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During the novel coronavirus pandemic, organ transplant recipients represent a frail susceptible category due to long-term immunosuppressive therapy. For this reason, clinical manifestations may differ from general population and different treatment approaches may be needed. We present the case of a 36-year-old kidney-transplanted woman affected by Senior-Loken syndrome diagnosed with COVID-19 pneumonia after a contact with her positive mother. Initial symptoms were fatigue, dry cough, and coryza; she never had fever nor oxygen supplementation. Hydroxychloroquine and lopinavir/ritonavir were started, and the antiviral drug was replaced with darunavir/cobicistat after 2 days for diarrhea. Immunosuppressant levels were closely monitored, and we observed very high tacrolimus trough levels despite initial dose reduction. The patient was left with steroid therapy alone. The peculiarity of clinical presentation and the management difficulties represent the flagship of our case report. We stress the need for guidelines in transplant recipients with COVID-19 infection with particular regard to the management of therapy., (© 2020 Wiley Periodicals LLC.)

Competing Interests: Competing interests: None declared.

Background: Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies., Materials and Methods: Case report of a  patient with genetically proven SLS presenting with headaches and swollen optic nerve heads, review of medical notes and ophthalmic imaging, with retinal photography, fundus autofluorescence, and OCT retinal nerve fibre layer analysis., Results: We present findings in a 15 year old girl with Senior-Løken syndrome associated with compound heterozygous mutations in the SDCCAG8 gene,  who initially presented with a retinal dystrophy, and subsequent renal failure requiring renal transplantation and immunosuppression. Four and a half years later, she presented with headaches, reduced vision and clinical findings of papilloedema.  Cerebrospinal fluid analysis revealed a high opening pressure of 37cmH 2 0 and neuroimaging was otherwise unremarkable.  Treatment with a reduced dose of oral acetazolamide resulted in symptomatic relief of headaches, and resolution of optic nerve swelling., Conclusion: The association of intracranial hypertension in a ciliopathy is a rare occurrence.  The aetiology of intracranial hypertension in this case is likely multi-factorial, due to renal transplantation, post-renal transplant medications and/ or weight gain.  With evidence of cilia involvement in the central nervous system, ciliary dysfunction may contribute to intracranial hypertension, and should be considered in these patients presenting with headaches. Diagnosis may be difficult with advanced retinal degeneration and baseline retinal nerve fibre layer thinning. Treatment requires careful monitoring of renal function.

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., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Background: GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) as a rare genetic disorder includes growth retardation, alopecia, pseudoanodontia, and optic atrophy. It was reported to be associated with craniosynostosis and intracranial hypertension., Case Report: A patient with such a rare disorder associated with multisuture craniosynostosis and headache is presented. Surgery has been done due to intracranial hypertension., Conclusions: Abnormal intraoperative findings including sever pericranium and dural adhesions and extraordinary bleeding related to this syndrome are described.

Nephronophthisis is an autosomal recessive cystic kidney disease characterized by tubular interstitial infiltration, periglomerular fibrosis, and cysts, and is the most frequent genetic cause of end-stage renal disease in children. Nephronophthisis is pleiotropic as almost all the causative genes are involved in primary cilium and centrosome function which are found in almost all human cells. Genetic heterogeneity in nephronophthisis makes the molecular and genetic diagnosis somewhat difficult. Homozygous deletions in the nephronophthisis 1 (NPHP1) gene are the major contributor of nephronophthisis cases, while other genes accounts for less than 3% each. Nephronophthisis-related ciliopathy is a term used for extrarenal symptoms in addition to nephronophthisis. Herein, we are reporting the molecular study of 7 children from independent families fulfilling the criteria of nephronophthisis. A deletion analysis of the NPHP1 gene was performed in each case, and NPHP5 mutation screening was performed in the absence of such deletion in patients with Senior Loken syndrome.

GAPO syndrome is characterized by growth retardation, alopecia, pseudoanodontia, and ophthalmic abnormalities. This very rarely reported syndrome affects various ethnic groups and can present with manifestations other than those usually reported. Pseudoanodontia is a rare clinical and radiologic manifestation that is always associated with GAPO syndrome. Osteomyelitis of the jaws is a less common disease that is usually attributed to odontogenic causes. This case report describes osteomyelitis of the mandible in a patient with GAPO syndrome. Further, an additional 3 cases of GAPO in the patient's family, with special emphasis on oral mucosal changes and pseudoanodontia, are discussed., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Premature ovarian insufficiency has the following causes: genetic, autoimmune, metabolic, infectious, and iatrogenic dysfunctions (including radiotherapy, chemotherapy and surgery). However, premature ovarian insufficiency remains without a definite cause in a substantial number of cases. This article describes GAPO syndrome in association with premature ovarian insufficiency, as well as a novel ANTXR1 gene mutation. Histopathological study of the ovaries of a woman with hypergonadotropic hypogonadism revealed extensive deposition of hyaline extracellular material, with bilateral parenchymal atrophy and follicular depletion. Molecular study revealed a novel ANTXR1 gene mutation. The homozygous c.378 + 3A > G transition at the consensus donor splice site of intron 4 was identified. Our results support the involvement of ANTRX1 gene mutations in deregulated extracellular matrix. In addition, our study identified a novel ANTXR1 mutation causing GAPO syndrome, indicating it as a new cause of early loss of ovarian function.

Primary mitochondrial diseases refer to a group of heterogeneous and complex genetic disorders affecting 1:5000 people. The true prevalence is anticipated to be even higher because of the complexity of achieving a diagnosis in many patients who present with multisystemic complaints ranging from infancy to adulthood. Diabetes is a prominent feature of several of these disorders which might be overlooked by the endocrinologist. We here review mitochondrial disorders and describe the phenotypic and pathogenetic differences between mitochondrial diabetes mellitus (mDM) and other more common forms of diabetes mellitus., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 37-year-old male, previously diagnosed with GAPO syndrome, was admitted to our hospital complaining of recurrent episodes of transient weakness and numbness in his left arm for 3 months, and severe headache with progressive dysphagia for 15 days. His cranial magnetic resonance (MR) images showed multiple ischemic foci in the bilateral periventricular and supraventricular white matter. Cerebral MR-angiography showed total occlusion of the right internal carotid artery and moderate stenosis in the left internal carotid. We also detected chronic thrombotic changes in the distal left sigmoid sinus, proximal right sigmoid sinus, and bilateral jugular veins on cerebral MR-venography. He was diagnosed with dilated cardiomyopathy at age 31 years, which was reported as a novel association; and later he had a myocardial infarction at age 34 years. To the best of our knowledge, this is the first patient with GAPO syndrome and arterial atherosclerosis in cerebral-as well as coronary-arteries and intracranial venous thrombosis. We report the evolution of the disease in this patient, who died at age 38 years due to respiratory failure secondary to lower respiratory tract infection., (© 2014 Wiley Periodicals, Inc.)

GAPO syndrome stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). To date, only about 35 cases of this extremely rare syndrome have been reported. Craniosynostosis/craniostenosis is a condition with an abnormal head shape due to premature fusion of the calvarial sutures and can be either non-syndromic or syndromic. Overall, craniosynostosis has an incidence of about 1 in 2500 live-births. We present a patient with GAPO syndrome in association with craniosynostosis along with intracranial hypertension, which was the cause of her headache. To the best of our knowledge, this is the first such association in the literature.

Introduction: Senior-Loken syndrome is a rare entity that combines familial nephronophthisisand retinal dystrophy. It has an autosomal recessive inheritance pattern and is characterized by a chronic tubulointerstitial nephritis that progress to terminal renal failure during the first or second decades of life. Systemic associations of this syndrome include sensorineural hearing loss, liver fibrosis or cerebral vermis hypoplasia. Acute pancreatitis has not been previously reported in this syndrome., Case Report: This is a 28- years-old patient who was diagnosed to have Senior Loken syndrome at the age of 10 years because of renal impairment and tapetoretinal degeneration and was later started on regular hemodialysis. He had no family history of renal disease, hypertriglyceridemia or cholelithiasis. He presented to our center complaining of acute abdominal pain and vomiting. He had abdominal tenderness without guarding. Investigations revealed a lipase level of 3856 I U/l and an abdominal CT scan showed features of acute pancreatitis. The abdominal ultrasound showed no biliary tree malformations or gallstone obstruction. He had no history of recent drug intake or alcohol consumption and his serum triglyceride level was normal. A diagnosis of moderate acute pancreatitis was made and the patient was managed conservatively with good outcome., Conclusion: Taking into consideration the uncertainty about the presence of liver fibrosis and the fact that imaging may have missed a passing gallstone, this case may indicate another rare systemic complication of Senior-Loken syndrome.

Purpose: To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children., Methods: Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing., Results: Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X)., Conclusions: We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.

Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive complicated form of hereditary spastic paraplegia, which is clinically defined by congenital optic atrophy, infancy-onset progressive spastic paraplegia and peripheral neuropathy. In this study, which included 61 individuals (age 5-72 years, 42 females) affected by SPOAN, a comprehensive motor and functional evaluation was performed, using modified Barthel index, modified Ashworth scale, hand grip strength measured with a hydraulic dynamometer and two hereditary spastic paraplegia scales. Modified Barthel index, which evaluate several functional aspects, was more sensitive to disclose disease progression than the spastic paraplegia scales. Spasticity showed a bimodal distribution, with both grades 1 (minimum) and 4 (maximum). Hand grip strength showed a moderate inverse correlation with age. Combination of early onset spastic paraplegia and progressive polyneuropathy make SPOAN disability overwhelming.

Purpose: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy, and invariably leads to blindness. LCA is a genetically and clinically heterogenous disorder. Although more than nine genes have been found to be associated with LCA, they only account for about half of LCA cases. We performed a comprehensive mutational analysis on nine known genes in 20 unrelated patients to investigate the genetic cause of LCA in Koreans., Methods: All exons and flanking regions of the nine genes (AIPL1, CRB1, CRX, GUCY2D, RDH12, RPE65, RPGRIP1, LRAT, and TULP1) were analyzed by direct sequencing. We also screened our patients for the common CEP290: c.2991+1655A>G mutation found in Caucasian., Results: Six different mutations including four novel ones were identified in three patients (15.0%): one frameshift, one nonsense, one splicing, and three missense mutations. These patients were compound heterozygotes and harbored two different mutations in CRB1, RPE65, and RPGRIP1, respectively. We identified three novel unclassified missense variants in RPGRIP1 of the three patients. These patients were heterozygous for each variant and did not have a large deletion or duplication in the same gene., Conclusions: This comprehensive mutational analysis shows marked genetic heterogeneity in Korean LCA patients and reveals a mutation spectrum that differs from those previously reported. In turn, this suggests that a different strategy should be used for the molecular diagnosis of LCA in Koreans.

There is much evidence in the literature suggesting that children with congenital blindness can also present autistic like features. The aetiopathogenetic and clinical significance of this association is still unclear. Given the central role played by vision in development, we set out to establish the significance of autistic-like behaviours in children with early-onset severe visual impairment. Our sample comprised 24 children (13 males, 11 females; mean age 5y 2mo; range 2-11y) affected by Leber's congenital amaurosis (LCA). The results of our administration of a modified Childhood Autism Rating Scale--excluding item VII (Visual Responsiveness)--showed that only four of the children gave an overall score indicating the presence of autism (moreover, of mild/moderate degree). Hardly any of the children in our LCA sample presented major dysfunctions in their relationships with other people or in their social and emotional responsiveness, thus allowing us to exclude a genuine comorbidity with a picture of autism. Indeed, the risk facing the visually impaired child seems to concern their early interactive experiences, which may be affected by their inability to connect with others, and may be prevented through the development of specific strategies of intervention.

Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available.

Introduction: In 1961, Garcin et al. described a family with several members affected with optic atrophy associated with cataract, and neurological symptoms. The authors believed this condition to be distinct from other diseases known at that time, e.g. the Behr syndrome, Marinesco-Sjogren syndrome and Friedreich's ataxia., Method: This family was followed over a period of 40 years and genes known to be responsible for optic atrophy were sequenced., Results: The G277A mutation of OPA3 gene was responsible for this familial disease., Discussion: A new clinical entity is identified: autosomal dominant optic atrophy and cataract, due to a heterozygous mutation of the OPA3 gene, a nuclear gene encoding a mitochondrial protein.

Aims: To provide a clinical update on the hereditary optic neuropathies., Methods: Review of the literature., Results: The hereditary optic neuropathies comprise a group of disorders in which the cause of optic nerve dysfunction appears to be hereditable, based on familial expression or genetic analysis. In some hereditary optic neuropathies, optic nerve dysfunction is typically the only manifestation of the disease. In others, various neurologic and systemic abnormalities are regularly observed., Conclusion: The most common hereditary optic neuropathies are autosomal dominant optic atrophy (Kjer's disease) and maternally inherited Leber's hereditary optic neuropathy. We review the clinical phenotypes of these and other inherited disorders with optic nerve involvement.

Purpose: To report a case of Leber hereditary optic neuropathy with multiple-sclerosis-like symptoms., Methods: Observational case report. A 34-year-old man was found to have Leber hereditary optic neuropathy and a mutation at position 11778 of the mitochondrial genome. The progression of vision loss and onset of weakness in the right leg warranted neuroimaging., Results: Magnetic resonance imaging documented multiple lesions in the brain and spinal cord., Conclusion: Although rarely reported, progression of optic neuropathy over months has been previously documented in Leber hereditary optic neuropathy. The emergence of multiple sclerosis-like symptoms and signs in our patient may be part of the spectrum of Leber hereditary optic neuropathy or a coincidental occurrence.

The hereditary optic neuropathies comprise a group of disorders in which the cause of optic nerve dysfunction seems to be heritable as demonstrated or suggested by familial expression or genetic analysis. Clinical variability, both within and among families with the same disease, often makes recognition and classification difficult. Genetic analysis now permits diagnosis of some of the hereditary optic neuropathies in the absence of family history or in the setting of unusual clinical presentations. The hereditary optic neuropathies are classified into three major groups: those that occur primarily without associated neurologic or systemic signs, those that frequently have associated neurologic or systemic signs, and those where the optic neuropathy is secondary in the overall disease process. This article reviewed the different hereditary optic neuropathies and emphasized the most common types.

A patient was diagnosed in 1974 with the unique combination of Leber hereditary optic neuropathy (LHON) and spondyloepiphyseal dysplasia. The entire mitochondrial DNA (mtDNA) sequence from this patient was determined in order to identify candidate pathogenic mutations. The patient's mtDNA carried the LHON mutation at nucleotide 14484, thus elucidating the etiology of his optic neuropathy. We also identified another ND6 mutation at nucleotide 14420. This latter mutation is probably a clinically benign private polymorphism, although a pathogenic role in his skeletal abnormalities or in his optic neuropathy cannot yet be ruled out., (Copyright 2001 Wiley-Liss, Inc.)

Myocardial thickening and isolated left ventricular abnormal trabeculation (ILVAT) have not been described in patients with Leber's hereditary optic neuropathy (LHON) before. Wolff-Parkinson-White syndrome, myocardial thickening and ILVAT were found by electrocardiogram, echocardiography and cardiac magnetic resonance imaging in a 48-year-old man with bilateral, severely reduced visual acuity since age 24 years, palpitations since age 43 years and lower limb muscle cramps since age 47 years. Because ILVAT is frequently associated with respiratory chain disorders, neurological investigations were initiated, revealing the primary LHON mutation G3460A in lymphocytic mitochondrial DNA. On the basis of the clinical and genetic data, LHON was diagnosed in the index patient, but also in the patient's brother who showed ILVAT as well. Wolff-Parkinson-White syndrome, myocardial thickening and ILVAT may be rare manifestations of LHON.

Purpose: To determine if tobacco or alcohol consumption is associated with vision loss among sibships harboring pathogenic mitochondrial mutations associated with Leber hereditary optic neuropathy., Methods: Retrospective case-control study with questionnaires obtained from both affected and unaffected siblings from 80 sibships with Leber hereditary optic neuropathy. Sibships harbored molecularly confirmed mitochondrial DNA mutations at nucleotide positions 11778 (63), 14484 (10), and 3460 (7). Exposure in affected individuals was calculated based on reported consumption before vision loss., Results: For male probands (67 sibships), the recurrence risk within a sibship was 10.3% (eight of 78) for males and 3.1% (three of 98) for females. For female probands (13 sibships), the recurrence risk within a sibship was 17.6% (three of 17) for males and 0% (zero of 22) for females. Greater risk of vision loss was associated with male sex (odds ratio [OR] = 6.63; 95% confidence interval [CI] = 2.96 to 14.84; P =.00001) and harboring a 3460 or 14484 in comparison with the 11778 mutation (OR = 2.071; 95% CI = 1.19 to 3.58; P =.0095). No significant association of maximal intensity of smoking or cumulative smoking, whether light or heavy, with vision loss was observed. Light (OR = 0. 31; 95% CI = 0.17 to 0.56; P =.0001) and heavy alcohol consumers (OR = 0.25; 95% CI = 0.11 to 0.58; P =.0011) were less likely to be affected than individuals who did not consume alcohol after adjusting for age, sex, and mutation. In a categorical analysis of sibships with the 3460 or 14484 mutation, no relationship of vision loss with tobacco or alcohol consumption was observed., Conclusion: Unlike previous studies, the present study calculated exposure based on self-reported consumption of tobacco or alcohol before vision loss. No significant deleterious association between tobacco or alcohol consumption and vision loss among individuals harboring Leber hereditary optic neuropathy mutations was observed. Tobacco and alcohol do not appear to promote vision loss in Leber hereditary optic neuropathy.

Objectives: The authors investigated the effectiveness of idebenone combined with vitamin B2 and vitamin C in the treatment of patients with Leber hereditary optic neuropathy (LHON) in an early stage as compared with untreated patients with LHON. These agents may stimulate the formation of ATP., Materials and Methods: For this retrospective study, the authors selected 28 outpatients with LHON from the Keio University Hospital. These patients were followed for 2 to 19 years from disease onset. They were divided into two groups: 14 untreated patients (11778 mutation in 10 patients, 3460 mutation in 2 patients, and 14484 mutation in 2 two patients); and 14 treated patients (11778 mutation in 11 patients, 3460 mutation in 1 patient, and 14484 mutation in 2 patients). The treated patients were administered medical treatment with idebenone, vitamin B2, and vitamin C for at least 1 year. The current study evaluated the following: 1) number of eyes with visual recovery > or = 0.3; 2) interval between the onset of LHON and the beginning of visual recovery; 3) interval between the onset of LHON and visual recovery to 0.3; and 4) interval between the beginning of medical treatment and the beginning of visual recovery in the treated subjects., Results: There was no significant difference in the number of eyes with visual recovery > or = 0.3 in the two groups with the 3460, 11778, or 14484 mutation. Patients with visual recovery showed a fenestrated scotoma or a clearing of central vision. The mean interval between the onset of LHON and the beginning of visual recovery was significantly shorter in the treated group (11.1 months) than in the untreated group (17.4 months) (P = 0.03). The mean interval between the onset of LHON and visual recovery to 0.3 was significantly shorter in the treated group (17.6 months) than in the untreated group (34.4 months) (P = 0.01). The mean interval between the initiation of medical treatment to the beginning of visual recovery was 5.4 months., Conclusions: Results suggest that the administration of idebenone, vitamin B2, and vitamin C sped the recovery of vision in patients with LHON.

Purpose: To report the identification of a novel mutation of the RP2 gene in two Japanese brothers with X-linked retinitis pigmentosa of a differing clinical severity. The mother was a carrier of both retinitis pigmentosa and optic atrophy., Methods: The older brother had a severe form of retinitis pigmentosa associated with macular degeneration and total optic atrophy, whereas the younger brother presented typical X-linked retinitis pigmentosa., Results: Each patient exhibited a novel 2-bp insertion at codon 278 in exon 3 of the RP2 gene as well as a 11778 mutation in mitochondrial DNA. This suggests that the older brother may have developed Leber hereditary optic neuropathy as well as retinitis pigmentosa., Conclusion: Molecular testing confirmed the clinical diagnosis in each case. However, such testing did not explain the differences in the severity of the ophthalmoscopic findings between the two brothers.

Purpose: The evaluation of the anomaloscope slope quotient in patients with acquired colour vision deficiency., Methods: Two patients with Stargardt's disease in combination with protanomaly and deuteranomaly, respectively, were selected and also 3 patients with a presumed dominant optic atrophy of the protan type. The anomaloscope examination was performed according to the Linksz procedure. The luminance fall was calculated as the slope quotient SQ:Y units luminance fall per X units width of the matching range., Results: The SQ of the 2 Stargardt patients was steeper than the SQ of congenital colour vision defectives, especially at the red end of the anomaloscope green-red mixture scale, indicating pathologic scotopization superimposed on the congenital deficiency. In optic atrophy of the protan type the SQ was flatter than in congenital deficiency, indicating that this deficiency has nothing to do with congenital protan deficiency., Conclusion: Calculation of the slope quotient SQ is helpful for the diagnosis of acquired colour vision deficiency, especially when the subject also has a congenital colour vision deficiency or is supposed to have such a deficiency.

Multiple sclerosis (MS) and Leber's hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding.

A patient with Leber Hereditary Opticus Neuropathy (LHON) and a pituitary adenoma is presented. The different ophthalmological signs of LHON are described and illustrated. A definite diagnosis is made by detecting a mitochondrial mutation. A radiological examination revealed a pituitary adenoma. The pituitary adenoma may be a trigger factor in the penetrance of LHON.

Background: Leber's hereditary optic neuropathy (LHON) mostly affects young males. In patients carrying one of the primary mutations the risk to develop LHON is 50% for males and 10% for females. We report a family with predominantly young girls affected., Methods: In a family with 14 known maternal relatives (11 females, 3 males) 9 patients in 4 generations developed LHON. Eight of the 9 patients were females. Three affected females could be examined and followed., Results: The only affected male showed the typical course of LHON with acute visual loss in both eyes (20/400-20/800) within 6 weeks at 20 years of age. Eight of 9 females developed signs of LHON. In these females acute visual loss occurred at about 10 years of age. Final visual acuity was about 20/200. Central or paracentral scotomata, color vision defects and delayed P100 latencies in the VEP were seen. Ophthalmoscopy showed hyperemic discs in the acute stage and optic atrophy in later stages. Molecular genetic analysis revealed the presence of the mtDNA ND4/np11778 mutation in this family. Specific clinical or additional molecular genetic risk factors could not be detected., Conclusion: Families with LHON may show considerable variations of the clinical course and the gender- or age-specific risk. We present a family with a high disease penetrance of 64% and a 2 times higher risk for young females than for males. Furthermore, early visual loss in this family is permanent.

Introduction: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder, confirmed at a molecular level 10 years ago. This had permitted better understanding of the condition. Since 1998, the Instituto de Neurología y Neurocirugía has used these techniques for the study of mutations which are considered to be the origin of the disorder., Patients and Methods: We describe the characteristics of 14 cases from 10 families with LHON and the molecular confirmation found between 1994 and 1998 in the Instituto de Neurología Neurocirugía de Cuba. We also review the few cases seen in the previous 18 years. These were from only two families. They were diagnosed on clinical grounds and in view of maternal inheritance., Results and Conclusions: In 80% of the families in which the presence of primary mutations was investigated there was A117789, and in 20% A3460G. The average age of appearance was 28 years. The ages of onset were within the limits of 11 years and 48 years. There were 43% women. Two cases were considered to be sporadic. The clinical features corresponded to those described in such cases, with severe visual defects, central scotomas, very reduced colour vision and severely altered visual evoked potentials, with normal diffuse light and pattern electroretinograms. An improvement in visual acuity of 0.2 was seen in two cases. Microangiopathy, described as characteristic of the early stages of this disorder was detected in five cases, in at least one eye. The others had different degrees of optic atrophy. Two generations of one complete family, all with mutation 3460, were studied. In several families with this mutation alterations were found in the colour vision test of Farnsworth Munsell Hue 100 and also microangiospathy of the retina.

A 37-year-old man developed choreic movements of the limbs over a few months. His medical history included bilateral visual loss detected at the age of 9 and worsening at age 20. Visual field testing showed a central scotoma. Fundus examination showed atrophy of the optic disks and narrowing of vessels. The diagnosis of Leber hereditary optic neuropathy (LHON) was considered. There was no family history of visual loss or movement disorders. Blood lactate:pyruvate ratio was moderately elevated. Skeletal muscle biopsy was normal. Magnetic resonance imaging showed bilateral hypointense lesions on T1-weighted sequences in the subthalamic nuclei and in the lateral part of the substantia nigra. Linear hyperlucencies in the pyramidal tract facing the lateral part of the ruber nuclei were also demonstrated on T2-weighted sequences. Nine LHON-associated mutations were ruled out by RFLP analysis. Treatment with 250 mg coenzyme Q10 per day and multiple vitamins was initiated. Gradual recovery in movement disorders occurred over 1 year. Lactate to pyruvate ratio normalized. No change of visual function was observed. On magnetic resonance imaging performed 3 years later, lesions of the subthalamic nuclei almost completely disappeared. We think the patient might have an unusual, genetically uncharacterized mitochondrial disorder, combining optic neuropathy and chorea.

Leber's hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis due to multiple sclerosis (MS). For several decades an association of LHON and MS has been suspected, and within the past 7 years the LHON nucleotide (nt)-3460 and nt-11778 mtDNA mutations have been identified in several patients with MS-like phenotypes. To further study this association, we tested 42 index patients with clinically definite, familial MS for the LHON mtDNA mutations at nt-3460, nt-11778, and nt-14484. No patients had a pathogenic LHON mtDNA mutation; however, two MS patients with unilateral optic neuritis harbored the nt-15257 mtDNA polymorphism that was reported originally as a pathogenic LHON mutation. Several investigators have shown evidence that the nt-15257 mtDNA mutation is not primarily pathogenic. Therefore, we conclude that pathogenic LHON mtDNA mutations are absent or rare in unselected patients with familial, clinically definite MS (95% confidence intervals for each of the negative mutations 0-7.0%).

Objectives: Leber's hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis seen in multiple sclerosis (MS). About half of the LHON patients harbor a mutation at nucleotide (nt) 11778 in the mitochondrial (mt) DNA. In addition, mutations at nt-3460 and nt-14484 have been associated with LHON. An association of LHON and MS has been suspected for decades, and, recently, the LHON nt-11778 and nt-3460 mtDNA mutations have been found in several patients with MS or MS-like disease. We attempted to determine which MS patients should be evaluated further for LHON mutations., Methods: We screened 103 clinically definite MS patients (age range from 18 to 72 years, 27 men and 76 women) for the LHON nt-11778 and nt-3460 mtDNA mutations., Results: Neither mutation was identified in the patients., Conclusions: Our findings confirm previous reports which found that both LHON mutations are rare in unselected MS patients. The reports to date suggest that MS patients with peripapillary teleangiectasia typical of LHON, with relatives harboring LHON or with early severe bilateral optic neuropathy, particularly if female, should be further evaluated for LHON mutations.

Purpose: The authors report Ewing's sarcoma in a patient with congenital optic atrophy. Congenital optic atrophy is an autosomal dominant disorder with variable expression. It manifests itself within the first decade of life and is accompanied by changes in visual acuity. This condition has not been known to cause a predisposition toward malignancy., Patient and Methods: In this article, a 16-year-old girl with dominant optic atrophy and Ewing's sarcoma is described., Results: After tumor resection, the patient was successfully treated for Ewing's sarcoma with chemotherapy and radiation therapy. Today she has no evidence of malignancy. However, she continues to have deterioration of her visual acuity., Conclusion: This report of cancer in a child with dominant optic atrophy suggests the possible need for a higher degree of suspicion of malignancy in these patients.

We report the clinical and genetic study of a Leber's Hereditary Optic Neuropathy (LHON) patient of North African origin harboring the 14484/ND6 mutation of mtDNA. For over a year we followed the ophthalmological course of this 24-year-old male with LHON treated with idebenone and vitamin B12. Serum lactate after effort was evaluated before, during and after therapy. Muscle biopsy was obtained for morphological study. Homo/heteroplasmy of 14484/ND6 mutation was studied in different tissues. Recovery of visual acuity was documented 6 months after onset and 3 months after therapy was established. Baseline serum lactate was elevated but normalized after 3.5 months of therapy. Muscle biopsy demonstrated only a few fibers with a slightly increased subsarcolemmal SDH activity. Genetic analysis showed homoplasmic 14484/ND6 mutation in all tissues investigated. The clinical phenotype of LHON/14484 in this patient closely resembles that commonly found in European patients. Even if LHON/14484 patients are reported to have a better prognosis for visual recovery, it is possible that the evolution of visual recovery in this patient could have been influenced by therapy as suggested by changes in serum lactate levels. Bioenergetic impairment of skeletal muscle was documented by lactate levels and muscle morphology. The 14484/ND6 mutation behaves as a primary mutation regardless of mtDNA population-specific backgrounds.

The occurrence of optic neuropathy in patients with MS-like disorders who carry one of the pathogenetically significant LHON mutations as well as the higher incidence of maternal transmission in familial cases of MS support the hypothesis that mitochondrial genes may be implicated in susceptibility to MS. We sequenced the entire mtDNA of six children with MS who developed optic neuritis as early and prominent visual involvement. The analysis revealed a high degree of nucleotide variations relative to the standard mtDNA sequence. After excluding various synonymous nucleotide changes and common neutral polymorphisms, eight discrete novel missense mutations within the protein coding, tRNA or rRNA genes were detected. None of the eight polymorphic sites were found in common between the patients with MS. Of particular interest was the observation that five of six children carried a total of nine secondary LHON mutations at nucleotide positions 4216, 4917 or 13708. We conclude that variation in mtDNA is unlikely to contribute to genetic predisposition for MS. However, secondary LHON mutations may be regarded as additional risk factor for developing prominent optic nerve involvement. The association of individual sets of mtDNA variations with phenotypic presentation in certain subgroups of MS patients remains to be clarified.

Purpose: It has been suggested that the pupillary light reaction is relatively preserved in the affected eyes of patients with Leber hereditary optic neuropathy (LHON). To test the hypothesis that visual-pupillomotor dissociation exists in LHON, we performed a retrospective study to evaluate the magnitude of the relative afferent pupillary defect (RAPD) in patients who had experienced monocular visual loss. We also compared the size of the measured RAPD with the size of the RAPD that would be expected on the basis of documented visual field loss., Methods: We identified a cohort of patients with LHON and monocular visual loss, whose pupillary reactions had been quantified using neutral density filters. From a review of the case records, we determined whether an RAPD was present, as well as the magnitude of the documented RAPDs. We also calculated the expected size of the RAPD for each patient, using previously established templates that correlated the size of the RAPD with the degree of visual field loss., Results: An RAPD was identified in all 10 patients in this study. There was no significant difference between the size of the measured and predicted RAPD, nor did the size of the RAPD correlate with visual acuity or the time interval between the onset of visual loss and evaluation., Conclusion: The results of this study do not support the hypothesis that visual-pupillomotor dissociation is a common feature of LHON.

Background: Assessment of the causes of childhood blindness is important to develop preventive and therapeutic strategies that can reduce the incidence of visual impairment., Methods: A retrospective survey of the clinical records of 395 consecutive children younger than 14 years of age who were attended by the Low Vision Service of State University of Campinas (UNICAMP) was conducted. Data on the age distribution, the causes of low vision, the types of low vision aids prescribed, the follow up of their use, and improvement in visual acuity were obtained., Results: Congenital bilateral toxoplasmic macular scars, optic atrophy, and congenital cataracts were the major causes of low vision in this population. The optical aid most frequently prescribed was a telescope. The improvement of visual acuity with the use of aids was highly significant.

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Leber's hereditary optic neuropathy (LHON) in Caucasian patients who show a high incidence of visual recovery. We evaluated four Japanese patients with LHON associated with the 14484 mutation who were negative for eight proposed secondary mutations. There was no family history of optic atrophy in three of the four patients. All four patients were initially diagnosed as having optic neuritis, either anterior (Cases 1 and 3) or retrobulbar (Cases 2 and 4), based upon their fundus findings and clinical history. Molecular genetic testing of mtDNA confirmed the diagnosis of LHON in all four patients. The three patients who experienced recovery had their vision return to 20/50 or better in both eyes. The patient who did not was a heavy consumer of alcohol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.