Phenotypic expansion of Bosch–Boonstra–Schaaf optic atrophy syndrome and further evidence for genotype–phenotype correlations

Bosch–Boonstra–Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss‐of‐function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in‐frame deletions in the DNA‐binding domain (DBD), and 32 individuals with other types of variants including whole‐gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long‐term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype–phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.     

Phylogenetic analysis of mtDNA haplogroup TJ in a Finnish population

An association between mitochondrial DNA (mtDNA) mutations 11778G>A and 14484T>C and mtDNA haplogroup J suggests that this haplogroup harbors substitutions capable of modifying the phenotype of Leber's disease. Our knowledge of the compilation of substitutions in haplogroup J is based on only a small number of complete mtDNA sequences, however. We constructed phylogenetic networks for mtDNA haplogroup TJ that were based on the sequence of the complete coding region and the hypervariable segment I, respectively, in 28 Finnish samples. The networks revealed a subdivision of the haplogroup into subclusters T1, T2, J1, and J2, while comparison of the two networks suggested nine fast evolving nucleotide sites in the hypervariable segment I. Genotypes of patients harboring 11778G>A or 14484T>C were obtained from the literature and were then placed in the network. Only four substitutions were found to be common to the patients, but none of these was unique to haplogroup J. If increased penetrance of the 11778G>A and 14484T>C mutations in patients belonging to haplogroup J is assumed, combinations of ancient substitutions must be implicated. Received: September 29, 2000 / Accepted: November 10, 2000     

The dendritic architecture of the medial terminal nucleus of the accessory optic system in the rat,rabbit, and cat

Summary The neurons of the medial terminal nucleus (MTN) of the accessory optic system (AOS) have been studied in the rat, rabbit and cat in Golgi-Cox and Golgi-Kopsch impregnated brain sections. The present anatomical findings permit a division of the MTN of these species into dorsal and ventral components (MTNd, MTNv), in agreement with other investigations. The MTNd contains predominantly linear-bipolar and linear-multipolar shaped neurons with cell bodies that measure in the range of 25–50 m. These neurons have 2 to 4 primary dendrites which, along with their smaller dendritic branches, are oriented in the plane of the long axis of the MTN (i.e. from ventromedial to dorsolateral). These linear-bipolar and linear-multipolar cells represent 70–80% of the neurons of the MTNd as seen in the Golgi impregnated sections. The remaining 20–30% of the MTNd neurons are nearly all multipolar in shape with somata measuring in the range of 15–25 m. An occasional multipolar neuron is larger, has a soma that measures around 30–60 m and has dendrites which extend outward from the cell body to cover large areas of the MTNd. There was considerable extension of the dendrites of MTNd neurons into the MTNv; however, the dendrites of MTNd neurons were not observed extending into the adjacent substantia nigra (SN) or ventral tegmental area (VTA) of Tsai (1925). Conversely, the dendrites of neurons in the neighboring SN and VTA course along the borders of the MTN but only occasionally extend into the MTN. The neuron population of the MTNv consists almost entirely of small-multipolar shaped cells with somata measuring from 15–25 m and dendritic trees resembling those described for multipolar cells of the MTNd. A small number of neurons of the ventral division are medium-multipolar in shape with cell bodies that measure approximately 30–60 m. Typically, these cells have several dendrites which extend ventrally within the MTNv and one or more dendrites that extend either across the MTNv or dorsally into the MTNd. Only a few linear-bipolar and linear-multipolar neurons were observed in the MTNv. The present findings are discussed in relation to anatomical, physiological, and histochemical studies on the MTN.Abbreviations to Figures CP Cerebral Peduncle - DTN Dorsal Terminal Nucleus - LG Lateral Geniculate Nucleus - LP Lateral Posterior Nucleus - MG Medial Geniculate Nucleus - ML Medial Lemniscus - MTNd Medial Terminal Nucleus, dorsal division - MTNv Medial Terminal Nucleus, ventral division - NTO Nucleus of the Optic Tract - PA Anterior Pretectal Nucleus - pn Nucleus Paranigralis - PP Posterior Pretectal Nucleus - Pul Pulvinar - PO Olivary Pretectal Nucleus - RN Red Nucleus - SGS Stratum Griseum Superficiale, Superior Colliculus - SN Substantia Nigra Supported by USPHS research grant EYO3642 from the National Eye Institute     

Development of the retinal pathway to the pretectum of the cat

The development of retinal projections to the pretectal complex of prenatal and early postnatal cats has been examined using the anterograde transport of horseradish peroxidase and tritiated amino acids. As early as embryonic day 38, the entire dorsal pretectum is penetrated by retinal ganglion cell axons. At this stage the bilateral complement of retinal efferents appears to be dispersed uniformly within the pretectal anlage. A week later, on embryonic day 46, indistinct foci of peroxidase reaction product can be discerned within 2 of the primordial nuclei: the nucleus of the optic tract and the olivary nucleus. By embryonic day 56, five distinct bilateral fields of retinal fiber termination are apparent within the following regions:

(i) the nucleus of the optic tract;

(ii) the pretectal olivary nucleus;

(iii) the posterior pretectal nucleus;

(iv) the anterior pretectal nucleus; and

(v) the medial pretectal nucleus. Four days before birth, on embryonic day 61, crossed and uncrossed retinal arbors are partially segregated within the nucleus of the optic tract and the pretectal olivary nucleus.

The early postnatal retinal connection to the pretectum has an overall pattern virtually indistinguishable from that of the mature cat. The ontogeny of the retinal influx to the pretectum is similar to that of the retinocollicular projection.⁶¹ However, the development of retinal projections to the pretectum and superior colliculus appears to lag behind those to the dorsal lateral geniculate nucleus.⁴⁹ These differences may reflect temporal and spatial gradients in the maturation of three major classes of retinal ganglion cells.     

High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy

Cardiac conduction abnormalities have been reported in families with Leber's hereditary optic neuropathy (LHON). The pre-excitation syndrome, Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome, is reportedly common in Finns with LHON, being seen in 14 (9%) of the 163 individuals with mitochondrial DNA (mtDNA) mutations. While this syndrome is thought to be rare in other ethnic groups with LHON, the present study of 35 Japanese LHON families confirmed that it is also relatively common among Japanese families, being seen in 5 (8%) of the 63 individuals with mtDNA mutations. It remains to be determined whether the high incidence of the pre-excitation syndrome in Finnish and Japanese LHON families is due to a particular genetic composition of ethnic groups such as in Finland and in Japan, or only to a reporting bias.     

Acute optic neuritis: a virological study in relation to multiple sclerosis.

Previous ultrastructural examination of peripheral blood lymphocytes revealed the presence of intranuclear filamentous structures in multiple sclerosis (MS) and in some optic neuritis (ON) patients. The present investigation was undertaken in the attempt to correlate the presence of such structures with the etiology of ON and MS and possibly to demonstrate the viral origin of the filaments. Suitable virological and serological techniques were used to detect and isolate infectious agents from peripheral blood samples and body excretions of 12 monosymptomatic ON patients at their first acute attack. Nevertheless, any efforts to demonstrate the presence of a virus in these patients have been unsuccessful: no evidence of active viral infection was obtained by serological studies of serum and cerebrospinal fluid samples, nor could viral antigens or inclusions be observed by immunofluorescence and cytochemical analysis. Negative results were also obtained from studies performed in parallel on MS patients and various controls. The significance of the failure to isolate infectious agents from either ON and MS patients is discussed.     

Screening for the two most frequent mutations in Leber's hereditary optic neuropathy by duplex PCR based on allele-specific amplification

This report describes a rapid and inexpensive assay, which allows detection, in whole blood and by PCR alone, of the two most frequent mitochondrial DNA mutations causing Leber's hereditary optic neuropathy. The assay is based on allele-specific amplification, using primers with the mutation-specific base in the 3′ position, and a deliberately introduced G→C Substitution of base no. four from the 3′ end, which prevents amplification of the wild-type allele. © 1993 Wiley-Liss, Inc.     

中国Leber遗传性视神经病变G11696A突变两个家系分析

目的对两个中国Leber遗传性视神经病变(Leber’shereditary optic neuropathy,LHON)家系的临床和分子遗传学特征进行分析。方法眼科临床检查发现在这两个家系中只有先证者1人出现视力障碍,发病年龄分别为10岁和17岁。对这两个家系先证者使用24对有部分重叠的引物进行线粒体DNA(mitochondrial DNA,mtDNA)全序列扩增分析。结果没有发现mtDNAG11778A、G3460A和T14484C3个常见的突变位点,而发现了与LHON相关的ND4G11196A同质性突变位点的存在,在167名正常对照只发现1例G11696A突变。结论线粒体DNA全序列分析发现两个家系呈现独特的mtDNA多态性,都属于东亚单体型D4。不完全外显率和正常对照频率(1/167)表明G11696A突变本身不足以导致LHON的发生,说明其它因素在这两个LHON家系的表型表达中也起一定的作用。在这些家系mtDNA中缺乏影响重要功能突变位点的存在,排除了线粒体背景对LHON临床表型的影响。因此,核修饰基因、环境因素可能对两个中国G11696A突变家系的外显率和发病严重程度起促进作用。     

大鼠受损视神经中神经前体细胞的变化及预变性腓总神经的调节

为了研究大鼠受损视神经内神经前体细胞的变化及调节,本研究建立了成年雄性大鼠视神经损伤及自体腓总神经移植模型,分正常组、损伤组和移植组,体外培养视神经的神经前体细胞,在相差显微镜下观测各组神经前体细胞神经球的形态和数目,以免疫荧光细胞化学方法对神经球细胞进行鉴定。结果显示:正常组神经球较小、较少,多数细胞表达nestin、GFAP或半乳糖脑苷脂(GC);视神经损伤后神经球的总数有所增加,但大神经球数明显减少,nestin、GFAP或GC阳性细胞也明显减少;神经移植后增加了各类神经球数,nestin、GFAP或GC阳性细胞也明显增加。本研究提示成年大鼠视神经内神经前体细胞较少,增殖能力较弱;视神经损伤也伤及其神经前体细胞并抑制其增殖;自体神经移植能保护神经前体细胞并促进其增殖。