Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous ...loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found ...in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head.
In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed.
Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001).
These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities.
Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and ...Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral nerve sheath tumors (PNSTs) are known to occur in the orbit and comprise 4% of all orbital tumors, but have not been well studied in contemporary literature. Ninety specimens involving the ...eye and ocular adnexa (1979-2015) from 67 patients were studied. The mean age was 32.5years. Locations included orbit (58.9%), eyelid (60.0%), and other ocular adnexa. Most specimens were neurofibromas (70.0%), followed by schwannomas (11.1%), neuromas (11.1%), granular cell tumors (n=4), nerve sheath myxomas (n=2), and malignant PNST (n=1). Fifty-six (88.9%) neurofibroma cases were neurofibromatosis 1 associated. Among neurofibromas, 31.7% were localized, 38.1% were plexiform, 25.4% were diffuse, and 4.8% were diffuse and plexiform. These tumors involved skin (31.7%), soft tissue (11.1%), skeletal muscle (22.2%), peripheral nerve (63.0%), lacrimal gland (20.6%), and choroid (n=1). Other histologic findings included pseudo-Meissner corpuscles (27%), Schwann cell nodules (4.8%), prominent myxoid component (7.9%), melanin-like pigment (3.2%), and inflammation (14.3%). Available immunostains included S100 (+ in 15/15 cases), EMA (+ in 2/4 cases), CD34 (+ in 4/4 cases), and Ki-67 (<1% in 4/4 cases). Among 10 schwannomas, 8 were conventional and 2 were plexiform. Observed features included capsule (n=5), hyalinized vessels (n=5), Verocay bodies (n=7), and Antoni B pattern (n=5). Immunostaining included S100+ in 4 of 4 cases, and collagen IV+ and Ki-67 <1% in 3 of 3 cases. Neurofibromas are the most common PNST involving the eye and ocular adnexa, and the majority are associated with neurofibromatosis 1. Plexiform and diffuse patterns and the presence of pseudo-Meissner corpuscles are relatively frequent in this area.
•Clinicopathological features of 90 nerve sheath tumors involving the eye and ocular adnexa were studied.•Neurofibroma was the predominant histologic type.•Most neurofibromas were NF1 associated and had frequent plexiform and diffuse components.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We describe a child from a consanguineous family born with a rare autosomal recessive disorder affecting
causing profound neurological and ophthalmological injury known as haemorrhagic brain ...destruction, subependymal calcifications, and congenital cataracts (HDBSCC; MIM# 613730). She was the product of an unremarkable pregnancy and was born near to term but was noted shortly after birth to have congenital cataracts, poor vision, increased muscle tone, seizures, and developmental delay. Her older sister had an identical syndrome and had previously been documented to have homozygous mutations in
. Examination in our patient, although difficult because of bilateral central cataracts, revealed very poor vision, attenuated retinal vessels, optic atrophy, and a retinal haemorrhage in the right eye, implying that abnormal development of the retinas and/or optic nerves may at times play a significant role in the poor vision noted in children with HDBSCC.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human ...syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
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IJS, NUK, SBMB, UL, UM, UPUK
PURPOSE OF REVIEWWe review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs).
RECENT FINDINGSRecent literature contains new ...genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype.
SUMMARYThe CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype–phenotype correlations in the future.
Genetic studies of the Arabian Peninsula are scarce even though the region was the center of ancient trade routes and empires and may have been the southern corridor for the earliest human migration ...from Africa to Asia. A total of 120 mtDNA Saudi Arab lineages were analyzed for HVSI/II sequences and for haplogroup confirmatory coding diagnostic positions. A phylogeny of the most abundant haplogroup (preHV)1 (R0a) was constructed based on 13 whole mtDNA genomes.
The Saudi Arabian group showed greatest similarity to other Arabian Peninsula populations (Bedouin from the Negev desert and Yemeni) and to Levantine populations. Nearly all the main western Asia haplogroups were detected in the Saudi sample, including the rare U9 clade. Saudi Arabs had only a minority sub-Saharan Africa component (7%), similar to the specific North-African contribution (5%). In addition, a small Indian influence (3%) was also detected.
The majority of the Saudi-Arab mitochondrial DNA lineages (85%) have a western Asia provenance. Although the still large confidence intervals, the coalescence and phylogeography of (preHV)1 haplogroup (accounting for 18 % of Saudi Arabian lineages) matches a Neolithic expansion in Saudi Arabia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To describe clinical and ocular abnormalities in a case of Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome).
Methods
A ...clinical report.
Case description
An infant born to a consanguineous Middle Eastern family who was delivered by cesarean section because of in utero growth restriction, premature labor, and breech presentation. Post‐partum medical problems included hypotension, generalized hypotonia, bradycardia, apnea requiring resuscitation and positive pressure ventilation, facial dysmorphia, skeletal malformations, and disorders of the gastrointestinal, immune, urinary, respiratory, cardiac, and visual systems. The family reported that a previous child had severe hypotonia at birth and was given the diagnosis of hypoxic ischemic encephalopathy; that child remains on a ventilator in a chronic care facility. Our patient was found to be homozygous for a novel pathogenic missense variant in theZNF699 zinc finger gene on chromosome 19p13 causing a syndrome known as Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). We review this variable syndrome, including abnormalities of the visual system not described previously.
Conclusions
We describe the 15th child to be presumably identified with the DEGCAGS syndrome and the first individual with homozygous missense variants in the ZNF699 gene who had complete clinical examination and detailed retinal imaging.
Our patient was found to be homozygous for a novel pathogenic missense variant in the ZNF699 zinc‐finger gene on chromosome 19p13 causing a syndrome known as developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities syndrome. We review this variable syndrome, including abnormalities of the visual system not described previously.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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