SENIOR-LØKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis.

PURPOSE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome. METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing. RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia. CONCLUSION: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.

Copy number variations and multiallelic variants in Korean patients with Leber congenital amaurosis.

Purpose: We comprehensively evaluated the mutational spectrum of Leber congenital amaurosis (LCA) and investigated the molecular diagnostic rate and genotype-phenotype correlation in a Korean cohort. Methods: This single-center retrospective case series included 50 Korean patients with LCA between June 2015 and March 2019. Molecular analysis was conducted using targeted panel-based next-generation sequencing, including deep intronic and regulatory variants or whole exome sequencing. The molecular diagnosis was made based on the inheritance pattern, zygosity, and pathogenicity. Results: Among the 50 patients, 27 patients (54%) were male, and 11 (22%) showed systemic features. Genetic variants highly likely to be causative were identified in 78% (39/50) of cases and segregated into families. We detected two pathogenic or likely pathogenic variants in a gene linked to a recessive trait without segregation analysis in three cases (6.0%). GUCY2D (20%), NMNAT1 (18%), and CEP290 (16%) were the most frequently mutated genes in Korean LCA. Copy number variations were found in three patients, which accounted for 6% of LCA cases. A possible dual molecular diagnosis (Senior-Løken syndrome along with Leigh syndrome, and Joubert syndrome with transposition of the great arteries) was made in two patients (4%). Three of 50 patients were medically or surgically actionable: one patient for RPE65 gene therapy and two patients with WDR19 Senior-Løken syndrome for early preparation for kidney and liver transplantations. Conclusions: This study demonstrated that approximately 4% of patients may have dual molecular diagnoses, and 6% were surgically or medically actionable in LCA. Therefore, accurate molecular diagnosis and careful interpretation of next-generation sequencing results can be of great help in patients with LCA.

[Genetic Causes and Genetic Diagnostic Testing of Inherited Optic Atrophies]. / Genetische Ursachen und genetische Diagnostik bei hereditären Optikusatrophien.

Hereditary optic atrophies are a heterogeneous group of rare degenerative disease affecting the retinal ganglion cells and their axons which form the optic nerve. With an estimated prevalence of 1 : 10 000 to 1 : 20 000, hereditary optic atrophies in their entirety affect about 4000 to 8000 people in Germany. The most common forms are Leber's hereditary optic atrophy (LHON) and autosomal dominant optic atrophy (ADOA). Besides the common forms of isolated optic atrophies which exclusively affect the visual system, there are a variety of conditions in which the optic atrophy is part of a syndromic disease with additional symptoms that are mostly neurosensory, neurological or neuromuscular. The mode of inheritance is heterogeneous with LHON showing maternal inheritance and an autosomal dominant inheritance in families with ADOA. There are rarer cases of optic atrophy following an autosomal recessive or X-linked recessive mode of inheritance. The penetrance is incomplete. Moreover, in LHON, there are many more males than females who develop the disease. The genetic causes of hereditary optic atrophies are complex in terms of the diversity of the involved genes. However, most of these causes are already known. Therefore, molecular genetic diagnostic testing yields a meaningful result in the majority of tested subjects and enables confirmation of the suspected clinical diagnosis, reliable counseling of the families with respect to the genetic risk, and - in subjects with genetically confirmed LHON - initiation of therapeutic intervention. This article provides an overview of current knowledge of the genetic causes of hereditary optic neuropathies, and the options and modalities of molecular genetic diagnostic testing, including practical guidelines.

[Ciliopathies]. / Retinale Ziliopathien.

Ciliopathies are disorders caused by ciliary dysfunction and can affect an organ system or tissues. Isolated or syndromic retinal dystrophies are the most common ocular manifestation of ciliopathies. The photoreceptor connecting cilium plays a leading role in these ciliopathy-related retinal dystrophies. Dysfunctional photoreceptor cilia cause the most severe type of retinal dystrophy: Leber's congenital amaurosis (LCA). The most common syndromic ciliopathies with an ocular manifestation are Bardet-Biedl syndrome (BBS) and Usher syndrome. Molecular-genetic analysis revealed a large number of cilia genes with a high phenotype heterogeneity. Diagnosis of ciliopathies require a multi-disciplinary approach. Causative treatment of ciliopathies is not yet available; therefore, rehabilitative and supportive treatment is mandatory.

Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options.

Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients.

Arterial and venous thrombosis of the cerebral vasculature in GAPO syndrome.

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.

[Modern opportunities and prospects for studying pathogenesis, diagnosing and treating hereditary optic neuropathies].

OBJECTIVE: To evaluate modern opportunities and prospects for studying pathogenesis and improving diagnostics and treatment of hereditary optic neuropathies (HON). MATERIAL AND METHODS: The article presents summarized data on the pathogenesis, diagnostics, and treatment of HON based on modern methods of assessment. RESULTS: The results of long-term worldwide studies and those performed in the Research Institute of Eye Diseases in collaboration with several other institutions are presented. Genetic testing for mitochondrial and nucleus DNA mutations that have a known association with Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic neuropathy (ADON) allow verification only in half of the cases. Particular features of hereditary diseases, such as incomplete penentrance, variable expression, clinical polymorphism, difficulties in detection of hereditary sings, and genetic heterogeneity, are shown to complicate the diagnosis of HON. Spectral retinal tomography revealed characteristic morphometric changes in the macular region and peripapillary nerve fiber layer in the acute stage of LHON. Hereditary optic neuropathies result from a genetically determined decrease in mitochondrial respiratory chain complexes activity, which is associated with a decrease in ATP production. From that standpoint, studying of mitochondrial oxidative phosphorylation biochemical defects in LHON and ADON is an option for detection of mitochondrial dysfunction. Results of a newly proposed method of mitochondrial membrane potential assessment in skin fibroblasts, which can be used for differential diagnosis of mitochondrial optic nerve diseases, are presented. Possible therapeutic measures for HON are discussed. CONCLUSION: In the prevailing number of cases the described clinical, molecular genetic, and cytological methods ensure proper diagnosis of hereditary optic neuropathies. Prospects of HON treatment, rather ambiguous, are associated with further studying of pathogenesis, development of drugs and gene therapy.

GAPO syndrome: a novel variant in ANTXR1 gene.

BACKGROUND: GAPO syndrome is a rare autosomal recessive disorder characterized by the acronym of growth retardation, alopecia, pseudo-anodontia and progressive optic atrophy. While the genetic alteration of the ANTXR1 gene has been known for its cause, the full range of its clinical and genetic manifestations is not well explored due to the syndrome's extreme rarity. MATERIALS/METHODS: We report two children born to a non-consanguineous parent in India with classical features of GAPO syndrome. The whole exome sequencing analysis (WES) was performed in both siblings, and the parent's genetic and clinical status was determined. The identified variation was characterized in silico using homology-based protein modelling. RESULTS: In WES analysis, a homozygous ANTXR1 gene indel variant c. 151_152 + 2delAAGT (p.Lys51fs) was identified in both siblings. The parents were identified as the carriers of the ANTXR1 variant. Additionally, they also displayed mild GAPO-related facial and glaucomatous features. In silico analysis and homology-based ANTXR1 protein structure illustrate a frameshift and the subsequent premature truncation of the protein. CONCLUSIONS: Our reports contribute to the comprehension of GAPO syndrome within the Indian context describing an ANTXR1 novel variant causing premature protein truncation. WES-based genetic testing can significantly aid in expertly diagnosing GAPO syndrome. In the present case scenario, a variable penetrance of ANTXR1 variation was acknowledged as the carrier parents also had a mild degree of GAPO-related features. Future reports that include parental clinical diagnosis can offer further insights in this context.

GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer.

This article reports on the ophthalmological features of four Turkish children with GAPO syndrome, a very rare autosomal recessive condition characterized by growth retardation (G), alopecia (A), pseudoanodontia (P) (failure of tooth eruption), and optic atrophy (O). The children were from two unrelated families born to consanguineous parents. They had the characteristic facial appearance of alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, midfacial hypoplasia, hypertelorism, and thickened eyelids and lips. Two children had severe end-stage glaucoma in both eyes and unilateral corneal opacity, whereas other two children had myelinated retinal nerve fiber layer; one with bilateral optic atrophy and the other one with persistent pupillary membrane in the left eye.

GAPO syndrome associated with pyoderma vegetans: an unreported co-existence.

GAPO syndrome is a rare autosomal recessive disease and an acronym composed of growth retardation, alopecia, pseudoanodontia, optic atrophy. Approximately 38 cases have been reported in literature until now. Pyoderma vegetans is a chronic inflammatory disease characterized with vesicopustular, exudative and vegetative lesions usually localized on face, scalp, axilla and genitalia. Pyoderma vegetans is attributed to a bacterial infection frequently occurring in individuals with an underlying immunosuppressive condition. A 30-year-old female patient was admitted to our clinic with complaint of a hemorrhagic, crusted, exudative vegetative two plaques on the scalp. On her physical examination, she had a prematurely aged face, predominant lower lips, total tooth loss, frontal bossing, enlarged anterior fontanelle, marked scalp veins, micrognatia, depressed nasal bridge, short stature, growth retardation. She was diagnosed as GAPO syndrome as the result of her physical examination. Result of the biopsy taken from scalp was evaluated as pyoderma vegetans. And the diagnosis of pyoderma vegetans was established based on the correlate of both clinical and histopathologic findings. Pyoderma vegetans coexisting with GAPO syndrome has not been reported previously. Thus we wished to report it.

[Hereditary optic neuropathies: clinical and molecular genetic characteristics].

The article presents a review of literature on hereditary optic neuropathies: Leber mitochondrial hereditary optic neuropathy, autosomal dominant and autosomal recessive optic neuropathies, X-linked optic atrophy. Clinical and molecular genetic characteristics are covered. Isolated optic neuropathies, as well as hereditary optic disorders, being a part of a complex syndromic disease are described.

[Hereditary optic neuropathies]. / Neuropathies optiques héréditaires.

Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated neurological signs are increasingly recognized.

New ophthalmic features in a family with triple A syndrome.

We report three subjects of a Greek family affected by triple A syndrome (AAAS). All patients underwent complete ophthalmic examination, full-field electroretinogram (ERG), visual evoked responses (VER), optical coherence tomography (OCT) and molecular analysis of the AAA gene. All patients had alacrima. In two of them, the proband and her brother, bilateral optic atrophy was assessed and the VER were pathological. In contrast, the ERG was normal. OCT showed a decrease of the retinal nerve fiber layer. The third case had only alacrima and the optic nerves were normal. The molecular genetic study of the AAAS gene revealed a homozygous missense mutation p.Ala167Val. To our knowledge this is the first time a family with AAAS has been investigated using OCT, VER and ERG. Our findings illustrate that the retina is not involved. There is also an interfamilial variability concerning the involvement of the optic nerves.

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies.

Clinical assessment and FGFR2 mutation analysis in a Chinese family with Crouzon syndrome: A case report.

RATIONALE: Crouzon syndrome is an autosomal dominant genetic disorder caused by mutations in fibroblast growth factor receptor 2 (FGFR2) and one of the most common types of craniosynostosis. Here we report the detection of FGFR2 mutation and its related clinical findings in 2 patients with Crouzon syndrome from a Chinese family. PATIENT CONCERNS: We report a case of a 28-year-old male patient presented with the chief complaint of gradually blurring of his eyes over the last 6 months before visiting our clinics. History revealed low visual acuity in his right eye since childhood. Physical examination showed that both the patient and his mother have the appearance of craniofacial dysostosis, mandibular prognathism, ocular proptosis, short superior lip, scoliosis, and thoracic deformity. DIAGNOSIS: Auxiliary examinations lead to the diagnosis of Crouzon syndrome with binocular optic atrophy, myelinated retina nerve fibers, and ametropia in both eyes, and amblyopia in the right eye of the male patient. The molecular genetic analysis confirmed the diagnosis by detecting a heterozygous pathogenic mutation c.1026C > G (C342W) in exon 10 of FGFR2 in both the patient and his mother, but not in any of the unaffected family members. INTERVENTIONS AND OUTCOMES: None. LESSONS: Our study confirms the presence of optic nerve atrophy in patients with Crouzon syndrome carrying FGFR2 C342W mutations and indicates that MRI and funduscopy should be performed to examine the optic nerve changes for patients with Crouzon syndrome.

[Hereditary optic atrophies]. / Les atrophies optiques héréditaires.

INTRODUCTION: Hereditary optic neuropathies, resulting from retinal ganglion cell degeneration, are a heterogeneous group of diseases ranging from asymptomatic forms to legal blindness. STATE OF KNOWLEDGE: Two most frequent phenotypes are Kjer's disease, an autosomal dominant optic atrophy caused by OPA1 gene mutations, and Leber's disease due to maternally inherited mitochondrial DNA mutations. PROSPECTS AND CONCLUSION: Both optic neuropathies usually isolated are sometimes associated with extraocular symptoms, especially neurological symptoms, thus justifying a systematic neurological evaluation and brain imaging.

Senior-Løken syndrome misdiagnosed as nephrosclerosis related to hypertensive disorders of pregnancy.

A 31-year-old woman with retinitis pigmentosa who had been diagnosed with renal failure due to nephrosclerosis related to hypertensive disorders of pregnancy was referred to our hospital to prepare for renal replacement therapy. Ultrasonography and MRI of the kidneys revealed multiple corticomedullary cysts. A renal biopsy showed that the tubules were tortuous and atrophic with segmented tubular basement membrane thickening. These findings indicated that she had Senior-Løken syndrome. A molecular genetic analysis was performed, and homozygous deletion of the gene encoding nephronophthisis-1 was found. Thus, the clinical diagnosis of Senior-Løken syndrome was genetically confirmed. Because her renal function was gradually worsening, she was scheduled to undergo living donor kidney transplantation. Senior-Løken syndrome, which is recognised as a very rare paediatric inherited disease characterised by nephronophthisis and eye problems, can cause adult-onset end-stage renal failure.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant syndrome of developmental delay, cortical vision loss with optic nerve atrophy, epilepsy, and autism spectrum disorder. Due to its many overlapping features with congenital disorders of glycosylation (CDG), the differential diagnosis between these disorders may be difficult and relies on molecular genetic testing. We report on a 31-year-old female initially diagnosed with ALG6-CDG based on glycosylation abnormalities on transferrin isoelectrofocusing and targeted genetic testing, and later diagnosed with BBSOAS by whole-exome sequencing (WES). Functional studies on cultured fibroblasts including Western blotting and RT-qPCR, as well as mass spectrometry of glycosylated transferrin and MALDI-TOF glycan analysis in serum, demonstrated normal glycosylation in this patient. In this report, we extend the phenotype of BBSOAS with ataxia and protein-losing enteropathy. This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes.