SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome.

OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.

Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients.

Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.

Síndrome de Aicardi: estudio retrospectivo de una serie de siete casos / Aicardi syndrome: retrospective study of a series of seven case reports

Introducción. El síndrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clásicamente definido por la tríada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y métodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediátrica de síndrome de Aicardi en dos hospitales universitarios durante un período de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolución fue a espasmos más allá de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, además de lesiones oftalmológicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio óptico (n = 3). Otros hallazgos fueron cardiopatía ongénita, anomalías costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El síndrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmológicas, las anomalías de la migración y organización neuronal y los quistes intracraneales. El pronóstico es grave por su elevada morbimortalidad y por la frecuente evolución a epilepsia refractaria y retraso mental grave (AU)

Introduction. The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. Patients and methods. Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. Results. We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. Conclusions. The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation (AU)

[Aicardi syndrome: retrospective study of a series of seven case reports]. / Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.

INTRODUCTION: The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. PATIENTS AND METHODS: Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. RESULTS: We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. CONCLUSIONS: The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation.

TITLE: Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.Introduccion. El sindrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clasicamente definido por la triada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y metodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediatrica de sindrome de Aicardi en dos hospitales universitarios durante un periodo de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolucion fue a espasmos mas alla de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, ademas de lesiones oftalmologicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio optico (n = 3). Otros hallazgos fueron cardiopatia congenita, anomalias costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El sindrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmologicas, las anomalias de la migracion y organizacion neuronal y los quistes intracraneales. El pronostico es grave por su elevada morbimortalidad y por la frecuente evolucion a epilepsia refractaria y retraso mental grave.