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Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic atrophy. Four genetic loci have been associated with ADOA: OPA1, OPA2, OPA3, and OPA4. Out of these four loci, only one gene has been identified, OPA1. We previously described a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia in two unrelated families associated with an R445H mutation in OPA1. The R445H mutation is the only OPA1 mutation that has been associated with this syndrome. In this manuscript, we clinically characterize an unrelated family with four members affected by optic atrophy and hearing loss without extraocular motility abnormalities or ptosis. This family also harbors the R445H mutation. These cases help illustrate the intra- and inter-family variability in phenotype associated with this mutation. As we continue to learn more about OPA1 and the function of its protein product, we will begin to understand the pathophysiology of optic atrophy. This understanding will ultimately lead to novel treatments directed toward preventing the visual loss and disability associated with this inherited disease.
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PMID:Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation. 1615 27

We here report on a Japanese family with congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with slowly progressive cerebellar ataxia. The pedigree indicated autosomal dominant inheritance. All affected individuals showed a complete loss of upgaze function with ptosis, and severe or moderate restriction of downgaze function probably from the birth. Horizontal gaze function was well preserved, except for the eldest patient, who showed both eyes almost totally fixed in exotrophic position. The primary vertical and horizontal position of each eye varied from patient to patient. Aberrant eye movements were observed on attempted upgaze. They showed amblyopia and/or astigmatism, but none of them complained of diplopia. Pupillary reactions were normal, and retinal pigmentary degeneration or optic atrophy was not observed. These ophthalmological findings were consistent with the CFEOM phenotype. The two middle-aged patients, but not the two younger patients, showed slowly progressive gait ataxia with juvenile onset. Magnetic resonance images of the brain indicated cerebellar atrophy in addition to congenital hypoplasia in the cerebellar vermis. Molecular genetic analysis provided a negative linkage to the FEOM3 locus. Linkage to the FEOM1 locus could not be excluded in our family, but mutation in KIF21A, a major cause of the CFEOM1 phenotype, was not detected. We consider that this family may broaden the spectrum of the clinical features of CFEOM or the related disorders presenting with the CFEOM phenotype.
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PMID:Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia. 1755 29

Degos disease, or malignant atrophic papulosis, is a rare vasculopathy of uncertain aetiology manifesting as a primary dermatological disorder in most cases, but with widespread systemic involvement developing in an undefined proportion of patients. Reported neurological features of Degos disease include ischaemic and haemorrhagic stroke, subdural effusion, seizures, neuropathy, transverse myelitis, and optic atrophy. The description of contrast enhancement of the leptomeninges possibly indicates a defect of blood vessel integrity likely explaining the pleiotropic neurological manifestations. Degos disease is usually considered a disorder of adulthood, although a small number of infantile cases have been described. Here, we report a female who demonstrated a neonatal onset of Degos disease, eventually showing the highly characteristic skin lesions together with ptosis and a generalized weakness as part of her systemic disorder. Subsequent exacerbations led to an inexorable neurodevelopmental and physical decline. CT scan revealed intracranial calcification, a feature described in two previous cases. Our report highlights the need to consider Degos disease in the differential diagnosis of childhood neurological disease with skin involvement.
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PMID:Infantile neurological Degos disease. 2065 9

Mitochondrial diseases are a clinically hetyerogenous group of disorders. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). Some affect a single organ, but many involve multiple organ systems and often present with prominent neurologic and myopathic features. The eye is frequently affected, along with muscles and brain, but multisystem disease is common. Ophthalmic manifestations include cataract, retinopathy, optic atrophy, cortical visual loss, ptosis and ophthalmoplegia. Kearns-Sayre Syndrome (KSS), Mitochondrial Encephalopathy, Lactic Acidosis Stroke (MELAS), Myoclonic Epilepsy and Ragged Red Fiber myopathy (MERRF) and Lebers Hereditary Optic Neuropathy (LHON) are well known clinical entities that are secondary to mtDNA abnormalities, which has ophthalmic manifestations. Mitochondrial Dysfunction should be considered in the differential diagnosis of progressive multisystem disorder and specifically if there is associated neuro-ophthalmic manifestations, which may be the presenting symptom of these disorders.
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PMID:Mitochondrial disorders with significant ophthalmic manifestations. 2134 43

Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.
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PMID:Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. 2296 62

We report on a sister and brother born to healthy, double first cousin Iranian parents with a seemingly unique combination of signs and symptoms consisting of intellectual disability, congenital absent voice (aphonia), hearing loss, optic atrophy, retinal dystrophy, mildly broad thumbs, and duplicated halluces. Their facial morphology was unusual: thick eyebrows, ptosis, full eyelashes, long palpebral fissures, downslanting palpebral fissures, small mouth, and low-set, posteriorly rotated ears. This phenotype does not meet the diagnostic criteria of any known entity. Because of parental consanguinity, absence of manifestations in parents, and occurrence in sibs of opposite sex, an autosomal recessive pattern of inheritance is likely.
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PMID:Aphonia, microstomia, deafness, retinal dystrophy, duplicated halluces and intellectual disability. 2299

A 26-year-old male presented to us with defective vision in the left eye. He had best corrected visual acuity (BCVA) of hand movement (HM) in right eye and 6/9 in left eye. He had ptosis with ectropion in both eyes and relative afferent pupillary defect (RAPD) in right eye. Intraocular pressure (IOP) was 46 and 44 mmHg in right and left eye, respectively. Fundus showed glaucomatous optic atrophy (GOA) in right eye and cup disc ratio (CDR) of 0.75 with bipolar rim thinning in left eye. Systemic examination showed hyperextensible skin and joints, acrogeria, hypodontia, high arched palate, and varicose veins. He gave history of easy bruising and tendency to fall and history of intestinal rupture 5 years ago for which he had undergone surgery. He was diagnosed as a case of Type IV Ehler-Danlos syndrome (EDS) with open angle glaucoma. He underwent trabeculectomy in both eyes. This is a rare case that shows glaucoma in a patient of EDS Type IV. Very few such cases have been reported in literature.
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PMID:Open angle glaucoma in a case of Type IV Ehler Danlos syndrome: a rarely reported association. 2523 Sep 66

Pathogenic mutations in the OPA1 gene can be associated with Autosomal Dominant Optic Atrophy (ADOA). In approximately 20 % of patients with OPA1 mutations, a more complex neurodegenerative disorder with extraocular manifestations, known as ADOA Plus, can arise. 12 members of a multigenerational family were assessed clinically and screened for a genetic mutation in OPA1. Eight family members displayed manifestations consistent with ADOA Plus and four did not. Affected members of the oldest available generation displayed the most severe phenotype, which included severe optic atrophy, deafness, ptosis, ophthalmoplegia, proximal myopathy, neuropathy and ataxia. The next generation was less severely affected but several members displayed manifestations only after the fifth decade. Genetic analysis revealed a heterozygous variant in the OPA1 gene (c.1053T>A, p.Asp351Glu) that segregated with disease. The affected family members described here exhibited visual loss later than is typical for OPA1-related disease, as well as later onset of other neurological abnormalities in the fifth or sixth decades of life that progressed to severe neurological disability by the seventh decade. These findings expand the clinical spectrum of OPA1-related disease associated with a novel OPA1 mutation.
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PMID:A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family. 2619 96

Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome.
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PMID:The Eye on Mitochondrial Disorders. 2627 73

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.
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PMID:Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes. 3147 73


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