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PURPOSE: To investigate the treatment of infantile epileptic spasm syndrome (IESS) in Denmark. METHODS: National retrospective cohort study of all patients born 1996-2019 who had a diagnosis of IESS in the National Patient Registry. Medical records were reviewed to evaluate the diagnosis. Patients were included if semiology was compatible with IESS, or if unclear semiology if there was an abnormal EEG or EEG with hypsarrhythmia. RESULTS: Number of cases with a register based IESS diagnosis was 538. Medical records were unavailable in 48 and 164 did not fulfil the inclusion criteria. Thereby the cohort consisted of 326 children. Mean age at onset of IESS was 5.9 months and mean lead time to treatment was 26.6 days (SD= 63.5). Consistent with the Danish treatment guidelines most patients received vigabatrin as first treatment. In the cohort 44.7 % of patients solely received vigabatrin, whereas combined vigabatrin and corticosteroid was given to 28.3 % (either hydrocortisone or prednisolone). Other anti-seizure medication was given to 28.4 % within 90 days of IESS onset. Aetiology was prenatal (40.3 %), perinatal (10.5 %), postnatal (3.7 %), with unknown timing (10.2 %) or with unknown aetiology (33.5 %). The cohort was followed to a mean age of 8.2 years. At latest follow-up severe neurodevelopmental outcome was seen in 44.2 % and 76.4 % still had epilepsy. The incidence of IESS was 22 per 100.000 live births. CONCLUSION: In Denmark treatment algorithm is based on start of treatment with vigabatrin. A total of 44.7 % became seizure free by vigabatrin. Neurodevelopmental outcome was severe. A national incidence could be established.
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Anticonvulsivantes , Espasmos Infantiles , Vigabatrin , Humanos , Dinamarca/epidemiología , Espasmos Infantiles/epidemiología , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/diagnóstico , Anticonvulsivantes/uso terapéutico , Lactante , Femenino , Masculino , Estudios Retrospectivos , Vigabatrin/uso terapéutico , Electroencefalografía , Sistema de Registros , Recién Nacido , Preescolar , Resultado del TratamientoRESUMEN
PURA is mapped to chromosome 5q31 and plays a vital role in neuronal development and synapse formation. Here, we aim to explore PURA's impact on cognitive development and epilepsy phenotype by comparing patients with single nucleotide variants (SNPs) in the PURA gene (PURA-SNP patients) to those with 5q31 microdeletions including PURA (5q31del + PURA) and those with 5q31 microdeletions not including the PURA gene (5q31del-PURA). A systematic literature search was conducted in PubMed. Two separate searches were performed in order to find patients with PURA SNPs and 5q31 microdeletions. This review includes data from 191 patients collected from a total of 18 articles; 174 of the patients had PURA SNPs, 13 had 5q31 microdeletions involving the PURA gene, and 4 had 5q31 microdeletions without PURA gene implication. All patients exhibited hypotonia, feeding difficulties and dysmorphic features, however epilepsy was primarily present in patients with PURA syndrome, that is, groups PURA-SNP and 5q31del + PURA. Regarding the developmental milestones the 5q31del + PURA group stood out as being the most severe, while the 5q31del-PURA group showed a relatively mild phenotype. Our findings support the hypothesis of PURA being the key contributor of developmental delay and epilepsy among patients with PURA syndrome.
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Deleción Cromosómica , Cromosomas Humanos Par 5 , Discapacidades del Desarrollo , Epilepsia , Humanos , Cromosomas Humanos Par 5/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Polimorfismo de Nucleótido Simple , Fenotipo , Proteínas de Unión al ADN/genética , Masculino , Femenino , Factores de Transcripción/genética , Síndrome , PreescolarRESUMEN
Cognitive dysfunction is a well-known consequence of epilepsy in children. This review summarizes cognitive difficulties presenting in different types of childhood epilepsy. The possibility of screening and monitoring cognitive dysfunction is desirable to provide optimal support and treatment. The clinical test tool EpiTrack Junior is introduced. It was developed for screening and continuous monitoring of cognitive function in children with epilepsy.
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Disfunción Cognitiva , Epilepsia , Niño , Humanos , Anticonvulsivantes/uso terapéutico , Pruebas Neuropsicológicas , Epilepsia/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , CogniciónRESUMEN
Self-limited epilepsy with centrotemporal spikes (SeLECTS) is one of the most frequent epilepsies in childhood, characterised by typical clinical presentation with characteristic EEG findings. This review investigates the existing knowledge regarding cognitive function, the potential effect of anti-seizure medicines on cognitive development as well as prognosis of SeLECTS based on recent studies. There is evidence supporting that SeLECTS may not be as benign as previously assumed due to the possible neurocognitive comorbidities.
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Electroencefalografía , Epilepsia Rolándica , Humanos , Cognición , PronósticoRESUMEN
OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.
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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have exacerbated existing socioeconomic inequalities in health. In Argentina, public hospitals serve the poorest uninsured segment of the population, while private hospitals serve patients with health insurance. This study aimed to assess whether socioeconomic inequalities in low birth weight (LBW) risk changed during the first wave of the COVID-19 pandemic. METHODS: This multicenter cross-sectional study included 15929 infants. A difference-in-difference (DID) analysis of socioeconomic inequalities between public and private hospitals in LBW risk in a pandemic cohort (March 20 to July 19, 2020) was compared with a prepandemic cohort (March 20 to July 19, 2019) by using medical records obtained from ten hospitals. Infants were categorized by weight as LBW < 2500 g, very low birth weight (VLBW) < 1500 g and extremely low birth weight (ELBW) < 1000 g. Log binomial regression was performed to estimate risk differences with an interaction term representing the DID estimator. Covariate-adjusted models included potential perinatal confounders. FINDINGS: Of the 8437 infants in the prepandemic cohort, 4887 (57â¢9%) were born in public hospitals. The pandemic cohort comprised 7492 infants, 4402 (58â¢7%) of whom were born in public hospitals. The DID estimators indicated no differences between public versus private hospitals for LBW risk (-1â¢8% [95% CI -3â¢6, 0â¢0]) and for ELBW risk (-0â¢1% [95% CI -0â¢6, 0â¢3]). Significant differences were found between public versus private hospitals in the DID estimators (-1â¢2% [95% CI, -2â¢1, -0â¢3]) for VLBW risk. The results were comparable in covariate-adjusted models. INTERPRETATION: In this study, we found evidence of decreased disparities between public and private hospitals in VLBW risk. Our findings suggest that measures that prioritize social spending to protect the most vulnerable pregnant women during the pandemic contributed to better birth outcomes. FUNDING: No funding was secured for this study.
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Psychotic symptoms such as hallucinations and delusions can be the result of a primary psychiatric disorder. However, they may also be the manifestation of various underlying somatic diseases. Rapid diagnosis and treatment are crucial to the outcome of the prognosis. A common evidence-based diagnostic approach during the initial phase has yet to be established, but a comprehensive medical evaluation may detect treatable causes. This review presents several potential diagnostic considerations for children and adolescents with psychotic symptoms based on novel systematic reviews and guidelines.
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Deluciones , Trastornos Psicóticos , Enfermedad Aguda , Adolescente , Niño , Alucinaciones , Humanos , Pronóstico , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/terapiaRESUMEN
While psychotic symptoms may be the result of a primary psychiatric disorder, they can also be the presenting symptom of an underlying somatic disease. The organic aetiology can vary from benign and transient to severe and enduring disorders. Early diagnosis and treatment can be crucial to the prognosis, though potentially challenging as well, given that several of the organic aetiologies are rare and therefore difficult to identify. This case report describes two pediatric patients with psychiatric manifestations as a result of 22q11.2 deletion syndrome and anti-N-methyl-D-aspartate receptor encephalitis.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Aracnodactilia , Craneosinostosis , Trastornos Psicóticos , Adolescente , Niño , Diagnóstico Precoz , Humanos , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/etiologíaRESUMEN
Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the treatment differs accordingly. Early diagnosis and treatment may improve the outcome, but many patients are initially misdiagnosed. Evaluation includes seizure semiology, electroencephalography, cerebral magnetic resonance imaging and genetic and metabolic testing. Treatment varies among centres, and initial treatment may include vigabatrin and/or corticosteroids. In recent years, as summarised in this review, knowledge has substantially increased regarding genetic aetiologies and treatment regimens.
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Espasmos Infantiles , Anticonvulsivantes/uso terapéutico , Niño , Electroencefalografía , Humanos , Lactante , Imagen por Resonancia Magnética , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/tratamiento farmacológico , Vigabatrin/uso terapéuticoRESUMEN
OBJECTIVE: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. METHODS: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. RESULTS: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. SIGNIFICANCE: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
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Epilepsia/genética , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.6/genética , Anticonvulsivantes/uso terapéutico , Ataxia/genética , Niño , Preescolar , Disfunción Cognitiva/genética , Electroencefalografía , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Movimiento/genética , Hipotonía Muscular/genética , Linaje , Índice de Severidad de la EnfermedadRESUMEN
Acquired demyelinating syndromes are inflammatory demyelinating CNS diseases. They can be either monophasic, such as acute disseminated encephalomyelitis (ADEM), or relapsing, such as multiple sclerosis (MS). In children, ADEM is more common before puberty, whereas MS becomes increasingly more frequent during puberty. This is a case report of a 13-year-old boy with acute onset of a spinal cord syndrome and possible encephalopathy. We discuss relevant diagnostic workup including testing for antibodies against myelin oligodendrocyte globulin and aquaporin-4, treatment, and risk of MS.
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Encefalomielitis Aguda Diseminada , Vaina de Mielina , Glicoproteína Mielina-Oligodendrócito , Adolescente , Autoanticuerpos , Niño , Encefalomielitis Aguda Diseminada/inmunología , Humanos , Masculino , Oligodendroglía , Médula Espinal , SíndromeRESUMEN
PREMISE OF THE STUDY: The production of banana (Musa spp.; Musaceae) plants is affected by various types of somaclonal variations (SV), including dwarfism. However, methods for specific detection of SV are still scarce. To overcome this, a metabolite-based method for detection of dwarf variants was evaluated. METHODS: The gas chromatography-mass spectrometry (GC-MS) metabolite profile of dwarf banana variants was investigated and compared to that of normal-healthy (N) and cucumber mosaic virus (CMV)-infected plants using principal components analysis and partial least squares discriminant analysis (PLS-DA). RESULTS: Significant differences among the sample groups were observed in 82 metabolites. Rhamnose was exclusively present in dwarf plants but allothreonine and trehalose were present in all but SV samples. Cellobiose was only detected in N plants, while 45 other metabolites, including methyl-glucopyranoside, allopyranose, lactose, phenylalanine, and l-lysine were detected in all but CMV-infected samples. PLS-DA models were able to detect SV, CMV, and N plants with 100% accuracy and specificity. DISCUSSION: The GC-MS metabolite profile can be used for the rapid, specific detection of SV at early plant production stages. This is the first metabolite-based characterization and detection of somaclonal variation in plants.
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Seizures in the neonatal period are practically always a symptom of an underlying illness. Quick diagnosis and treatment can be crucial to the outcome. A few aetiological factors account for most of the seizures. However, a significant number is caused by rare conditions such as metabolic or genetic disorders, and arriving at the right diagnosis can be challenging. Previous studies indicate, that a standardized algorithm clearly improves the diagnostic success. This article presents an overview of aetiological factors and an algorithm for a standardized work-up.
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Algoritmos , Convulsiones/diagnóstico , Infarto Cerebral/complicaciones , Infarto Cerebral/diagnóstico , Humanos , Hipoglucemia/complicaciones , Hipoglucemia/diagnóstico , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/diagnóstico , Recién Nacido , Hemorragias Intracraneales/complicaciones , Hemorragias Intracraneales/diagnóstico , Errores Innatos del Metabolismo de los Metales/complicaciones , Errores Innatos del Metabolismo de los Metales/diagnóstico , Pruebas en el Punto de Atención , Convulsiones/etiología , Convulsiones/genética , Convulsiones/terapiaRESUMEN
OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.
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Epilepsias Mioclónicas/genética , Proteínas de Homeodominio/genética , Fenotipo , Convulsiones/genética , Adolescente , Niño , Proteínas de Unión al ADN/genética , Bases de Datos Genéticas , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/genética , Femenino , Humanos , Lactante , Masculino , Adulto JovenRESUMEN
Ketogenic diet (KD) has for a long time been known as an effective treatment for medically intractable epilepsy. However, the underlying mechanism is still unknown. Recent work indicates, that several mechanisms exist for KD, including neurotransmitter regulation, glucose restriction, effects of fatty acids, altered mitochondrial function and mammalian target of rapamycin pathway. Revealing the mechanisms of KD provides a better insight in the pathophysiology of epilepsy and helps the development of new treatments of epilepsy and other neurological disorders.
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Dieta Cetogénica , Niño , Epilepsia/dietoterapia , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Humanos , Mitocondrias/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
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Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.2/fisiología , Trastornos del Neurodesarrollo/genética , Bloqueadores de los Canales de Sodio/uso terapéutico , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Dinamarca/epidemiología , Epilepsia/epidemiología , Femenino , Humanos , Lactante , Masculino , Mutación , Fenotipo , Adulto JovenRESUMEN
Until now, ethosuximide (ESM), sodium valproate (VPA) and lamotrigine have been considered the drugs of choice in the management of childhood absence epilepsy, and there has been no high-validated evidence to distinguish their effects. New research shows, however, that while VPA and ESM are equally effective, ESM is the best tolerated of the two drugs, when considering cognitive adverse effects. This is of major importance, as cognitive comorbidities can be dire in childhood absence epilepsy, possibly affecting the psychosocial prognosis of the patients. More research is needed in this area.
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Epilepsia Tipo Ausencia , Anticonvulsivantes/uso terapéutico , Niño , Trastornos del Conocimiento/epidemiología , Comorbilidad , Electroencefalografía , Epilepsia Tipo Ausencia/diagnóstico , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/epidemiología , Epilepsia Tipo Ausencia/fisiopatología , Etosuximida/uso terapéutico , Medicina Basada en la Evidencia , Humanos , Pronóstico , Ácido Valproico/uso terapéuticoRESUMEN
Chronic tic disorder and Tourette syndrome are both chronic and impairing neurobiological disorders starting in childhood with a prevalence between 0.4 and 1.6%. Traditionally, pharmacological therapies have been first-line treatment but are often associated with adverse effects. Recently behavioural therapy has shown to be effective in treating tics and today both habit reversal (HR) and exposure and response prevention (ERP) are recommended as first-line treatments. HR and ERP are now available for Danish patients. This article describes the evidence and recommendations for both therapies.
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Terapia Conductista/métodos , Inhibición Psicológica , Trastornos de Tic/terapia , Adolescente , Adulto , Niño , Medicina Basada en la Evidencia , Hábitos , Humanos , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Síndrome de Tourette/terapia , Adulto JovenRESUMEN
Isolated complex II deficiency is a rare cause of mitochondrial disease and bi-allelic mutations in SDHB have been identified in only a few patients with complex II deficiency and a progressive neurological phenotype with onset in infancy. On the other hand, heterozygous SDHB mutations are a well-known cause of familial paraganglioma/pheochromocytoma and renal cell cancer. Here, we describe two additional patients with respiratory chain deficiency due to bi-allelic SDHB mutations. The patients' clinical, neuroradiological, and biochemical phenotype is discussed according to current knowledge on complex II and SDHB deficiency and is well in line with previously described cases, thus confirming the specific neuroradiological presentation of complex II deficiency that recently has emerged. The patients' genotype revealed one novel SDHB mutation, and one SDHB mutation, which previously has been described in heterozygous form in patients with familial paraganglioma/pheochromocytoma and/or renal cell cancer. This is only the second example in the literature where one specific SDHx mutation is associated with both recessive mitochondrial disease in one patient and familial paraganglioma/pheochromocytoma in others. Due to uncertainties regarding penetrance of different heterozygous SDHB mutations, we argue that all heterozygous SDHB mutation carriers identified in relation to SDHB-related leukoencephalopathy should be referred to relevant surveillance programs for paraganglioma/pheochromocytoma and renal cell cancer. The diagnosis of complex II deficiency due to SDHB mutations therefore raises implications for genetic counselling that go beyond the recurrence risk in the family according to an autosomal recessive inheritance.