Sabrina Signorini

Cognitive visual dysfunctions in preterm children with periventricular leukomalacia

Aim  Cognitive visual dysfunctions (CVDs) reflect an impairment of the capacity to process visual information. The question of whether CVDs might be classifiable according to the nature and distribution of the underlying brain damage is an intriguing one in child neuropsychology.

MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain‐hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel‐like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene‐phenotype correlates in JSRDs.

Neuro-ophthalmological disorders in cerebral palsy: ophthalmological, oculomotor, and visual aspects

Aim  Cerebral visual impairment (CVI) is a disorder caused by damage to the retrogeniculate visual pathways. Cerebral palsy (CP) and CVI share a common origin: 60 to 70% of children with CP also have CVI. We set out to describe visual dysfunction in children with CP. A further aim was to establish whether different types of CP are associated with different patterns of visual involvement.

BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome

OBJECTIVE To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). METHODS Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. RESULTS In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed. CONCLUSIONS Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype. CLINICAL RELEVANCE It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

Leber's congenital amaurosis: an update

Lebers congenital amaurosis (LCA) is a clinically and genetically heterogeneous disorder characterized by severe loss of vision at birth. It accounts for 10-18% of cases of congenital blindness. Some patients exhibit only blindness of retinal origin whereas others show evidence of a multi-systemic involvement. We review the literature relating to this severe disorder, highlighting unresolved questions, in particular the nature of the association of LCA with mental retardation and with systemic findings and syndromic pictures. In recent years, genetic advances in the diagnosis of LCA have opened up new horizons, also from a therapeutic point of view. A better understanding of this pathology would be valuable for paediatric neurologists.

Molecular and Clinical Characterization of Albinism in a Large Cohort of Italian Patients

PURPOSE The purpose of this study was to identify the molecular basis of albinism in a large cohort of Italian patients showing typical ocular landmarks of the disease and to provide a full characterization of the clinical ophthalmic manifestations. METHODS DNA samples from 45 patients with ocular manifestations of albinism were analyzed by direct sequencing analysis of five genes responsible for albinism: TYR, P, TYRP1, SLC45A2 (MATP), and OA1. All patients studied showed a variable degree of skin and hair hypopigmentation. Eighteen patients with distinct mutations in each gene associated with OCA were evaluated by detailed ophthalmic analysis, optical coherence tomography (OCT), and fundus autofluorescence. RESULTS Disease-causing mutations were identified in more than 95% of analyzed patients with OCA (28/45 [62.2%] cases with two or more mutations; 15/45 [33.3%] cases with one mutation). Thirty-five different mutant alleles were identified of which 15 were novel. Mutations in TYR were the most frequent (73.3%), whereas mutations in P occurred more rarely (13.3%) than previously reported. Novel mutations were also identified in rare loci such as TYRP1 and MATP. Mutations in the OA1 gene were not detected. Clinical assessment revealed that patients with iris and macular pigmentation had significantly higher visual acuity than did severe hypopigmented phenotypes. CONCLUSIONS TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency than that found in other populations. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

The Development of Visual Object Recognition in School-Age Children

This study documents the age-dependent development of visual object recognition abilities in 115 children aged 6 to 11 years, using a battery of neuropsychological tests based on Marrs model (Efron test, Warringtons Figure-Ground Test, Street Completion Test, Poppelreuter-Ghent Test, a selection of stimuli from the Birmingham Object Recognition Battery, a series of color photographs of objects presented from unusual perspectives or illuminated in unusual ways). The results suggest a maturation of complex visual perceptual abilities, possibly related to the development of the cerebral processes involved in object recognition, and could be the starting point for future investigations of these skills in impaired populations.

Septo-optic dysplasia in childhood: the neurological, cognitive and neuro-ophthalmological perspective.

Aim  We set out to describe 17 patients with septo‐optic dysplasia (SOD), focusing on the little‐explored neurological, cognitive, and neuro‐ophthalmological components. A further aim was to identify possible clinical correlations and phenotypic characteristics within the diagnostic spectrum.

Visual function in infants with West syndrome: correlation with EEG patterns.

Summary:  Purpose: Several studies have reported behavioral and electrophysiological evidence of visual impairment during the active stage of West syndrome. The underlying mechanisms are, however, poorly understood, and little has been reported about the correlation between visual impairment, EEG patterns, and brain lesions. The aim of the study was to assess visual function at the onset of spasm and 2 months thereafter and relate visual findings to brain lesions and EEG features.