Hypoplasia Of Corpus Callosum Research Articles

P144 – 3081: A new mutation for pontocerebellar hypoplasia type 6

Objective Pontocerebellar hypoplasia is part of a group of autosomal recessive neurodegenerative disorders with perinatal onset. The rarity and genetic heterogeneity of this group of pathologies make diagnosis a challenge. Cerebellar hypoplasia is usually present with variable atrophy of cerebellum, ventral pons and neocortex, ventriculomegaly and microcephaly. At least ten subtypes of pontocerebellar hypoplasia have been identified. The type 6 is associated with encephalopathy, hypotonia, apnea and seizures difficult to control. The gene involved is the RAR2 that encodes mitochondrial protein arginil-TRNA sintetase2. The goal of this work is present a new mutation of this entity. Methods Herein we present two clinical cases of a new mutation in the gene of Pontocerebellar hypoplasia type 6, and briefly review the pathogenesis. Results Two siblings of a co-sanguineous family developed feeding problems within the first days after birth. A generalized hypotonia that evolved to hypertonia and pyramidal signs during the first month. They both had in the first two-weeks of life seizures that progressed to a refractory epilepsy, general deterioration and apneas, and utterly dying before 12 months. Lab tests were normal (Transferrin cdt, VLFA chain, sialic acid, amino-acids and organic-acids chromatography, pipecolic acid, purines and pyrimidines). The CSF's lactate was slightly elevated but a dysfunction of pyruvate desidrogenase could never be proved, and CSF's glicose, neurotransmitters and folate were normal. The aCGH was normal. Muscle biopsy with normal pattern. The MRI showed hypoplasia of corpus callosum and cerebellum. Due to lack of diagnosis, exome sequence was performed revealing homozygous mutation (c.451+4A>G) in gene RARS2 that leads to a change in position +4 of intron 6, which can be presumed to affect the splincing. Conclusion This case illustrates, the clinical presentation and evolution of pontocerebellar hypoplasia type 6. The authors emphases the importance of exome sequence, in order to achieve a diagnosis.

Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice

Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia.

UNUSUAL PRESENTATION OF SPLIT CORD MALFORMATION TYPE I ASSOCIATED WITH MYELOMENINGOCELA

Objective – We report an unusual case of split cord malformation (SCM) associated with open spinal dysraphism and other anomalies of the central nervous system. Case report – A male newborn was admitted to the Pediatric Intensive Care Unit immediately after birth by Caesarean delivery. Clinical examination and diagnostics (MRI) showed open spinal dysraphism in the distal part of the spine (level L5 and S1), split cord malformation type I which separated two hemicords, tethered cord and syringomyelia. Two days after birth microneurosurgery was performed. Cranial and cervical MRI showed Chiari I and corpus callosum hypoplasia. There was no hydrocephalus. Preoperatively the patient had paraparesis and discretely moved his left foot. MRI showed a dilated bladder so he may have had urinary retention. The postoperative recovery was satisfactory. The patient did not have any additional neurological deficit. The patient was followed up by a neurosurgeon, pediatric surgeon, pediatrician and physiatrist. Control MRI scans showed significant regression of the syrinx and some ascensus of the medulla. About 18 months after operation the patient had discrete paresis of the left foot. Conclusion – Complex spina bifida is an extremely rare condition. In this paper we describe this interesting case of complex spina bifida: a split cord malformation characterized by atypical bony morphology with a dural fold into the bone septum.

Truncating mutation in NFIA causes brain malformation and urinary tract defects.

Chromosome 1p32-p31 deletion syndrome involving the Nuclear factor I/A (NFIA) gene is characterized by corpus callosum hypoplasia or defects and urinary tract defects. Herein we report on a case resembling the 1p32-p31 deletion syndrome carrying a de novo truncating mutation (c.1094delC; p.Pro365Hisfs*32) in the NFIA gene, confirming that haploinsufficiency of the NFIA gene is a major determinant of this syndrome.

Intervenção neurofuncional pediátrica em agenesia do corpo caloso: relato de caso

ObjectiveTo describe a clinical report pre- and post-neurofunctional intervention in a case of agenesis of the corpus callosum. Case descriptionPreterm infant with corpus callosum agenesis and hypoplasia of the cerebellum vermis and lateral ventricles, who, at the age of two years, started the proposed intervention. Functional performance tests were used such as the neurofunctional evaluation, the Gross Motor Function Measure and the Gross Motor Function Classification System. In the initial evaluation, absence of equilibrium reactions, postural transfers, deficits in manual and trunk control were observed. The intervention was conducted with a focus on function, prioritizing postural control and guidance of the family to continue care in the home environment. After the intervention, there was an improvement of body reactions, postural control and movement acquisition of hands and limbs. The intervention also showed improvement in functional performance. Comments: Postural control and transfers of positions were benefited by the neurofunction intervention in this case of agenesis of the corpus callosum. The approach based on function with activities that involve muscle strengthening and balance training reactions, influenced the acquisition of a more selective motor behavior.

Central nervous system abnormalities in retinoblastoma patients

AbstractPurpose Presence of CNS abnormalities on MR images in a large group of patients with retinoblastoma (rtb) is evaluated. Mental retardation and congenital brain anomalies are reported in patients with rtb, mostly in combination with 13q deletion syndrome. Pinealoblastoma is the most important and “life threatening” condition associated with hereditary rtb, but recent studies suggest an association with pineal cysts. This association is important because some pinealoblastomas mimic pineal cysts.Methods CNS MR images of 420 consecutive patients with rtb from 2000 to 2014 were evaluated by neuroradiologists for tumors, structural anomalies, myelinization, and coincidental findings. Clinical records were reviewed for laterality, heredity, and the presence of the 13q del syndrome.Results Patients with bilateral and unilateral proved RB1‐germline mutation were 42 (48.2%) out of 87 hereditary cases. 9 patients had 13q deletion syndrome. Normal findings on brain MR images were seen in 307 out of 420 patients. 1 pinealoblastoma was detected in a patient with hereditary rtb, one arachnoid cyst in a sporadic unilateral RTB girl, 1 cerebral and corpus callosum atrophy and 3 pineal cysts were detected (2 non hereditary, 1 in 13q deletion syndrome). Corpus callosum agenesis was found in 3 patients (2 13q deletion syndrome, 1 hereditary RTB), corpus callosum hypoplasia in 3 patients (2 twins, 1 sporadic RTB), both in combination with 13q deletion syndrome.Conclusion Pinealoblastoma is associated with hereditary retinoblastoma, and structural brain abnormalities are associated not only with 13q deletion syndrome patients. Pineal cysts can be detected in patients with sporadic rtb and/or with 13q deletion syndrome.

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Is there an encephalographic trait to septo-optic dysplasia? (de Morsier syndrome)

Objectives. Septo-optic dysplasia (SOD), also known as de Morsier syndrome is a rare congenital syndrome involving variable midline brain structures, characterized by visual impairment, pituitary deficiencies and specific brain abnormalities (especially midbrain malformations). The clinical phenotype is highly variable, from mild to extremely severe. The purpose of this paper is to present the electroencephalographic abnormalities in two clinical cases and correlate with the ones that have been described in the literature in order to find a specific trait of this syndrome. Methods and results. A 12-year-old girl was hospitalized in the pediatric neurology clinic for focal seizures, developmental delay and cerebral palsy. Clinical examination showed visual disturbances (nystagmus and oculomotor nerve palsy), unilateral pyramidal syndrome – left hemiparesis. Electroencephalography (EEG) revealed bilateral photosensitive epileptic form discharges, but asymmetrical, right more than left, with abnormal, slower background. MRI showed optic nerve hypoplasia and hypoplasia of the corpus callosum. The second case was also a girl, a 7-year-old who had only 2 focal right motor seizures with secondary generalization and developmental delay. Clinical examination showed visual impairment and bilateral nystagmus. The standard EEG evaluation didn’t reveal any abnormalities, with normal background. Cerebral MRI showed midline brain defects – agenesis of the septum pellucidum, agenesis of corpus callosum and optic nerve hypoplasia. Endocrine evaluation for pituitary function showed in the first case – increased thyroid-stimulating hormone and in the second case – decreased IGF1. Antiepileptic treatment was started in both cases, but seizures were refractory to treatment and persistent EEG abnormalities still present in the first case, with good evolution of epilepsy in the second case. Conclusions. The epileptiform abnormalities associated to SOD are present only if there is an associated cortical malformation.

Fetal Onset Ventriculomegaly and Subependymal Cysts in a Pyridoxine Dependent Epilepsy Patient

Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene encoding α-aminoadipic semialdehyde dehydrogenase. The classic clinical presentation is neonatal seizures responsive only to pyridoxine therapy. White matter abnormalities, corpus callosum agenesis or hypoplasia, megacisterna magna, cortical dysplasia, neuronal heterotopias, intracerebral hemorrhage, and hydrocephalus in neuroimaging have been reported in patients with PDE. We report a new patient with asymmetric progressive ventriculomegaly noted on fetal sonography at 22 weeks' gestation. Postnatal brain sonography on day 1 and MRI on day 5 confirmed bilateral asymmetric ventriculomegaly caused by bilateral subependymal cysts. Intractable seizures at age 7 days initially responded to phenobarbital. Markedly elevated urinary α-aminoadipic acid semialdehyde levels and compound heterozygous mutations in the ALDH7A1 gene (c.446C>A/c.919C>T) confirmed the diagnosis of PDE caused by ALDH7A1 genetic defect. Despite the presence of structural brain malformations and subependymal cysts, PDE should always be included in the differential diagnosis of neonatal seizures that are refractory to treatment with antiepileptic drugs.

Septo-optic dysplasia plus: a case report

BackgroundSepto-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction. Sometimes, other various malformations appear within syndrome.Case presentationAn 11 and 1/2-year-old Caucasian Southeast European female patient with earlier established diagnoses of growth hormone deficiency, diabetes insipidus, seizures, mental retardation, optic nerve atrophy and right ptosis, was directed to us for consultative examination.The girl of short stature and low weight for her age had bilateral optic nerve hypoplasia, poor vision, nystagmus and right eye oculomotor palsy. Electroencephalogram revealed epileptic changes. Magnetic resonance imaging showed an empty sella syndrome, partial hypoplasia of corpus callosum, cavum of pellucid septum and diffuse polymicrogyria of the left temporal lobe. We found all elements of septo-optic dysplasia plus syndrome with right oculomotor nerve involvement.ConclusionBy earlier findings and evaluation, we established a diagnosis of septo-optic dysplasia plus. The case confirms the existence of various malformations within the syndrome and the need for the cooperation of several specialists in the diagnosis and treatment of children with the syndrome.

Multiple congenital anomalies‐intellectual disability (MCA‐ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion

Neuroblastoma is the most frequent extra cranial solid tumor in infants and children. Genetic predisposition to neuroblastoma has been suspected previously due to familial cases of sporadic NB and predisposition to NB in several syndromes. Here, we report on a de novo 14q23.1-q23.3 microdeletion in a male presenting with a neuroblastoma diagnosed at 9 months, and spherocytosis, congenital heart defect, cryptorchidism, hypoplasia of corpus callosum, epilepsy, and developmental delay. Myc-associated-factor X (MAX) haploinsufficiency could be regarded as the predisposing factor to NB. Indeed 14q deletion is a recurrent somatic rearrangement in NB and MAX somatic and germline loss of function mutation have recently been described in pheochromocytoma and paraganglioma. However, MAX was expressed in the tumor of the patient we report on and, accordingly, loss of heterozygosity, mutation, or promoter methylation were excluded. In addition, we discuss the potential involvement in the clinical spectrum presented by the patient of five of the deleted genes, namely DAAM1, PLEKHG3, SPTB, AKAP5, and ARID4A.

LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome

Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574–91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.

Comparison of ultrasound and magnetic resonance imaging in the prenatal diagnosis of Apert syndrome: report of a case

The birth prevalence of Apert syndrome is estimated at 1:64,500 and accounts for about 4.5 % of all craniosynostosis with a male/female ratio equal to 1:1. It is associated to allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Majority cases are sporadic. Prenatal ultrasound diagnosis is based on the detection of abnormal cranial shape, midfacial hypoplasia and bilateral syndactyly of hands and feet, hypertelorism, and exorbitism. Other abnormalities includes central nervous system anomalies, congenital heart diseases, cleft palate, and urogenital diseases. A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine ultrasound at 21 weeks of gestation. We detected irregular head shape, dolicocephaly, prominent forehead, bilateral mild ventriculomegaly, suspicion of partial agenesis of the corpus callosum, hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge and syndactyly, prompting a suspicion for Apert syndrome. Magnetic resonance excluded agenesis of corpus callosum and confirmed bilateral mild ventriculomegaly. A follow-up ultrasound, performed at 23 weeks, confirmed the anomalies showed in the previous scan. An amniocentesis was performed. The results showed a normal male karyotype, while the molecular genetic test confirmed a mutation in FGFR2 gene. Fetus macroscopic analysis showed compatible features. Our case underlines the complementary role of ultrasound and magnetic resonance imaging in the early prenatal diagnosis of Apert syndrome.

Pericallosal Lipomas: A Series of 10 Cases with Clinical and Radiological Features.

A pericallosal lipoma is a fat-containing lesion occurring in the interhemispheric fissure closely related to the corpus callosum, which is often abnormal. This is the most common location for an intracranial lipoma. In this study, we aim to report on the clinical and radiographic aspects of ten patients diagnosed with pericallosal lipomas. A retrospective analysis of patients who presented to the neurology and neurosurgery outpatient clinics of Kayseri Training and Research Hospital between 2010 and 2014 revealed that 10 patients had the diagnosis of pericallosal lipoma. The clinical and magnetic resonance imaging data were obtained by reviewing their files. Ten patients with an average age of 35.8 years (11-80 years) were included in the study. The mean follow-up was 17 months (8-31 months). No neurological deficits related to the lesions were found during neurological examination in any of the patients. Four patients had tubulonodular lipomas while the other 6 presented with curvilinear lipomas. Four patients (40%) displayed a coexistent corpus callosum hypoplasia. In contrast to previous reports, 3 of these patients had a curvilinear lipoma while the remaining one had tubulonodular lipoma. Also, one of the patients displayed plaque lesions attributable to multiple sclerosis. During the follow-up period, no growth in the lipomas was recorded in any of the patients. No surgical intervention was performed as none of the patients displayed symptoms caused by the lipoma. In this study, we found a stronger association of corpus callosum hypoplasia with posteriorly situated curvilinear lipomas. Our results are in disagreement with previous studies, which suggested corpus callosum anomalies were more often associated with anteriorly situated tubulonodular lipomas. Pericallosal lipomas are benign, self-limiting or slow-growing lesions that generally remain asymptomatic. These lesions occur in the midline and surround critical neurovascular structures. Therefore, surgical intervention should be avoided in asymptomatic cases.

Septo-optic dysplasia with pachygyria

Optic nerve hypoplasia can be associated with other central nervous system malformations. When associated with the absence of the septum pellucidum or thinning of corpus callosum and pituitary hypoplasia, it is termed septo-optic dysplasia. Pachygyria is a rare congenital disorder characterized by a defect in migration of cerebral neurons resulting in failure of cortical gyri to develop.We report a case of a young learning-disabled male presenting with decreased vision, nystagmus, esotropia,, and seizures since childhood. Fundoscopy revealed bilateral optic nerve hypoplasia. Growth hormone levels were reduced. Magnetic resonance imaging revealed thinned optic nerves, optic chiasma and pituitary infundibulum, absent septum pellucidum, box-shaped ventricles and right frontal cortical thickening with few and broad gyri.This case report highlights a rare case of septo-optic dysplasia with pachygyria. It also emphasizes that every patient with optic nerve hypoplasia should have an endocrinal and neurological evaluation and neuro-radiographic imaging for associated abnormalities.

An 11-month-old boy with refractory epilepsy: Answer

The patient’s MRI (Fig. 1 of Images in Neuroscience: Question) shows right hemispheric lissencephaly of the temporo-parietooccipital region with frontal sparing (long arrows). There is associated right subcortical band heterotopia (arrowheads in A and B) and focal left sided subependymal nodular heterotopias (short arrows in A and B). Lissencephaly and the related malformation, subcortical band heterotopia, are classical neuronal migration defects [1]. Lissencephaly denotes a smooth brain with areas of absent and abnormally wide gyri (agyria and pachygyria, respectively), whereas subcortical band heterotopia indicates a double cortex condition [2]. The most common clinical presentation is epilepsy followed by global developmental delay, early infantile hypotonia, feeding difficulty and ophisthotonus [3]. Brain MRI displays a spectrum which varies from agyria (grade 1 and 2) to pachygyria (grade 3 and 4) to normal convolutions separated by narrow sulci overlying a heterotopia. In most patients a gradient exists between anterior and posterior regions. They may have associated corpus callosum and cerebellar hypoplasia. Recognition of these patterns enables focused molecular diagnosis, prognostication and estimation of genetic risk. To our knowledge, six associated genes have been described: LIS 1 (posterior predominance), DCX (anterior predominance), RELN and VLDLR (anterior predominant lissencephaly

Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/resultsWe characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient’s immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.ConclusionWe propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syndrome involving the cranium, face, and thorax. The characteristic features are cranial involvement with macrocrania at birth, brachycephaly, various CT/MRI findings including hypoplasia of corpus callosum, enlargement of septum pellicidum, and diffuse hypodensity of the grey matter, flat face, hypertelorism, cleft lip and cleft palate, low-set, posteriorly rotated ears, short neck, and multiple costal and vertebral anomalies. The underlying genetic defect remains unknown. Using combination of homozygosity mapping and whole-exome sequencing, we identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in the human transmembrane and coiled-coil domains protein 1 (TMCO1) in four out of five families of Turkish origin. The entire critical region on chromosome 1q24 containing TMCO1 was excluded in the fifth family with characteristic findings of CFT providing evidence for genetic heterogeneity of CFT spectrum. Another founder TMCO1 mutation has recently been reported to cause a unique genetic condition, TMCO1-defect syndrome (OMIM #614132). TMCO1-defect syndrome shares many features with CFT. This study supports the fact that "TMCO1-defect syndrome," initially thought to represent a distinct disorder, indeed belongs to the genetically heterogeneous CFT dysplasia spectrum.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome

AIMRecently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.METHODWe conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6–20y) with genetically proven EAST syndrome.RESULTSAll children presented with tonic–clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm.INTERPRETATIONThe neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.