Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.
- MeSH
- Adult MeSH
- Dystonic Disorders genetics MeSH
- Phenotype MeSH
- Genetic Association Studies MeSH
- Humans MeSH
- Intellectual Disability genetics MeSH
- Hearing Loss genetics MeSH
- Codon, Nonsense * MeSH
- Vision Disorders genetics MeSH
- Frameshift Mutation * MeSH
- Child, Preschool MeSH
- Calcium-Binding Proteins genetics MeSH
- Pedigree MeSH
- Sequence Deletion * MeSH
- Exome Sequencing MeSH
- Trans-Activators genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.
- MeSH
- Ceramides genetics metabolism MeSH
- Farber Lipogranulomatosis * enzymology genetics pathology MeSH
- Acid Ceramidase genetics metabolism MeSH
- Mutation, Missense * MeSH
- Disease Models, Animal MeSH
- Mice, Mutant Strains MeSH
- Mice MeSH
- Optic Nerve * enzymology pathology MeSH
- Vision Disorders * enzymology genetics pathology MeSH
- Retina * enzymology pathology MeSH
- Sphingolipids genetics metabolism MeSH
- Amino Acid Substitution MeSH
- Inflammation enzymology genetics pathology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
CONTEXT: Methanol poisoning induces acute optic neuropathy with possible long-term visual damage. OBJECTIVE: To study the dynamics and key determinants of visual pathway functional changes during 4 years after acute methanol poisoning. METHODS: A total of 42 patients with confirmed methanol poisoning (mean age 45.7 ± 4.4 years) were examined 4.9 ± 0.6, 25.0 ± 0.6, and 49.9 ± 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping. RESULTS: Abnormal VEP P1 latency was registered in 18/42 right eyes (OD) and 21/42 left eyes (OS), abnormal N1P1 amplitude in 10/42 OD and OS. Mean P1 latency shortening during the follow-up was 15.0 ± 2.0 ms for 36/42 (86%) OD and 14.9 ± 2.4 ms for 35/42 (83%) OS, with maximum shortening up to 35.0 ms. No significant change of mean N1P1 amplitude was registered during follow-up. A further decrease in N1P1 amplitude ≥1.0 mcV in at least one eye was observed in 17 of 36 patients (47%) with measurable amplitude (mean decrease -1.11 ± 0.83 (OD)/-2.37 ± 0.66 (OS) mcV versus -0.06 ± 0.56 (OD)/-0.83 ± 0.64 (OS) mcV in the study population; both p < .001). ApoE4 allele carriers had lower global and temporal RNFL thickness and longer initial P1 latency compared to the non-carriers (all p < .05). The odds ratio for abnormal visual function was 8.92 (3.00-36.50; 95%CI) for ApoE4 allele carriers (p < .001). The presence of ApoE4 allele was further associated with brain necrotic lesions (r = 0.384; p = .013) and brain hemorrhages (r = 0.395; p = .011). CONCLUSIONS: Improvement of optic nerve conductivity occurred in more than 80% of patients, but evoked potential amplitude tended to decrease during the 4 years of observation. ApoE4 allele carriers demonstrated lower RNFL thickness, longer P1 latency, and more frequent methanol-induced brain damage compared to non-carriers.
- MeSH
- Apolipoprotein E4 genetics MeSH
- Time Factors MeSH
- Adult MeSH
- Gene Frequency MeSH
- Genetic Predisposition to Disease MeSH
- Middle Aged MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- Methanol poisoning MeSH
- Follow-Up Studies MeSH
- Optic Nerve Diseases chemically induced diagnosis genetics physiopathology MeSH
- Optic Nerve drug effects physiopathology MeSH
- Vision Disorders chemically induced diagnosis genetics physiopathology MeSH
- Prognosis MeSH
- Prospective Studies MeSH
- Reaction Time MeSH
- Risk Factors MeSH
- Case-Control Studies MeSH
- Vision, Ocular drug effects genetics MeSH
- Evoked Potentials, Visual MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
BACKGROUND: Leber hereditary optic neuropathy (LHON) and mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) syndromes are mitochondrially inherited disorders characterized by acute visual failure and variable multiorgan system presentation, respectively. MATERIALS AND METHODS: A 12-year-old girl with otherwise unremarkable medical history presented with abrupt, painless loss of vision. Over the next few months, she developed moderate sensorineural hearing loss, vertigo, migraines, anhedonia and thyroiditis. Ocular examination confirmed bilateral optic nerve atrophy. Metabolic workup documented elevated cerebrospinal fluid lactate. Initial genetic analyses excluded the three most common LHON mutations. Subsequently, Sanger sequencing of the entire mitochondrial DNA (mtDNA) genome was performed. RESULTS: Whole mtDNA sequencing revealed a pathogenic heteroplasmic mutation m.13046T>C in MTND5 encoding the ND5 subunit of complex I. This particular variant has previously been described in a single case report of MELAS/Leigh syndrome (subacute necrotizing encephalopathy). Based on the constellation of clinical symptoms in our patient, we diagnose the condition as LHON/MELAS overlap syndrome. CONCLUSIONS: We describe a unique presentation of LHON/MELAS overlap syndrome resulting from a m.13046T>C mutation in a 12-year-old girl. In patients with sudden vision loss in which three of the most prevalent LHON mitochondrial mutations have been ruled out, molecular genetic examination should be extended to other mtDNA-encoded subunits of MTND5 complex I. Furthermore, atypical clinical presentations must be considered, even in well-described phenotypes.
- MeSH
- Child MeSH
- Phenotype MeSH
- Polymorphism, Single Nucleotide * MeSH
- Optic Atrophy, Hereditary, Leber diagnosis genetics MeSH
- Humans MeSH
- DNA, Mitochondrial genetics MeSH
- Mitochondrial Proteins genetics MeSH
- DNA Mutational Analysis MeSH
- Vision Disorders diagnosis genetics MeSH
- Electron Transport Complex I genetics MeSH
- MELAS Syndrome diagnosis genetics MeSH
- Visual Field Tests MeSH
- Visual Acuity physiology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- Stargardtova choroba, SD-OCT, ABCA4,
- MeSH
- ATP-Binding Cassette Transporters * genetics MeSH
- Retinal Degeneration diagnosis genetics pathology MeSH
- Adult MeSH
- Exons genetics MeSH
- Genotyping Techniques MeSH
- Humans MeSH
- Macular Degeneration diagnosis MeSH
- Mutation genetics MeSH
- DNA Mutational Analysis * MeSH
- Retinal Diseases * diagnosis genetics MeSH
- Tomography, Optical Coherence MeSH
- Pigment Epithelium of Eye pathology MeSH
- Vision Disorders diagnosis genetics physiopathology MeSH
- Retinal Photoreceptor Cell Inner Segment pathology MeSH
- Visual Acuity MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
Cíl: Popsat klinický nález a provést molekulárně genetickou analýzu u dvou probandů českého původu s diagnózou Stargardtovy choroby. Poskytnout souhrn praktických poznatků plynoucích z mutační analýzy genu ABCA4 a poukázat na některé problematické aspekty spojené se screeningem tohoto genu. Metody: U obou mužů ve věku 39 a 26 let jsme provedli oční vyšetření včetně optické koherenční tomografie se spektrální doménou (SD-OCT). DNA byla izolována z venózní krve. Identifikace patogenních sekvenčních variant byla provedena pomocí genotypovacího mikročipu pro gen ABCA4, verze 11.0 (Asper Ophthalmics, Estonsko) detekující 558 známých mutací a jednonukleotidových polymorfismů. Výsledky: U prvního probanda byla nejlepší korigovaná zraková ostrost obou očí 0,1, u druhého probanda 0,05. Klinické vyšetření prokázalo typický nález atrofie makuly s přítomností žlutavých skvrn na očním pozadí. Vyšetření SD-OCT odhalilo oboustranně chybění linie elipsoidů vnitřních segmentů fotoreceptorů, také v literatuře označovaná jako linie junkce vnitřních a zevních segmentů fotoreceptorů, ztenčení neuroretiny a nepravidelnosti pigmentového epitelu sítnice. V souladu s autozomálně recesivním typem přenosu byla rodinná anamnéza pro Stargardtovu chorobu v obou případech negativní. Molekulárně genetickým vyšetřením bylo zjištěno, že první proband je nositelem mutace c.4234C>T; p.(Gln1412*) v exonu 28 a c.5882G>A; p.(Gly1961Glu) v exonu 42. U druhého probanda byla detekována pouze jedna známá patogenní mutace c.1988G>A p.(Trp663*) v exonu 14. Závěr: Poprvé byly u českých pacientů zjištěny mutace zodpovědné za vznik Stargardtovy choroby. Nemožnost nalézt jednu nebo obě patogenní sekvenční varianty je u této choroby za použití současných metod poměrně častým jevem. Budoucí studie by se měly zaměřit na stanovení spektra a frekvence jednotlivých mutací v ABCA4 u rozsáhlejšího souboru pacientů českého původu. Znalost příčinných mutací zlepšuje klinické poradenství pacientům a v indikovaných případech umožňuje preimplantační diagnostiku.
Purpose: The aim of our study was to describe the phenotype and to perform molecular genetic investigation in two probands of Czech origin diagnosed with Stargardt disease (STGD). Methods: Both males underwent ocular examination including assessment by high-resolution spectral domain optical coherence tomography (SD-OCT). DNA was isolated from venous blood. Mutation detection was performed using the ABCA4 genotyping microarray (Asper Ophthalmics, Estonia). Results: The best corrected visual acuity in proband 1 (aged 39 years) was 0.1 bilaterally, and 0.05 in proband 2 (aged 26 years). Fundus examination showed typical multiple yellow-white lesions and macular atrophy. Alterations of retinal pigment epithelium, retinal thinning and disruption of the photoreceptor inner segment ellipsoid band were detected with an SD-OCT. Two known disease-causing mutations in ABCA4 were identified in proband 1; c.4234C>T, p.(Gln1412*) in exon 28; and c.5882G>A, p.(Gly1961Glu) in exon 42. Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified. Conclusion: The frequency and full spectrum of ABCA4 mutations in Czech patients with inherited retinal disorders is yet to be established. The inability to detect a second pathogenic change in ABCA4 coding sequences in proband 2 warrants further investigation.
- Keywords
- Stargardtova choroba, SD-OCT, ABCA4,
- MeSH
- ATP-Binding Cassette Transporters * genetics MeSH
- Retinal Degeneration diagnosis genetics pathology MeSH
- Adult MeSH
- Exons genetics MeSH
- Genotyping Techniques MeSH
- Humans MeSH
- Macular Degeneration diagnosis MeSH
- Mutation genetics MeSH
- DNA Mutational Analysis * MeSH
- Retinal Diseases * diagnosis genetics MeSH
- Tomography, Optical Coherence MeSH
- Pigment Epithelium of Eye pathology MeSH
- Vision Disorders diagnosis genetics physiopathology MeSH
- Retinal Photoreceptor Cell Inner Segment pathology MeSH
- Visual Acuity MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
Turnerův syndrom patří mezi nejčastější chromosomální aberace. Je způsoben chyběním nebo strukturální anomálií jednoho X chromosomu, případně chromosomální mozaikou. Bývá spojen s častějším výskytem některých očních vad. Během sedmi let jsme opakovaně vyšetřili 81 dívek a žen s Turnerovým syndromem ve věku 7 až 26 let. Sledovali jsme výskyt očních vad a jejich případnou souvislost s karyotypem. Nejčastěji se vyskytovala u těchto dívek myopie (29 %), dále hypermetropie (24 %), epikantus (20 %), poruchy barvocitu (17 %), amblyopie (12 %), strabismus (10 %) a ptóza ( 5 %). Porucha barvocitu byla definována jako protanie v 8,5 %, deuteranie v 3,4 % a tritanie v 5,2 %. Výskyt strabismu a ptózy byl vyšší než u běžné populace. Celkový rozsah refrakčních vad byl nepatrně vyšší než u běžné populace, s rozdílným rozložením dle karyotypu. Hypermetropie byla zaznamenána častěji u karyotypu 45,X, a to ve 28 %, zatímco u chromosomální mozaiky byla pouze v 18 %. Obrácený poměr byl u myopie - u chromosomální mozaiky v 31 % a u karyopytu 45,X ve 26 %. Celkově při srovnání výskytu jednotlivých očních vad u karyotypu 45,X a chromosomální mozaiky jsme zaznamenali obdobné nálezy.
Turner's syndrome belongs to the most common chromosomal aberrations. It is caused by the deficiency or structural anomaly of one X chromosome, possibly by chromosomal mosaic. In this syndrome, some ocular diseases are more common. During the seven years period, we repeatedly examined 81 girls and women with Turner's syndrome; the range of age was 7-26 years. We observed the eye diseases appearance and their possible association with the karyotype. In these girls, the most common is myopia (29 %), item hyperopia (24 %), epicanthus (20 %), color vision disturbances (17 %), amblyopia (12 %), strabismus (10 %) and ptosis (5 %). The color vision disturbances were defined as protanopia in 8.5 %, deuteranopia in 3.4 % a tritanopia in 5.2 %. The occurrence of strabismus and ptosis were higher than in the average population. The total incidence of refractive errors was slightly higher than in normal population, with different incidence according to the karyotype. Hyperopia was found more often in karyotype 45, X (28 %), whereas in chromosomal mosaic in 18 % only. Inverse proportion was in myopia – in chromosomal mosaic was found in 31 % and in karyotype 45, X in 26 %. Generally, while comparing the incidence of separate ocular diseases in karyotype 45, X and in chromosomal mosaic, the findings were similar.
