Esotropia, nystagmus and optic disk staphyloma in Donnai-Barrow syndrome / Esotropia, nistagmo e estafiloma de disco óptico na síndrome de Donnai-Barrow

ABSTRACT A 12-year-old boy with Donnai-Barrow syndrome diagnosed intra-uterus presented esotropia, high myopia, nystagmus, and optic disk staphyloma in an ophthalmologic examination. The patient had associated Fanconi syndrome and sensorineural hearing loss as well as facial manifestations as hypertelorism, downward slanting of palpebral fissures and low ear implantation. Magnetic resonance imaging revealed agenesis of the corpus callosum. To our knowledge, this is the first reported case associated with esotropia, nystagmus, and optic disk staphyloma.

RESUMO Paciente do sexo masculino, 12 anos, com diagnóstico intrauterino de síndrome de Donnai-Barrow, apresentava ao exame oftalmológico esotropia, alta miopia, nistagmo e estafiloma de disco óptico. Associado ao quadro, apresentava síndrome de Falconi e perda auditiva neurossensorial, além de alterações faciais, como hipertelorismo, inclinação inferior das fissuras palpebrais e implantação baixa das orelhas. Ressonância magnética revelou agenesia de corpo caloso. Ao nosso conhecimento, este é o primeiro caso relatado associando esotropia, nistagmo e estafiloma de disco óptico.

A novel heterozygous loss-of-function DCC Netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature.

Agenesis of the corpus callosum (ACC) is a common prenatally-detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4-year-old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss-of-function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss-of-function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination.

Agenesis of the corpus callosum and hepatoblastoma.

Agenesis of the corpus callosum is a congenital brain malformation that can occur in isolation or as a component of a congenital syndrome. Hepatoblastoma (HB) is a rare tumor that comprises two thirds of primary hepatic neoplasms in children and adolescents. Up to 20% of children with HB have associated congenital anomalies. In addition to defined genetic syndromes such as Familial Adenomatous Polyposis, Beckwith-Wiedemann syndrome, Trisomy 13, and Trisomy 18, HB is significantly associated with kidney/bladder abnormalities. We present two children with multiple congenital anomalies, including agenesis of the corpus callosum, who were subsequently diagnosed with HB. Review of the literature revealed two patients with clinically-diagnosed Aicardi syndrome and HB. Due to the rarity of both agenesis of the corpus callosum and HB, this is likely a true association. Further investigation into the underlying genetic and molecular basis of this probable association is warranted.

Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis.

Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation. We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1.

Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach.

BACKGROUND: Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. METHODS: A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. RESULTS: Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11 patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. CONCLUSION: A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil.

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

Agenesis of the Corpus Callosum and Aicardi Syndrome: A Neuroimaging and Clinical Comparison.

BACKGROUND: Agenesis of the corpus callosum can occur in individuals with epilepsy, either in isolation or as part of various neurological conditions, such as Aicardi syndrome. In this study, we evaluated the clinical and neuroradiological differences between children with nonsyndromic agenesis of the corpus callosum and those with Aicardi syndrome. METHODS: We evaluated 31 children with epilepsy and agenesis of the corpus callosum (11 males, 20 females), 14 of whom had Aicardi syndrome (all females). We compared their clinical evaluations, radiological and electrophysiological findings, treatments, and their outcome. RESULTS: Median age at seizure onset was lower in the Aicardi syndrome group compared with nonsyndromic agenesis of the corpus callosum (two versus five months, P = 0.006). The developmental impairment in terms of verbalization and ambulation was significantly worse in patients with Aicardi syndrome. The severity of magnetic resonance imaging (MRI) and glucose metabolism positron emission tomography (PET) involvement was more extensive in children with Aicardi syndrome than in nonsyndromic agenesis of the corpus callosum. In both groups, the PET scan showed a much more extensive area of involvement than suggested by the MRI scan. Four children underwent epilepsy surgery with significant improvement, but were not seizure free. Outcome was worse in those with PET showing abnormalities in the nonsurgical hemisphere despite normal appearance on MRI. All children who did not undergo surgery also continued to have seizures at last follow-up. CONCLUSIONS: Children with Aicardi syndrome have earlier seizure onset, worse developmental outcome, and larger areas of brain abnormalities on neuroimaging compared with nonsyndromic agenesis of the corpus callosum patients. PET reveals larger area of abnormalities, compared with MRI. Although epilepsy surgery in agenesis of the corpus callosum may offer some palliative benefit in seizure frequency, none of our patients became seizure free.

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.

In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.

[Pathophysiological aspects of K+: Cl- cotransporters]. / Aspectos fisiopatologicos de los cotransportaores de K+ :CI- .

The K+:Cl- cotransporters or KCCs are membrane proteins that move K+ and Cl- ions across the membrane without changing the transmembrane potential. KCCs belong to the SLC12 (Solute Carrier Family 12) family of electroneutral cation-chloride cotransporters (CCC), and they are secondary active ion transporters because use the established gradients from the primary active transporter through the Na+/K+- ATPase. Although there are nine members identify in this family, up today only seven genes had been characterized. Among them are two loop diuretics-sensitive Na+:K+:2Clcotransporters (NKCC1/NKCC2), the thiazide-sensitive Na+:Cl- cotransporter (NCC), and finally the K+:Cl- cotransporters (KCC), encoded for at least four homologous genes (KCC1-KCC4), and from which there are many isoforms due to alternative splicing. KCC1 is a ubiquitous isoform, KCC3 and KCC4 isoforms are widely expressed, particularly in epithelial cells, while KCC2 is restricted to the central nervous system (CNS). All these cotransporters play an essential role in many physiological processes such as cell volume regulation, transepithelial salt transport and regulation of the intraneuronal chloride concentration. This review has the purpose to show briefly the molecular characteristics as well as the physiological importance and roles of the KCCs in several pathologies.

Gli3 controls corpus callosum formation by positioning midline guideposts during telencephalic patterning.

The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/ß-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2(-/-) embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/ß-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development.

Cingulate cortex aplasia and callosal dysgenesia combined with schizencephaly in a patient with chronic lying.

We report on a 19-year-old patient with a 4-year history of lying and cheating who presented neuropsychological abnormalities regarding attention deficits, hyperactivity and impulsivity. Cerebral magnetic resonance imaging scans revealed schizencephaly of the right central region, dysgenesia of the corpus callosum, a noneverted gyrus cinguli and hypoplasia of the left cerebellar hemisphere. Although the patient did not fulfill the diagnostic criteria for attention-deficit/hyperactivity disorder, we suggest that the patient's behavioral alteration could be related to the neuroanatomical alterations, especially the aplasia of the gyrus cinguli.