Claudia B Catarino

Ludwig-Maximilians-University of Munich | LMU · Department of Neurology

Brainstorming diseases Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric...

Autosomal dominant optic atrophy (ADOA) is frequently caused by mutations in the optic atrophy 1 (OPA1) gene with haploinsufficiency being the major genetic pathomechanism. Almost 30% of the OPA1-associated cases suffer from splice defects. We identified a novel OPA1 mutation, c.1065+5G>A, in patients with ADOA. In patient-derived fibroblasts, the...

Background and purpose: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. W...

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide...

Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial com...

Idebenone is the only approved treatment for Leber's hereditary optic neuropathy (LHON). It promotes recovery of visual function in up to 50% of patients, but, based on the current knowledge, we can neither predict nor understand the non‐responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electron...

Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing...

Background: The aim of this study was to investigate the neuroretinal structure of young patients with Leber Hereditary Optic Neuropathy (LHON). Methods: For this retrospective cross-sectional analysis, the peripapillary retinal nerve fiber layer (pRNFL) thickness and the macular retinal layer volumes were measured by optical coherence tomograph...

IntroductionLenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we rep...

Background: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12...

Objective In Leber’s hereditary optic neuropathy (LHON) in children and teenagers, the influence of age on visual prognosis has not yet been investigated. Methods Patients from the mitoNET registry with LHON onset at age 4–16 years with at least 4 years of follow-up without treatment were included. Visual acuity (VA) at baseline, lowest VA ever re...

The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome (LS) challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of LS, the most frequent paediatric mitochondrial disease. Herein, we characterise 28 so far unreported ind...

Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy c...

Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. Methods: In RESCUE...

Objective: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. Methods: RESCUE and REVERSE were 2 phase III clinical trials...

Background Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial disorder, characterized by acute or subacute bilateral vision loss, frequently leading to significant chronic disability, mainly in young people. The causal LHON mutations of the mitochondrial DNA have incomplete penetrance, with the highest risk of disease manifestation...

Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic a...

Leber’s hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in the mitochondrial DNA (mtDNA). A molecular diagnosis is reached in up to 95%, the vast majority of which are accounted for by three mutations within mitochondrial complex I (CI) subunit encoding ge...

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision los...

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of al...

BACKGROUND Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS Open-label, multicenter, retrospective, noncontr...

Objective Clinical, neuroimaging, and genetic characterization of 3 patients with LINS1 -associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits. Methods Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clini...

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. Methods: Open-label, multicenter, retrospective, nonco...

Since hyperexcitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele fr...

Purpose LHON is a mitochondrial disorder leading to progressive, irreversible loss of visual acuity (VA). Here we report on the long term treatment outcomes in real world clinical practice in which we evaluated the efficacy and safety of idebenone. Methods Patients were treated with idebenone as part of an Expanded Access Program. Efficacy was ass...

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is...

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most lik...

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most lik...

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings...

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...

Cerebrotendinous xanthomatosis (CTX, MIM 213700) is a rare autosomal recessive lipid storage disorder caused by CYP27A1 mutations. Treatment with chenodeoxycholic acid (CDCA) may slow the progression of the disease and reverse some symptoms in a proportion of patients. In a non-consanguineous Caucasian family, two siblings with CTX were evaluated b...

Purpose LHON is a mitochondrial disease resulting in progressive, severe central vision loss, which is caused by 1 of 3 mitochondrial DNA mutations in >95% of patients. Idebenone, at a dose of 900 mg/day, is effective and safe in patients with LHON. Here, we report long‐term treatment outcomes in real world clinical practice. Methods The Expanded...

Purpose LHON is a mitochondrial disease resulting in progressive, severe central vision loss, which in >95% of patients is characterized by 1 of 3 primary mitochondrial DNA mutations. However, further rare mutations have also been identified. To date the only treatment approved for LHON is idebenone, which is safe and effective at a dose of 900 mg/...

Leber’s hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mi...

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Her...

Purpose LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. More than 90% of patients harbor one of three mitochondrial DNA mutations in the genes coding of complex I of the respiratory chain. Idebenone, a short-chain benzoquinone, is a potent antioxidant and also...

Objective: The lateral and mesial aspects of the central and frontal cortex were studied by direct electrical stimulation of the cortex in epilepsy surgery candidates in order to determine the localization of unilateral and bilateral negative motor responses. Methods: Results of electrical cortical stimulation were examined in epilepsy surgery c...

OBJECTIVE: To evaluate the efficacy and safety of Raxone® (idebenone) in LHON using a multicentre Expanded-Access Program (EAP). BACKGROUND: LHON is an inherited mitochondrial disorder leading to severe bilateral vision loss from which recovery is rare. An increasing body of evidence from a randomized placebo-controlled study, from a number of case...

Defects in mitochondrial translation may lead to combined respiratory chain deficiency and typically cause childhood-onset multisystem disease. Only recently, a homozygous missense mutation (c.467T > G, p.Leu156Arg) in MRPL44, encoding a protein of the large subunit of the mitochondrial ribosome, has been identified in two siblings with hypertrophi...

Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loc...

This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4). 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5). 3) A case series of p...

This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4). 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5). 3) A case series of p...

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandatin...

The long-term outcome of chronic epilepsy remains largely unknown, despite a long historical experience. We report the lifelong course of epilepsy of an historical cohort of 235 subjects who were in residential care at the Chalfont Centre for Epilepsy: 122 had comprehensive post-mortem examination. The populations admitted as resident to the centre...

Hypoxia-inducible factor-1α (HIF-1α) is involved in critical aspects of cell survival in response to hypoxia and regulates vascular endothelial growth factor (VEGF) expression. Previous experimental and human studies in epilepsy show up-regulation of VEGF following seizures, although expression of HIF-1α as its potential regulator has not been expl...

Blood-brain barrier dysfunction is implicated in various neurological conditions. Modulating the blood-brain barrier may have therapeutic value. Progress is hindered by our limited understanding of the pathophysiology of the blood-brain barrier in humans, partly due to restricted availability of human tissue, and because human tissue can only provi...

Detailed neuropathological studies of the extent of hippocampal sclerosis (HS) in epilepsy along the longitudinal axis of the hippocampus are lacking. Neuroimaging studies of patients with temporal lobe epilepsy support that sclerosis is not always localised. The extent of HS is of relevance to surgical planning and poor outcomes may relate to resi...

Dravet syndrome has been found recently as an important underlying condition in cases of alleged vaccine encephalopathy after pertussis vaccination, where vaccination seemed to have precipitated the occurrence of the disease without modifying the long-term course. We report on a patient diagnosed with Angelman syndrome in her fifth decade, in whom...

Video-electroencephalographic (EEG) ictal recordings play an important role in the pre-surgical evaluation of patients with medically refractory focal epilepsy. Paradoxical lateralization of the scalp EEG ictal onset patterns, consistently contralateral to the side of the proven epileptogenic lesion is rare but important to recognize, with possible...

The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we...

PROS1 copy number analysis by quantitative PCR. Results of PROS1 copy number analysis by quantitative PCR analysis. RQ -relative quantity. (TIF)

Hippocampal sclerosis in Case 3. (A) T1-weighted magnetic resonance imaging of the Case 3 revealed right hippocampal volume loss (arrow) compatible with hippocampal sclerosis. (B) Histopathology of the lobectomy specimen from Case 3 confirmed hippocampal sclerosis, without mossy fibre sprouting. There was neuronal loss in CA1, CA4 and gliosis on GF...

Dense surface morphology (DSM) results for Case 1 and Case 2. (A) The scatter plot shows age (horizontally) against DSM distance (vertically) between the matched mean face and the patient and 200 control faces. Distance from the patient-matched mean face was linearly regressed against age for all controls. The patient was fitted to the appropriate...

Dynamic profiles of glucose, insulin, and other carnitine esters. Dynamic profiles of glucose, insulin, and other carnitine esters. NEFA - non-esterified fatty acids.NEFA - non-esterified fatty acids. (TIF)

Supplementary methods and results. (DOC)

Animations of face morphs. Animations of face morphs offer the best visualisation of face shape differences when comparing each case and its age/sex-matched mean face. The unusual narrowness of Case 3's face is dysmorphic. S1 - Case 1. (WMV)

Animations of face morphs. Animations of face morphs offer the best visualisation of face shape differences when comparing each case and its age/sex-matched mean face. The unusual narrowness of Case 3's face is dysmorphic. S2 - Case 2. (WMV)

Animations of face morphs. Animations of face morphs offer the best visualisation of face shape differences when comparing each case and its age/sex-matched mean face. The unusual narrowness of Case 3's face is dysmorphic. S3 - Case3. (WMV)

Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained. We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic...

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical hist...

Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain...

Zonisamide (ZNS) is an antiepileptic drug (AED) with multiple putative mechanisms of action. It is chemically unrelated to other AEDs. It has been available in Japan since 1989 but was only licensed in Europe in 2005. Its efficacy and tolerability have been shown in several randomised controlled trials, but large studies on long-term performance in...

Brain magnetic resonance imaging (MRI) studies in patients with Dravet syndrome and SCN1A mutations have shown abnormal findings in a small minority of patients. The origin of the structural abnormalities--such focal brain atrophy, cortical dysplasia, and hippocampal sclerosis--observed in some children remains unclear. There seems to be no correla...

One possible cause for surgical failure following temporal lobectomy for the treatment of epilepsy due to classical hippocampal sclerosis (CHS) is the presence of more widespread cortical changes. Neocortical changes in CHS shown by quantitative neuroimaging studies may involve hippocampal projection pathways. Our aim was to quantitate neocortical...

A 61-year-old woman, who lived alone, presented with severe problems with her sleep pattern. She had a history of cryptogenic partial epilepsy since she was 8 years old. Her epilepsy consisted of complex partial seizures, starting with vocalisation, followed by unresponsiveness and oro-alimentary automatisms. For 38 years she had taken phenytoin (3...

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-po...

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy s...

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy s...

The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19...