndrome, whole exome sequencing was performed, which revealed a de novo heterozygous c.2068 + 1G > A mutation in the CASK gene (NM_001126055). Brain MRI revealed mild pontocerebellar hypoplasia compatible with the clinical phenotype of MICPCH.DiscussionThis case suggests that MICPCH with a CASK mutation might cause developmental regression after adolescence and might be regarded as a neurodegenerative disorder.     

A novel splice site CUL3 variant in a patient with neurodevelopmental delay

BackgroundCUL3-related neurodevelopmental disorder is a recently described rare genetic condition characterized by global developmental delay and intellectual disability. Five affected individuals have been reported worldwide. The molecular and phenotypic spectrum of the disorder has yet to be fully elucidated. Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder. We report the first individual with a neurodevelopmental disorder attributed to a CUL3 splice site variant.Case ReportThe patient presented with congenital developmental dysplasia of the hip and global developmental delay. A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site.ConclusionThis is the first report of an individual with a splice site variant causing CUL3-related neurodevelopmental disorder and expands our understanding of this rare condition.     

A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome

BackgroundAutism spectrum disorder is a major neurodevelopmental disorder. Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum.MethodsWe report a case of a male child who presented with global developmental delay, and autism. Additional clinical features in the child were prominent eyes, long palpebral fissures with eversion of lateral third of the lower eyelid, hypoplastic nipples, and persistent fetal fingertip pads. The clinical features were in favor of Kabuki-like syndrome. MRI brain revealed corpus callosal dysgenesis, mild cerebellar para-vermian, and vermian atrophy.ResultsTrio exome sequencing has revealed a novel pathogenic compound heterozygous variant c.145A >T (p.Lys49Ter) and c.224_242del (p.Val85GlufsTer88) in exon 2 of the C12orf57 gene.ConclusionThis is the first case of Temtamy syndrome reported from India with additional novel phenotypic features not reported previously and broadens the phenotypic spectrum of the disorder. In addition, it expands the spectrum of pathogenic variants in the C12orf57 gene.     

A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy

BackgroundCHOPS syndrome, caused by a mutation in the AFF4 gene, is a recently established and extremely rare genetic disorder, which has moderate phenotypic overlap with Cornelia de Lange syndrome. The main phenotypes include characteristic facial features, short stature, obesity, skeletal and pulmonary involvement, and neurodevelopmental impairment.Case reportWe report on a Korean girl with CHOPS syndrome presenting with an atypical manifestation. The patient was referred to the out-patient clinic to evaluate the underlying etiology of short stature, obesity, developmental delay, and Moyamoya disease. The patient showed characteristic facial features including a round face, thick eyebrows, and synophrys. Her developmental milestones had been delayed since infancy and a moderate degree of intellectual disability persisted. She was also diagnosed with Moyamoya disease at 6 years of age and had undergone synangiosis surgery thrice. Her renal arteries and infrarenal aorta were diffusely narrowed. A novel de novo missense variant, c.758C > T (p.Pro253Leu) in AFF4 was identified by whole exome sequencing. No additional candidate variants for her vascular manifestation were found except a susceptibility variant, c.14429G > A (p.Arg4810Lys) in RNF213, inherited from asymptomatic mother.ConclusionThis is the first case of CHOPS syndrome accompanied by systemic vasculopathy. More clinical observations and functional studies are required to clarify this association.     

A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders

IntroductionMutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders.Case reportThe patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as “variants of uncertain significance” and later upgraded to “likely pathogenic” based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNA^Gln aminoacylation with the c.1574G > A variant.ConclusionWe describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.     

Aromatic L-Amino acid decarboxylase deficiency: A new case from Turkey with a novel mutation

Aromatic L-amino acid decarboxylase (AADC), a vitamin B6-requiring enzyme that converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Deficiency of this enzyme results in developmental delay, muscular hypotonia, dystonia, involuntary movements, autonomic dysfunction, and oculogyric crises. We now report a 2-year-old Turkish boy with AADC deficiency confirmed by greatly reduced AADC activity in the plasma and by genetic studies. Mutation analysis revealed a homozygous mutation c.208C > T (p. His70Tyr) in exon 3 of the AADC gene which has not been described to date.     

Longitudinal study of striatal aromatic l-amino acid decarboxylase activity in patients with idiopathic rapid eye movement sleep behavior disorder

Study objectivesTo determine if nigrostriatal dopaminergic system function, evaluated by aromatic l-amino acid decarboxylase (AADC) activity using 6-[¹⁸F]fluoro-meta-tyrosine brain positron emission tomography (FMT-PET) can accurately and efficiently identify idiopathic rapid-eye-movement behavior disorder (IRBD) individuals at risk for conversion to a clinical diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB).MethodsWe assessed prospectively striatal aromatic l-amino acid decarboxylase activity using FMT brain PET imaging in IRBD patients who were followed systematically every 1–3 months for 1–10 years. IRBD patients (n = 27) were enrolled in this prospective cohort study starting in 2009. Those who underwent follow-up scans between January 2011 and September 2014 (n = 24) were analyzed in the present study.ResultsOf the 24 IRBD patients with baseline and follow-up FMT-PET scans, 11 (45.8%) developed PD (n = 6) or DLB (n = 5). Compared to IRBD patients who were still disease-free, those who developed PD (n = 5) or DLB with parkinsonism (n = 1) had significantly reduced bilateral putaminal FMT uptake during the follow-up. Furthermore, the rate of FMT decline between baseline and follow-up scans was higher in all converted patients, even for those with DLB without parkinsonism, than in IRBD patients who remained disease-free.ConclusionsFMT-PET, which represents a dynamic change in AADC activity over time, may also be a useful predictor for the risk of conversion to PD or DLB over short-term clinical follow-up periods, or when testing neuroprotective and restorative strategies in the prodromal phases of PD or DLB.     

Developmental delay and non-phenylketonuria (PKU) hyperphenylalaninemia in DNAJC12 deficiency: Case and approach

BackgroundHyperphenylalaninemia is a biomarker for several monogenic neurotransmitter disorders where the body cannot metabolise phenylalanine to tyrosine. Biallelic pathogenic variants in DNAJC12, co-chaperone of phenylalanine, tyrosine, and tryptophan hydroxylases, leads to hyperphenylalaninemia and biogenic amines deficiency.Methods and ResultsA male firstborn to non-consanguineous Sudanese parents had hyperphenylalaninemia 247 µmol/L [reference interval (RI) < 200 µmol/L] at newborn screening. Dried blood spot dihydropteridine reductase (DHPR) assay and urine pterins were normal. He had severe developmental delay and autism spectrum disorder without a notable movement disorder. A low phenylalanine diet was introduced at two years without any clinical improvements. Cerebrospinal fluid (CSF) neurotransmitters at five years demonstrated low homovanillic acid (HVA) 0.259 µmol/L (reference interval (RI) 0.345–0.716) and 5-hydroxyindoleaetic acid (5HIAA) levels 0.024 µmol/L (reference interval (RI) 0.100–0.245). Targeted neurotransmitter gene panel analysis identified a homozygous c.78 + 1del variant in DNAJC12. At six years, he was commenced on 5-hydroxytryptophan 20 mg daily, and his protein-restricted diet was liberalised, with continued good control of phenylalanine levels. Sapropterin dihydrochloride 7.2 mg/kg/day was added the following year with no observable clinical benefits. He remains globally delayed with severe autistic traits.ConclusionsUrine, CSF neurotransmitter studies, and genetic testing will differentiate between phenylketonuria, tetrahydrobiopterin or DNAJC12 deficiency, with the latter characterised by a clinical spectrum ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and movement disorder, normal DHPR, reduced CSF HIAA and HVA. DNAJC12 deficiency should be considered early in the differential workup of hyperphenylalaninemia identified from newborn screening, with its genotyping performed once deficiencies of phenylalanine hydroxylase (PAH) and tetrahydrobiopterin (BH4) have been biochemically or genetically excluded.     

Microstructural changes of brain in patients with aromatic L‐amino acid decarboxylase deficiency

Aromatic L‐amino acid decarboxylase (AADC) deficiency is an uncommon inherited neurometabolic disease. The clinical presentations and MR findings in children with AADC deficiency were investigated. Total 12 children (6 boys, 6 girls), aged from 9 to 50 months (mean, 23 ±13 months), with AADC deficiency, were enrolled for analysis. Of 12 patients enrolled, clinical presentations included global developmental delay with generalized hypotonia in 12 (100%), dystonia in 12 (100%), oculogyric crisis in 12 (100%), and excessive sweating in 8 (67%). Sleep problem was also found in 4 (33%). Of 15 MR examinations, the major changes included 6 (40%) with diffusely prominent bilateral frontal sulci, 10 (67%) with prominent frontal horns, and 12 (80%) with hypomyelination. In AADC patients, the frontal horn was significantly widened (P < 0.01), and the volume of caudate nucleus was also significantly smaller than that of controls (P = 0.02). The ratios of thickness of the splenium to that of the genu of corpus callosum were also significantly increased (P < 0.01). There was also significant decrease of fiber density indices in major white matter fiber tracts. Using Tract‐Based Spatial Statistics approach, we also revealed significant change in major fiber tracts related to language function and motor function. In conclusion, the present study indicated that AADC deficiency may have significant impact on brain development, especially the frontal lobe and fiber tracts related to language function and motor function. Long‐term follow‐up of brain MRI in patients with AADC deficiency may clarify the possible effect of AADC deficiency on brain development. Hum Brain Mapp 38:1532–1540, 2017. © 2016 Wiley Periodicals, Inc.     

Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants

BackgroundST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004.CaseWe report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy.DiscussionReports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.     

A nationwide survey of monocarboxylate transporter 8 deficiency in Japan: Its incidence,clinical course,MRI and laboratory findings

BackgroundMonocarboxylate transporter 8 (MCT8) deficiency is an X-linked recessive developmental disorder characterized by initially marked truncal hypotonia, later athetotic posturing, and severe intellectual disability caused by mutations in SLC16A2, which is responsible for the transport of triiodothyronine (T3) into neurons. We conducted a nationwide survey of patients with MCT8 deficiency to clarify their current status.MethodsPrimary survey: In 2016–2017, we assessed the number of patients diagnosed with MCT8 deficiency from 1027 hospitals. Secondary survey: in 2017–2018, we sent case surveys to 31 hospitals (45 cases of genetic diagnosis), who responded in the primary survey. We asked for: 1) perinatal history, 2) developmental history, 3) head MRI findings, 4) neurophysiological findings, 5) thyroid function tests, and 5) genetic test findings.ResultsWe estimated the prevalence of MCT8 deficiency to be 1 in 1,890,000 and the incidence of MCT8 deficiency per million births to be 2.12 (95 % CI: 0.99–3.25). All patients showed severe psychomotor retardation, and none were able to walk or speak. The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38). Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional.ConclusionFor early diagnosis, including in mild cases, it might be important to consider the clinical course, early head MRI, SEP, and fT3/fT4 ratio.     

Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Shanxi province

BackgroundPhenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive inborn error that affects phenylalanine (Phe) metabolism. It has a complex phenotype with many variants and genotypes among different populations. Shanxi province is a high-prevalence area of PAHD in China.MethodsIn this study, eighty-nine PAHD patients were subjected to genetic testing using Sanger sequencing, followed by multiplex ligation-dependent probe amplification analysis (MLPA). Allelic and genotypic phenotype values (APV and GPV, respectively) were used for genotype-based phenotypic prediction.ResultsFifty-one types of variants, including three novel forms, were identified. The predominant variant was p.R243Q (22.09%), followed by p.R53H (10.47%), p.EX6-96A > G (9.30%), p.V399V (5.23%) and p.R413P (3.49%). Notably, mild hyperphenylalaninemia (MHP) has a high prevalence in this region (up to 45.76%), and the variant p.R53H was solely observed in patients of MHP. According to the genotype–phenotype prediction, the APV/GPV system was well correlated with the metabolic phenotype of most PAHD patients.ConclusionWe have systematically constructed the mutational and phenotypic spectrum of PAH in Shanxi province. Hence, this study will help to further understand the genotype-phenotype associations in PAHD patients, and it may offer more reliable genetic counseling and management.     

Expanding the phenotype of COL4A1-related disorders—Four novel variants

ObjectiveCOL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes.MethodsWe identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing.ResultsAll the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants.ConclusionsOur findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.     

Aromatic L-amino acid decarboxylase deficiency associated with epilepsy mimicking non-epileptic involuntary movements

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inborn error of neurotransmitter biosynthesis that leads to a combined deficiency of catecholamines and serotonin and is characterized by global developmental delay, involuntary movements, and autonomic dysfunction. We report the case of an 11-year-old male patient with AADC deficiency who also had epileptic spasms and generalized tonic seizures with asymmetrical features, in addition to frequent involuntary non-epileptic movements. The clinical manifestation of the epileptic attacks apparently resembled that of non-epileptic attacks. It was difficult to differentiate between both attacks without the help of an ictal electroencephalographic study. The epileptic attacks were finally controlled by appropriate antiepileptic drugs. Because an association with epileptic seizures is uncommon in AADC deficiency, some cases may have been regarded as involuntary non-epileptic movements. This indicates that the differentiation of epileptic attacks from non-epileptic ones is indispensable for the adequate treatment of patients with AADC deficiency.     

A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay

BackgroundHeterozygous variants in TMEM63A have been recently identified as the cause of infantile-onset transient hypomyelination. To date, four TMEM63A variants have been reported in five patients. These patients exhibited favorable clinical course, developmental progress, and completion of myelination.Case reportThe patient was a 5-year-old girl with severe global developmental delay, absent speech, no turning over, no gazing, hypotonia, and daily episodes of autonomic seizures. Brain MRI showed hypomyelination of deep and subcortical white matter that appeared hyperintense in T2-weighted imaging from 2 months of age and that showed no change at 4 years of age. Exome sequencing of the patient and her parents revealed a novel de novo missense variant, NM_014698.3:c.1658G>T, p.(Gly553Val), in the TMEM63A gene, which was confirmed by Sanger sequencing. The variant has not been registered in public databases, and it substitutes a highly conserved glycine residue located in a pore-lining transmembrane helix. No other candidate variants were identified.ConclusionsAlthough TMEM63A variants are generally thought to cause transient hypomyelination with favorable developmental progress, identification of a de novo TMEM63A variant in our patient suggests that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures.     

Folinic Acid Responsive Epilepsy in Ohtahara Syndrome Caused by STXBP1 Mutation

BackgroundOhtahara syndrome is a severe condition with early onset of recurrent unprovoked seizures associated with abnormal electroencephalography and global developmental delay. Folinic acid–responsive seizures are treatable causes of Ohtahara syndrome, which is thought to be due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin.MethodHere we report a girl with Ohtahara syndrome who exhibited transient folinic acid responsiveness but without evidence of antiquitin dysfunction.ResultsShe was later found to have a known missense mutation (c.1439 C > T, p.P480 L) in exon 16 of the STXBP1 gene.ConclusionFor infants presenting with Ohtahara syndrome with responsiveness to folinic acid and negative antiquitin deficiency analyses, genetic testing for other possible causative genes such as STXBP1 mutation is recommended.     

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants

ObjectivePatients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.MethodsWe recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.ResultsWe identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.ConclusionOur patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.     

A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism

IntroductionMutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD).Objectiveto report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype.Patient and methodsAn Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood.A brain MRI showed moderate frontal atrophy. ¹⁸FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed.Results and conclusionA heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l-dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants.