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Objective To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. Methods A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. Results In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R2 = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean – 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: −3.85 ± 0.96 SD and −1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive value (PPV) was 56%. Combination of the HC and FCD criteria raised the PPV to 78%, decreasing the number of false positives from 11 to four, without missing any of the 14 micB cases. Conclusions Fetal vertical cranial biometric assessment in the mid-sagittal plane is feasible and correlates well with gestational age. In our series, a vertical cranial deformation was a frequent cause of a false Fmic diagnosis made on the basis of HC alone. Combination of the new vertical cranial biometric measurement with HC measurement can exclude these cases and thus improve diagnostic accuracy for Fmic. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Introduction: The prenatal diagnosis of fetal craniosynostosis is challenging, especially in single-suture cases. When sutures are obliterated, sound waves fail to penetrate the cortical bone, creating an evident acoustic shadow on the underlying brain. The objective of this study was to evaluate the yield of the ‘brain shadowing sign' (BSS) as a novel sonographic marker for craniosynostosis. Subjects and Methods: Patients with an antenatal diagnosis of fetal craniosynostosis (cases) and healthy controls paired for gestational age were enrolled in this retrospective case-control study. Two-dimensional scans were assessed by three examiners for the presence of the BSS and additional fetal findings. Results: The BSS was clearly depicted in all 24 cases on the first analysis and in 22 cases on the second analysis. No fetus from the control group (n = 48) presented the BSS in any of the analyses. Fifteen cases had isolated craniosynostosis and 9 were syndromic (Apert, Saethre-Chotzen and craniofrontonasal syndromes), which were diagnosed significantly earlier due to additional malformations. Discussion: The BSS is a novel sonographic marker of craniosynostosis which can be used to increase the diagnostic rate of this rare condition and does not require the use of high-definition three-dimensional transducers to be depicted.

Pontocerebellar hypoplasia (PCH) encompasses a group of neurodegenerative disorders. There are ten known subtypes with common characteristics of pontine and cerebellar hypoplasia or atrophy, neocortical atrophy, and microcephaly. PCH is associated with anterior horn cell degeneration in PCH1a and PCH1b due to mutations in the VRK1 and EXOSC3 genes. Late onset PCH1 has been described in single case reports. The molecular etiology remains mostly unknown. We describe two siblings from a consanguineous Moslem Arabic family with a unique combination of progressive cerebellar atrophy and a SMA-like anterior horn cell degeneration due to a homozygous mutation in the PLA2G6 gene (NM_003560.2). The PLA2G6 gene encodes phospholipase A2 beta, which is involved in the remodeling of membrane phospholipids, signal transduction and calcium signaling, cell proliferation and apoptosis. Mutations in PLA2G6 are known to cause Neurodegeneration with brain iron accumulation 2 (NBIA2): Our patients have some similarities with NBIA2; both are characterized by rapidly progressive psychomotor regression and cerebellar atrophy. However, NBIA2 is not known to exhibit anterior horn cell degeneration. Our patients' phenotype is more consistent with late onset PCH1; thus, indicating that the spectrum of clinical and radiological presentations of PLA2G6 mutations should be extended and that this gene should be included in the molecular evaluation of patients with late onset PCH1.

OPA1 related disorders include: classic autosomal dominant optic atrophy syndrome (ADOA), ADOA plus syndrome and a bi-allelic OPA1 complex neurological disorder. We describe metabolic stroke in a patient with bi-allelic OPA1 mutations. A twelve-year old girl presented with a complex neurological disorder that includes: early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment. A metabolic stroke occurred at the age of 12 years. The patient was found to harbor a de novo heterozygous frame shift mutation c.1963_1964dupAT; p.Lys656fs (NM_015560.2) and a missense mutation c.1146A > G; Ile382Met (NM_015560.2) inherited from her mother. The mother, aunt, and grandmother are heterozygous for the Ile382Met mutation and are asymptomatic. The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease. This case adds to a growing number of patients recently discovered with bi-allelic OPA1 mutations presenting with a complex and early onset neurological disorder resembling Behr syndrome. To the best of our knowledge metabolic stroke has not been described before as an OPA1 related manifestation. It is important to be aware of this clinical feature for a prompt diagnosis and consideration of available treatment.

Objectives To describe a unique posterior fossa neuroimaging characteristic of prenatal PHACES syndrome (PS): unilateral cerebellar hypoplasia (UCH) and ipsilateral posterior fossa (PF) cyst communicating with an asymmetrically distended 4th ventricle. Methods The registries of seven prenatal diagnosis centers were searched for cases with PF findings and a postnatal diagnosis of PS. All records were evaluated for ultrasound and MRI findings and the postnatal outcome. PS was diagnosed after birth according to the consensus statement on diagnostic criteria for PS from 2009. The imaging findings of the PS fetuses were compared to a group of consecutive cases with fetal UCH, whose postnatal diagnosis was not PS. Results The PS group included 10 fetuses. All were referred due to UCH accompanied by an ipsilateral retrocerebellar cyst. All pregnancies resulted in livebirths, all newborns had a large segmental facial hemangioma. In all PS fetuses the affected cerebellar hemisphere was upwardly displaced by an ipsilateral PF cyst communicating with an asymmetrically distended 4th ventricle. An upwardly rotated and deviated vermis merged with the contralateral cerebellar peduncles forming an elongated oblique connection between the cerebellar hemispheres, resulting in a unique cerebellar shape, “a tilted telephone receiver sign” (TTRS), on the coronal plane through the upper vermis.The non-PS group included 11 fetuses with UCH: clastic cerebellar lesions (8) and a unilateral PF arachnoid cyst (3). The TTRS was not depicted in any of them (p Conclusions The cerebellar TTRS is a specific fetal imaging feature of PHACES syndrome enabling its prenatal diagnosis.

To construct prenatal age-specific reference intervals for sonographic measurements of the optic nerve sheath diameter (ONSD) during gestation in normal fetuses. Prospective cross-sectional study of fetuses assessed in antenatal ultrasound units between 2010 and 2014. The examination was based on a technique for the sonographic assessment of ONSD previously published by our group. The mean values and SDs of the ONSD were modeled as a function of the gestational week by curve estimation analysis based on the highest adjusted R2 coefficient. Repeatability tests were performed to assess intraobserver variability and interobserver agreement. During the study period 364 healthy fetuses were enrolled. The mean values for the ONSD varied from 0.6 mm at 15-16 weeks to 2.8 mm at 37-38 weeks. The ONSD grows in a linear fashion throughout gestation, with a quadratic equation providing an optimal fit to the data (adjusted R2 = 0.957). Sonographic age-specific references for the fetal ONSD are presented. This data may assist in the decision-making process in fetuses with a suspected increase in intracranial pressure, or anomalies affecting the development of optic stalks, such as optic hypoplasia and septo-optic dysplasia.ZIEL: Bestimmung von pränatalen, altersbezogenen Referenzintervallen für sonografische Messungen des Durchmessers der Sehnervscheide („optic nerve sheath diameter“ = ONSD) bei normalen Feten über die gesamte Schwangerschaft. Prospektive Querschnittsstudie an Feten, die zwischen 2010 und 2014 in Zentren für Pränataldiagnostik beurteilt wurden. Die Untersuchung basierte auf einer zuvor von unserer Gruppe publizierten Methode zur sonografischen Bewertung des ONSD. Die Mittelwerte und SDs des ONSD wurden als Funktion der Schwangerschaftswoche durch Kurvenschätzungsanalyse basierend auf dem höchsten bereinigten R2-Koeffizienten dargestellt. Für die Bewertung der Intraobserver-Variabilität und Interobserver-Übereinstimmung wurden Reproduzierbarkeitsteste durchgeführt. Im Studienzeitraum wurden 364 gesunde Feten aufgenommen. Die Mittelwerte für den ONSD variierten von 0,6 mm in der 15. –16. Woche bis 2,8 mm in der 37. –38. Woche. Der ONSD nimmt während der Schwangerschaft linear zu, wobei eine quadratische Gleichung eine optimale Anpassung an die Daten liefert (bereinigter R2 = 0,957). Es wurden sonografische altersspezifische Referenzwerte für den fetalen ONSD vorgestellt. Diese Daten können bei Feten mit Verdacht auf intrakraniellen Druckanstieg oder bei Anomalien, die die Bildung der Augenstiele beeinträchtigen, wie z. B. optische Hypoplasie und septo-optische Dysplasie, zur Entscheidungsfindung beitragen.

Objectives Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Several studies have reported a significant association between ARSA and Down syndrome, as well as 22q11.2 microdeletion. The objective of this study was to assess the risk of abnormal chromosomal microarray analysis (CMA) findings in a large cohort of pregnancies with fetal ARSA as an isolated, as well as a non-isolated, sonographic anomaly. A secondary objective was to review the literature, examining the frequency of chromosomal microarray aberrations in fetuses with isolated ARSA. Methods Data from all pregnancies referred for invasive testing and CMA due to sonographic diagnosis of fetal ARSA, between 2013 and 2017, were obtained retrospectively from the computerized database of the Israeli Ministry of Health. The rate of clinically significant CMA findings in these fetuses was compared to that in a local control population of 2752 low-risk pregnancies with normal ultrasound and serum screening results. In addition, a literature search was conducted in PubMed, from inception to February 2018, of original studies in the English language describing the frequency and nature of microscopic and submicroscopic aberrations in fetuses with isolated ARSA. Results Of 246 pregnancies with isolated ARSA that underwent CMA analysis, a clinically significant finding was detected in one (0.4%) pregnancy (trisomy 21). This rate did not differ significantly from that in the control population (P = 0.1574). Of 22 fetuses with non-isolated ARSA, one (4.5%) additional case of trisomy 21 was noted. The frequency of trisomy 21 in this cohort also did not differ from that in the control population (relative risk, 5.5 (95% CI, 0.8-37.6)). The literature search yielded 13 additional relevant papers, encompassing 333 cases of isolated ARSA. Of 579 cases overall (including those of the present study), 13 (2.2%) cases of trisomy 21 were detected, with no cases of 22q11.2 microdeletion. Conclusion While an association may exist between non-isolated ARSA and Down syndrome, isolated ARSA might better serve as a soft marker for Down syndrome, rather than a routine indication for invasive prenatal testing. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Agenesis of the corpus callosum is currently diagnosed prenatally with ultrasound and MRI. While the diagnostic aspects of callosal defects are widely addressed, anatomo-histological data from fetal autopsies are sparse. Callosal defects were present in 50 fetal autopsies. Four distinct groups of complete, partial, hypoplastic, and mixed defects were determined by the gross and histologic details of the corpus callosum. These details helped to rule out other midline defects such as holoprosencephaly. Additional autopsy findings enabled specific diagnoses and suggested etiopathogeneses. Hypoplastic and mixed defects were associated with more abnormalities of the cerebral hemispheres and internal organs. The four groups did not differ according to gender, external dysmorphism, or cerebellar and brainstem anomalies. Defects were classified as syndromic (68 %), encephaloclastic (8 %), undetermined (14 %), or isolated (10 %) based on the autopsy findings. Isolated agenesis of the corpus callosum was diagnosed in only 10 % of the cases in this series, compared to higher numbers diagnosed by prenatal ultrasonography and MRI. Therefore, the autopsy, through its detailed, careful evaluation of external, as well as gross and histological internal features, can elucidate the etiopathogenesis of agenesis of the corpus callosum and suggest specific diagnoses which cannot be ascertained by prenatal imaging.

Background ARSACS (autosomal–recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. Methods We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. Results A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. Conclusions Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the “atypical” presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.

Objective Paroxysmal tonic upward gaze was initially described as a benign phenomenon with negative investigations and eventual complete resolution of symptoms. Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the CACNA1A gene has only been reported once. Methods We describe three patients with multiple episodes of paroxysmal tonic upward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. Results Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. Conclusion CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event.

SummaryObjective Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. Methods Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. Significance Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

Objectives Periventricular nodular heterotopia (PNH) is a malformation of cortical development which presents with heterogeneous imaging, neurological phenotype and outcome. There is a paucity of comprehensive description detailing the prenatal diagnosis of PNH. The aim of this study is to report neuroimaging features and correlated outcomes in order to delineate the spectrum of prenatally diagnosed PNH. Methods It was a retrospective study over 15 years in five tertiary centers. All fetuses with prenatally diagnosed PNH were collected. Fetal ultrasound and MRI were reviewed and genetic screening collected. Prenatal findings were analyzed in correlation to fetopathological analyses and post-natal follow up. Results Thirty fetuses (22 females and 8 males) with PNH were identified. The two major ultrasound signs were ventriculomegaly associated with dysmorphic frontal horns (60%) and posterior fossa anomalies (73.3%). On MRI, two groups of PNH were identified: the contiguous and diffuse PNH (n = 15, 50%), often associated with megacisterna magna, and the non-diffuse, either anterior, posterior or unilateral PNH. FLNA mutations were found in 6/11 cases with diffuse PNH. Additional cortical malformations were exclusively observed in non diffuse PNH (9/15; 60%). Twenty-four pregnancies (80%) were terminated. Six children aged 6 months to 5 years are alive. Five have normal neurodevelopment (all had diffuse PNH) whereas one case with non diffuse PNH has developmental delay and epilepsy. Conclusion PNH is heterogeneous but patients with diffuse PNH are a common subgroup with specific findings on prenatal imaging and implications for prenatal counseling.

Objective To examine the risk for clinically significant chromosomal microarray analysis (CMA) among fetuses with apparently isolated horseshoe kidney. Methods Data from all CMA analyses performed due to isolated horseshoe kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained from a computerized database. Risk estimation was performed comparing the rate of abnormal CMA findings to the general population, based on a systematic review encompassing 9272 pregnancies with normal ultrasound, and local data cohort of 5541 pregnancies undergoing CMA due to maternal request. Results Of 82 pregnancies with isolated horseshoe kidney, one loss-of-copy-number variant compatible with 16p13.11 microdeletion syndrome was demonstrated (1.2%). In addition, two variants of unknown significance (VOUS) were detected (2.4%). The relative risk for pathogenic CMA findings among pregnancies with isolated single horseshoe kidney was not significantly different from the control population (1.03–1.39%). Discussion To our best knowledge, our study is the first report describing the rate of clinically significant CMA findings in fetuses with isolated horseshoe kidney. The detection of one pathogenic CMA findings in our cohort implies that the value of CMA analysis in such pregnancies is similar to the general population.

Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes.

Aicardi-Goutières syndrome is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Mutations in 6 genes are known to cause the disease: 3 prime repair exonuclease1, ribonucleases H2A, B, and C, SAM domain and HD domain 1, and most recently ADAR1. HD domain 1 mutations were previously reported in the Ashkenazi-Jewish community. We report an additional patient of Ashkenazi-Jewish descent and review the other 3 cases affected with Aicardi-Goutières syndrome due to SAM domain and HD domain 1 ( SAMHD1) mutations described in Israel. We propose that there may be a phenotypic-genotypic correlation in accordance with the type of mutations inherited in the SAMHD1 genotype and suggest that Aicardi-Goutières syndrome may not be a rare disease in the Ashkenazi-Jewish population.

Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis. Our aim was to study the clinical spectrum of CS and natural history using a cross-sectional study design. Consecutive patients with CS were recruited to the study. Patients were diagnosed based on clinical features, along with elevated urinary levels of methylglutaconic and methylglutaric acid, and by identification of the disease-causing mutation in the OPA3 gene in most. All patients were examined by a neurologist and signs and symptoms were rated. 28 patients with CS (16 males, 21 families, age at last observation 28.6 ± 16.1 years, range 0.5-68 years) were included. First signs of neurological deficit appeared in infancy or early childhood, with delayed motor milestones, choreiform movements, ataxia and visual disturbances. Ataxia and chorea were the dominant motor features in childhood, but varied in severity among patients and did not seem to worsen with age. Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment. The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade. While visual acuity seemed to deteriorate, it did not correlate with age. CS is a rare neurogenetic disorder that causes serious disability and worsens with age. Spasticity significantly increases over the years and is the most crucial determinant of neurological dysfunction.

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.

Objective To examine the long-term neuropsychological outcome of children with a prenatal diagnosis of asymmetric ventricles or unilateral ventriculomegaly. Design A clinic-based neuropsychological study. Setting Paediatric neurology clinic. Population Thirty-three of 41 children, previously assessed at kindergarten age, with asymmetric ventricles or unilateral ventriculomegaly identified in utero, were recruited at school age for a neuropsychological follow-up. Methods All children, 9–11 years of age, underwent a battery of neuropsychological tests and the parents completed behavioural rating questionnaires. Main outcome measures Results of the neuropsychological assessment and parents' questionnaires. Results There were no significant differences between children diagnosed with either asymmetric ventricles or unilateral ventriculomegaly in most parameters relative to the general population; the full-scale IQ scores were 103.13 ± 12.43 and 103.56 ± 10.5, respectively. A significantly lower performance was found only on one measure of attention among the unilateral ventriculomegaly group and on writing speed tasks among the asymmetric ventricles group. Both study groups showed significantly higher scores than expected in the normal population on a verbal fluency test. Comparison of both groups combined with the normative population yielded significantly lower scores only in attention tests. Yet, the clinical population showed significantly higher scores on writing accuracy, processing speed and verbal fluency and lower rates of executive dysfunction. Conclusions Asymmetric ventricles or unilateral ventriculomegaly identified in utero does not appear to affect long-term mental development and school achievements. Further prospective research on a larger sample is needed in order to confirm our findings.

Introduction There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging. Patient and Methods We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed. Results The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease. Conclusions Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.

Genetic syndromes with proportionate severe short stature are rare. We describe two sisters born to nonconsanguineous parents with severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and severe intellectual disability. During infancy and early childhood, the girls had transient hepatosplenomegaly and low blood cholesterol levels that normalized later. A thorough evaluation including metabolic studies, radiological, and genetic investigations were all normal. Cholesterol metabolism and transport were studied and no definitive abnormality was found. No clinical deterioration was observed and no metabolic crises were reported. After due consideration of other known hereditary causes of post-natal severe linear growth retardation, microcephaly, and intellectual disability, we propose that this condition represents a newly recognized autosomal recessive multiple congenital anomaly-intellectual disability syndrome.

Background Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy, was diagnosed in four non-consanguineous apparently unrelated families of Jewish Moroccan ancestry. Common founder mutation(s) were assumed. Methods Genome-wide linkage analysis and whole exome sequencing were done, followed by realtime PCR and immunofluorescent microscopy. Results Genome-wide linkage analysis mapped the disease-associated gene to 0.5 Mb on chromosome 17p13.3. Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53 , segregating as expected for autosomal recessive heredity within all four families, and common in Moroccan Jews (∼1:37 carrier rate). The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi; c.2084A>G and c.1556+5G>A VPS53 founder mutations are predicted to affect the C-terminal domain of VPS53, known to be critical to its role as part of this complex. Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals. Conclusions Autosomal recessive PCCA type 2 is caused by VPS53 mutations.

Purpose: Epileptic encephalopathies (EEs) are a devastating group of epilepsies characterized by refractory seizures, cognitive arrest or regression, associated with ongoing epileptic activity, and a poor prognosis. De novo mutations in a number of genes, as well as rare, de novo copy number changes, are known to cause EE. However, the vast majority of cases have an unknown etiology...

Summary Purpose Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously. Methods We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. Key Findings We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients. Significance Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing.

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

Hereditary neuralgic amyotrophy is a rare autosomal dominant disorder involving recurrent episodes of painful brachial plexus neuropathies. Involvement of other nerves has been described in some families. The age of onset is from infancy to adulthood. Mutations in the SEPT9 gene were identified in approximately half of the hereditary neuralgic amyotrophy families. We evaluated a family with six affected members from three generations with a point mutation in the SEPT9 gene. One of the patients presented in the neonatal period with vocal cord paralysis necessitating intubation and prolonged ventilation. The neonatal presentation of vocal cord paralysis broadens the phenotypic spectrum of hereditary neuralgic amyotrophy. The identification of a SEPT9 mutation in a neonate with respiratory distress due to vocal cord paralysis expands the differential diagnosis in these patients.

Objective: To describe the prenatal imaging features enabling diagnosis of developmental venous anomalies (DVA). Methods: Four fetuses with unexplained persistent echogenic parenchymal brain lesions were studied. The evaluation included dedicated neurosonography, fetal MRI, serology for intrauterine infection, screening for coagulation abnormalities, and chromosomal microarray. Postnatal neurodevelopmental follow-up or autopsy results were assessed. Results: DVA presented as very slowly growing echogenic brain lesions without cystic components, calcifications, or structural changes on otherwise normal neurosonographic scans performed at 2- to 3-week intervals. A specific Doppler feature was a collecting vein draining the echogenic parenchyma. Fetal brain MRI depicted normal anatomy on half-Fourier acquisition single-shot turbo spin-echo and diffusion-weighted imaging. The rest of the evaluation was normal. Conclusions: In cases with a persistent, parenchymal echogenic lesion without clastic or structural changes, DVA should be considered. Demonstration of a collecting vein draining the lesion and normal brain anatomy on MRI confirm the diagnosis.

Introduction: We report the rare finding of recurrent periventricular pseudocysts (PVPC) in consecutive pregnancies in 4 families and their postnatal outcome. Materials and Methods: We reviewed the databases of 3 large ultrasound units searching for the diagnosis of PVPC in 2 pregnancies of the same patient. Results: The first case of recurrent PVPC was diagnosed in 2011 and since then 3 additional families were diagnosed (8 cases of PVPC all in all). All fetuses underwent fetal MRI that confirmed the presence of frontal or frontocaudal PVPC. Amniocentesis, when performed, demonstrated a normal karyotype. Termination of pregnancy was carried out in 2 pregnancies in 2 of 4 families. The remaining 6 pregnancies ended with a term delivery, and to date all babies are developing normally. Conclusion: The rare finding of recurrent brain PVPC in consecutive pregnancies raises the possibility of a hereditary etiology as opposed to a sporadic event. As in isolated PVPC, frontocaudal ‘familial PVPC' appears to carry a favorable prognosis.

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

Item does not contain fulltext OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.

Objectives To describe a cohort of fetuses with non-visualization of the cavum septi pellucidi (CSP) without callosal agenesis and to assess the significance of this finding with respect to postnatal development. Methods We reviewed the files of all patients referred because of suspected fetal supratentorial midline anomalies, and identified those fetuses with a diagnosis of non-visualization or obliteration of the CSP. Results From an initial cohort of 114 patients we identified 23 cases. Mean ( ± SD) gestational age at referral was 24.5 ± 1.3 weeks; referral diagnoses (with more than one in some cases) included: non-visualization or an echogenic CSP (n = 18), suspected callosal anomaly (n = 5), other findings (n = 5). The fetuses were examined for the first time at the Fetal Neurology Clinic at a mean gestational age of 26.6 ± 3.1 weeks (range, 22–34 weeks; median, 27 weeks). In all of the fetuses the zone where fluid should have been observed was echogenic. In 17 fetuses this was an apparently isolated finding and in six it was associated with other findings, but only one fetus had associated malformations. Follow-up was available for 16 children at a mean age of 17.4 months (range, 4–36 months; median, 19.5 months). Normal development was reported in 14 children. One child had infantile hypotonia but normal developmental milestones and another had mild motor delay and language delay. These two children did not have associated anomalies at the prenatal scan. Conclusion Non-visualization of the CSP is not always associated with agenesis of the corpus callosum. When isolated it may be considered a variation of normal development. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Mutations in the potassium channel-related gene KCTD7 were described so far in a single family with progressive myoclonus epilepsy. We describe a unique phenotype: acute onset of myoclonus and ataxia, associated with abnormal opsoclonus-like eye movements; improvement of clinical symptoms under steroid treatment; and appearance of epileptic activity on EEG 2 years later without overt seizures. After excluding possible genetic causes, whole-genome exome sequencing was performed in order to identify the causative gene. One heterozygous missense mutation (R84W) was detected by exome sequencing and a large heterozygous deletion of exons 3 and 4 by MLPA analysis. The father is heterozygous for the R84W mutation and the mother is heterozygous for the exon 3+4 deletion. The mutation affects a highly conserved segment of the predicted protein, changing a basic amino acid into neutral. The large deletion probably results in a truncated protein. The different phenotype broadens the spectrum of KCTD7-related diseases. Therefore, patients diagnosed as having opsoclonus-myoclonus with an atypical course should be evaluated for KCTD7 mutations.

Congenital myasthenic syndromes (CMS) are rare genetic disorders characterized by impaired neuromuscular transmission. They are caused by mutations in synaptic, presynaptic and post synaptic proteins. Rapsyn is a postsynaptic peripheral membrane protein that anchors the nicotinic acetylcholine receptor to the motor endplate. CMS patients of Iraqi and Persian Jewish origin, carry a common founder mutation in the E box of the RAPSN promoter region (− 38A-G) that causes impaired transcriptional activities of the promoter region. We describe a Persian Jewish family with two siblings affected with typical CMS, harboring the common heterozygous (− 38A-G) E-box mutation associated with a previously unreported heterozygous p.224 insT causing an insertion of Threonine in the TPR6 domain. To the best of our knowledge, this is the first mutation in the TPR6 domain and might give supportive evidence to the role of this domain in rapsyn self association and consequently co-clustering with AchR in the post synaptic membrane.

We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis, intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.

Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation.

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia. © 2012 Wiley Periodicals, Inc.

Silver–Russell syndrome (SRS) is a heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features. In 5–10% of SRS patients, a maternal uniparental disomy of chromosome 7 (UPD7) can be detected. We describe a 4.5-y old boy. Physical examination at the age of 4.5 y was remarkable for small stature, relatively big head, triangular face, broad forehead, pointed chin and clinodactyly. He had hypopigmented macules on his back with no evidence of asymmetry/hemihypertrophy. Clinical diagnosis of Silver–Russell syndrome was made. Maternal UPD of chromosome 7 was found, confirming the diagnosis. Along with the clinical findings that are described in this syndrome he had moderate developmental delay which is not commonly found in these patients and underwent an autistic regression around the age of 2 years. This association has only once been described before in this syndrome. A possible explanation is that the autism is not a part of SRS but is due to the UPD. Our case suggests an association of autistic regression with a locus on chromosome 7.

Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive disease. At present, no treatment or prevention of symptoms are available. There is considerable clinical variability, even within families. The gene whose defect causes FSHD has not been identified, but molecular diagnosis can be made by analyzing D4Z4 repeat length on chromosome 4q35. The results can support or rule out the clinical diagnosis of FSHD, but there are also “gray zone”, non-conclusive results. During the years 2000–6, 66 individuals (including 7 asymptomatic individuals), were tested in our institute for D4Z4 repeat number. In 77% of the cases the results were conclusive: two thirds of them supported a diagnosis of FSHD while in a third this diagnosis was ruled out. In 23% the results were in the gray zone. Cognitive involvement was rare, occurring only when the D4Z4 repeat size was very small (

The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity. Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by a slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the most frequent gene associated with HSP-TCC, encodes spatacsin, a protein of unknown function. We describe two siblings from an Arabic consanguineous family with slowly progressive spastic paraparesis, mental retardation, seizures, thin corpus callosum and periventricular white matter abnormalities. Homozygosity mapping identified a novel single candidate region of 7.3 Mb on chromosome 1p13.2-1p12. The finding of a new locus for AR-HSP-TCC further demonstrates the extensive genetic heterogeneity of this condition.

Various rearrangements involve the proximal long arm of chromosome 15, including deletions, duplications, translocations, inversions and supernumerary marker chromosome of an inverted duplication. The large marker 15, that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region, is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, early-onset central hypotonia, autism and autistic-like behavior, schizophrenia and mild dysmorphic features. We report a ten year-old girl with normal intelligence prior to the onset of seizures, who developed severe intractable epilepsy at the age of seven years. Family history was significant for a mother with recurrent episodes of acute psychosis. The patient’s and mother’s karyotype revealed 47,XX+m. Array comparative genomic hybridization (A-CGH) identified a gain of 13 BAC clones from 15q11.2 through 15q13.1, which was then confirmed by FISH to be part of the marker chromosome. This duplicated region contains the SNRPN/UBE3A locus. This case demonstrates that a duplication of 15q11-13 can present differently in the same family either as intractable epilepsy or as a psychiatric illness and that intelligence can be preserved. We suggest that CGH microarray should be performed in cases with intractable epilepsy or schizophrenia, with or without mental retardation.