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We aim to describe double gonosomal mosaicism in the GRIN2A gene in a mother who passed on two different pathogenic variants at the same nucleotide to her two affected children. We studied a boy with epilepsy and intellectual disability, along with his sister and mother who exhibited language impairment and learning difficulties without epilepsy. We identified in the proband a splice-site variant in GRIN2A (c.1008-1G>A) inherited from his mother. Subsequent testing of his sister revealed a different change at the same nucleotide c.1008-1G>T, which was also present in the mother's DNA at 3.9% allele frequency. The co-occurrence of two mutational events at the same nucleotide is extremely rare. Since a chance occurrence is unlikely, we hypothesise that a base mismatch may introduce instability triggering a second event. In this family, the mother carries three alleles, of which one is at very low frequency. This complex genetic landscape poses diagnostic challenges since low-level mosaicism may escape detection via conventional methods. Applying specific technology becomes crucial, as double mosaicism might prove to be more prevalent than anticipated severely impacting diagnostic accuracy and genetic counselling.
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Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.
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Moléculas de Adhesión Celular Neuronal , Movimiento Celular , Proteínas de la Matriz Extracelular , Mutación Missense , Proteínas del Tejido Nervioso , Proteína Reelina , Serina Endopeptidasas , Humanos , Animales , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratones , Femenino , Masculino , Movimiento Celular/genética , Neuronas/metabolismo , Neuronas/patología , Polimicrogiria/genética , Polimicrogiria/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Heterocigoto , Lisencefalia/genética , Lisencefalia/patología , AlelosRESUMEN
COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.
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KCNB1-associated encephalopathy is characterized by intellectual disability (ID), autism spectrum disorder and epilepsy. Specific treatments are still lacking. We describe a 12-year-old boy with severe ID and treatment-resistant seizures due to a pathogenic KCNB1 variant. His EEG showed a CSWS pattern. Aged 11, he started treatment with highly purified cannabidiol (CBD) and has been seizure free for 18 months, with significant EEG and social skills improvements. This suggests CBD may benefit CSWS, likely due to its anti-inflammatory properties. Some preclinical studies also indicate CBDs interact with voltage-gated channels, leading us to speculate its possible role for treating KCNB1 related encephalopathy.
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Cannabidiol , Electroencefalografía , Niño , Humanos , Masculino , Cannabidiol/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/complicaciones , Canales de Potasio Shab/genéticaRESUMEN
OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.
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Epilepsia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto Joven , Estudios de Cohortes , Discapacidades del Desarrollo/genética , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Epilepsia/patología , Estudios de Asociación Genética , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , FenotipoRESUMEN
Biallelic CNTNAP2 variants have been associated with Pitt-Hopkins-like syndrome. We describe six novel and one previously reported patients from six independent families and review the literature including 64 patients carrying biallelic CNTNAP2 variants. Initial reports highlighted intractable focal seizures and the failure of epilepsy surgery in children, but subsequent reports did not expand on this aspect. In all our patients (n = 7), brain MRI showed bilateral temporal gray/white matter blurring with white matter high signal intensity, more obvious on the T2-FLAIR sequences, consistent with bilateral temporal lobe dysplasia. All patients had focal seizures with temporal lobe onset and semiology, which were recorded on EEG in five, showing bilateral independent temporal onset in four. Epilepsy was responsive to anti-seizure medications in two patients (2/7, 28.5%), and pharmaco-resistant in five (5/7, 71.5%). Splice-site variants identified in five patients (5/7, 71.5%) were the most common mutational finding. Our observation expands the phenotypic and genetic spectrum of biallelic CNTNAP2 alterations focusing on the neuroimaging features and provides evidence for an elective bilateral anatomoelectroclinical involvement of the temporal lobes in the associated epilepsy, with relevant implications on clinical management.
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Epilepsia del Lóbulo Temporal , Epilepsia , Niño , Humanos , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/cirugía , Electroencefalografía , Epilepsia/complicaciones , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/cirugía , Convulsiones/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed.
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Espasmos Infantiles , Humanos , Espasmos Infantiles/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Convulsiones/patología , Atrofia/patología , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Dynamin 1 is a GTPase protein involved in synaptic vesicle fission, which facilitates the exocytosis of neurotransmitters necessary for normal signaling. Pathogenic variants in the DNM1 gene are associated with intractable epilepsy, often manifested as infantile spasms at onset, developmental delay, and a movement disorder, and are located in the GTPase and middle domains of the protein. We describe a 36-year-old man with autism and moderate intellectual disability who experienced only a few generalized seizures between the age 16 and 30 years. Using a whole sequencing approach, we identified the c.1994T>C p.(Leu665Pro) de novo novel missense pathogenic variant in the GTPase effector domain (GED) of the DNM1 protein. Structural analyses suggest that this substitution impairs both the stalk formation and its interactions, known to be important for the dynamin-1 physiological cellular function. Our data expand the spectrum of phenotypes associated with pathogenic variants in the DNM1 gene, linking a variant in the GED domain with autism and onset in the adolescence of mild epilepsy, a phenotypic presentation remarkably different from the early infantile epileptic encephalopathy associated with pathogenic variants in the GTPase or middle domains.
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Background: Walker-Warburg syndrome (WWS) (OMIM #236670) is an autosomal recessive disorder characterized by congenital muscular dystrophy, hydrocephalus, cobblestone lissencephaly, and retinal dysplasia. The main genes involved are: POMT1, POMT2, POMGNT1, FKTN, LARGE1, and FKRP. Case report: We present a fetus with WWS showing at ultrasound severe triventricular hydrocephalus. Pregnancy was legally terminated at 21 weeks +2 days of gestation. In vivo and postmortem magnetic resonance revealed corpus callosum agenesis and cerebellar hypoplasia. Cobblestone lissencephaly was observed at post-mortem. Next generation sequencing (NGS) of 193 genes, performed on fetal DNA extracted from amniocytes, detected two heterozygous mutations in the POMT2 gene. The c.1238G > C p.(Arg413Pro) mutation was paternally inherited and is known to be pathogenic. The c.553G > A p.(Gly185Arg) mutation was maternally inherited and has not been previously described. Conclusion: Compound heterozygous mutations in the POMT2 gene caused a severe cerebral fetal phenotype diagnosed prenatally at midgestation allowing therapeutic pregnancy termination.
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Lisencefalia de Cobblestone , Hidrocefalia , Síndrome de Walker-Warburg , Humanos , Femenino , Embarazo , Síndrome de Walker-Warburg/diagnóstico , Síndrome de Walker-Warburg/genética , Mutación Missense , Lisencefalia de Cobblestone/genética , Mutación , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Presentación en Trabajo de Parto , Pentosiltransferasa/genéticaRESUMEN
Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.
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Lisencefalia , Proteína Reelina , Adulto , Cerebelo/anomalías , Niño , Discapacidades del Desarrollo/genética , Humanos , Lisencefalia/complicaciones , Mutación , Malformaciones del Sistema Nervioso , Proteína Reelina/genéticaRESUMEN
In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in "real life" clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies - mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available.
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Epilepsia , Epilepsia/diagnóstico , Epilepsia/genética , Exoma , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mosaicismo , FenotipoRESUMEN
CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.
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Epilepsia , Trastornos del Neurodesarrollo , Proteínas de Unión al ADN/genética , Electroencefalografía , Epilepsia/genética , Humanos , Mutación , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
PURA syndrome is a distinct form of developmental encephalopathy, characterized by early-onset hypotonia, severe developmental delay, intellectual disability, epilepsy and respiratory and gastrointestinal disorders. We report a child with PURA syndrome, harbouring a previously described mutation, whose phenotype included two peculiar aspects: (1) hypokinetic-rigid syndrome, which was part of the clinical presentation from an early stage of the disease, and (2) reflex seizures, consisting of a series of spasms. We provide detailed clinical description and video recordings demonstrating both these aspects that are newly described in PURA syndrome. The early clinical features described here may therefore be included in the complex phenotype associated with PURA gene mutations and may help in the early diagnosis of patients. Furthermore, PURA syndrome should be considered in the differential diagnosis of early-onset bradykinetic rigid syndromes.
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Epilepsia , Discapacidad Intelectual , Proteínas de Unión al ADN/genética , Humanos , Hipotonía Muscular , Mutación , Fenotipo , Reflejo , Convulsiones/diagnóstico , Convulsiones/genética , Síndrome , Factores de Transcripción/genéticaRESUMEN
Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo-occipito-parietal regions of both hemispheres with "double-cortex" (Dobyns' 1-2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the CEP85L gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic CEP85L variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with CEP85L variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.
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Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/complicaciones , Proteínas del Citoesqueleto/genética , Lisencefalia/genética , Proteínas de Fusión Oncogénica/genética , Fenotipo , Preescolar , Heterocigoto , Humanos , Lisencefalia/complicaciones , Masculino , Secuenciación del ExomaRESUMEN
OBJECTIVE: To report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters. METHODS: Clinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology. RESULTS: Since their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum. CONCLUSIONS: This report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.
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Cerebral folate transporter deficiency syndrome, caused by FOLR-1 mutations is characterized by late infantile onset, severe developmental regression, epilepsy, and leukodystrophy. An extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid provides a crucial clue to its diagnosis and is a treatment target. Oral or intravenous folinic acid (5-formyltetrahydrofolate) administration improves clinical symptoms and brain magnetic resonance imaging (MRI) findings. We describe three siblings carrying a novel homozygous FOLR1 nonsense mutation, that were referred due to intractable epilepsy and progressive neurological decline. Brain MRI showed hypomyelination and cerebellar atrophy. Folinic acid (oral and intravenous) supplementation, initiated after over 15 years illness, has failed to result in any sizeable clinical or neurophysiological improvement. Cerebral folate transport deficiency bears overlapping clinical features with many severe developmental encephalopathies. It is crucial to recognize FOLR1 signs and establish an early clinical and molecular diagnosis in order to provide timely folinic acid treatment and improve outcome.
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Receptor 1 de Folato/deficiencia , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Distrofias Neuroaxonales/diagnóstico , Distrofias Neuroaxonales/genética , Hermanos , Adolescente , Alelos , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Consanguinidad , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Manejo de la Enfermedad , Epilepsia/diagnóstico , Epilepsia/genética , Femenino , Receptor 1 de Folato/genética , Ácido Fólico/administración & dosificación , Pruebas Genéticas , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación , Distrofias Neuroaxonales/terapia , Fenotipo , Síndrome , Resultado del TratamientoRESUMEN
Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that â¼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.