TY  - JOUR
AB  - BACKGROUND: The genetic landscape of neurodevelopmental disorders is constantly expanding and children with early-onset neurological phenotypes increasingly receive a genetic diagnosis. Nonetheless, the awareness of the chronic course of these conditions, and consequently their recognition and management in the adult population, is still limited. RESULTS: Herein, we describe four patients with rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1-related diseases), who received a genetic assignment only in the adulthood. All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood, prompting the referral to a neurologist. This phenotypic combination led eventually to the genetic testing. We report previously unrecognized features and highlight the peculiarities of the adult presentation of four neurodevelopmental disorders. CONCLUSIONS: This report expands the current knowledge on four rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1), which was mainly based on reports from paediatric cases. This case series emphasize the importance of a tight neurological surveillance extending beyond the childhood.
AU  - Indelicato, E.*
AU  - Zech, M.
AU  - Amprosi, M.*
AU  - Boesch, S.*
C1  - 64358
C2  - 52199
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Untangling neurodevelopmental disorders in the adulthood: a movement disorder is the clue.
JO  - Orphanet J. Rare Dis.
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2022
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - Background: Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results: We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions: Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.
AU  - Rus, C.M.*
AU  - Weissensteiner, T.*
AU  - Pereira, C.*
AU  - Susnea, I.*
AU  - Danquah, B.D.*
AU  - Morales Torres, G.*
AU  - Rocha, M.E.*
AU  - Cozma, C.*
AU  - Saravanakumar, D.*
AU  - Mannepalli, S.*
AU  - Kandaswamy, K.K.*
AU  - Di Bucchianico, S.
AU  - Zimmermann, R.
AU  - Rolfs, A.*
AU  - Bauer, P.*
AU  - Beetz, C.*
C1  - 64949
C2  - 52025
TI  - Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center.
JO  - Orphanet J. Rare Dis.
VL  - 17
IS  - 1
PY  - 2022
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - Background STAT3 hyper-IgE syndrome (STAT3-HIES) is a rare primary immunodeficiency that clinically overlaps with atopic dermatitis. In addition to eczema, elevated serum-IgE, and recurrent infections, STAT3-HIES patients suffer from characteristic facies, midline defects, and retained primary teeth. To optimize dental management we assessed the development of dentition and the long-term outcomes of dental treatment in 13 molecularly defined STAT3-HIES patients using questionnaires, radiographs, and dental investigations. Results Primary tooth eruption was unremarkable in all STAT3-HIES patients evaluated. Primary tooth exfoliation and permanent tooth eruption was delayed in 83% of patients due to unresorbed tooth roots. A complex orthodontic treatment was needed for one patient receiving delayed extraction of primary molars and canines. Permanent teeth erupted spontaneously in all patients receiving primary teeth extraction of retained primary teeth during average physiologic exfoliation time. Conclusions The association of STAT3-HIES with retained primary teeth is important knowledge for dentists and physicians as timely extraction of retained primary teeth prevents dental complications. To enable spontaneous eruption of permanent teeth in children with STAT3-HIES, we recommend extracting retained primary incisors when the patient is not older than 9 years of age and retained primary canines and molars when the patient is not older than 13 years of age, after having confirmed the presence of the permanent successor teeth by radiograph.
AU  - Meixner, I.*
AU  - Hagl, B.
AU  - Kröner, C.I.*
AU  - Spielberger, B.D.*
AU  - Paschos, E.*
AU  - Dückers, G.*
AU  - Niehues, T.*
AU  - Hesse, R.*
AU  - Renner, E.D.
C1  - 60066
C2  - 49205
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Retained primary teeth in STAT3 hyper-IgE syndrome: Early intervention in childhood is essential.
JO  - Orphanet J. Rare Dis.
VL  - 15
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - Background: Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts.Results: We showed that, other than ScNDI1, two different NDH-2 ( AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells.Conclusions: In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.
AU  - Catania, A.*
AU  - Iuso, A.
AU  - Bouchereau, J.*
AU  - Kremer, L.S.
AU  - Paviolo, M.*
AU  - Terrile, C.
AU  - Bénit, P.*
AU  - Rasmusson, A.G.*
AU  - Schwarzmayr, T.
AU  - Tiranti, V.*
AU  - Rustin, P.*
AU  - Rak, M.*
AU  - Prokisch, H.
AU  - Schiff, M.*
C1  - 57215
C2  - 47618
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Arabidopsis thaliana alternative dehydrogenases: A potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls.
JO  - Orphanet J. Rare Dis.
VL  - 14
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - Background: Thoroughly annotated data resources are a key requirement in phenotype dependent analysis and diagnosis of diseases in the area of precision medicine. Recent work has shown that curation and systematic annotation of human phenome data can significantly improve the quality and selectivity for the interpretation of inherited diseases. We have therefore developed PhenoDis, a comprehensive, manually annotated database providing symptomatic, genetic and imprinting information about rare cardiac diseases. Results: PhenoDis includes 214 rare cardiac diseases from Orphanet and 94 more from OMIM. For phenotypic characterization of the diseases, we performed manual annotation of diseases with articles from the biomedical literature. Detailed description of disease symptoms required the use of 2247 different terms from the Human Phenotype Ontology (HPO). Diseases listed in PhenoDis frequently cover a broad spectrum of symptoms with 28% from the branch of 'cardiovascular abnormality' and others from areas such as neurological (11.5%) and metabolism (6%). We collected extensive information on the frequency of symptoms in respective diseases as well as on disease-associated genes and imprinting data. The analysis of the abundance of symptoms in patient studies revealed that most of the annotated symptoms (71%) are found in less than half of the patients of a particular disease. Comprehensive and systematic characterization of symptoms including their frequency is a pivotal prerequisite for computer based prediction of diseases and disease causing genetic variants. To this end, PhenoDis provides in-depth annotation for a complete group of rare diseases, including information on pathogenic and likely pathogenic genetic variants for 206 diseases as listed in ClinVar. We integrated all results in an online database (http://mips.helmholtz-muenchen.de/phenodis/) with multiple search options and provide the complete dataset for download. Conclusion: PhenoDis provides a comprehensive set of manually annotated rare cardiac diseases that enables computational approaches for disease prediction via decision support systems and phenotype-driven strategies for the identification of disease causing genes.
AU  - Adler, A.*
AU  - Kirchmeier, P.
AU  - Reinhard, J.
AU  - Brauner, B.
AU  - Dunger, I.
AU  - Fobo, G.
AU  - Frishman, G.
AU  - Montrone, C.
AU  - Mewes, H.-W.
AU  - Arnold, M.
AU  - Ruepp, A.
C1  - 52807
C2  - 44496
CY  - London
TI  - PhenoDis: A comprehensive database for phenotypic characterization of rare cardiac diseases.
JO  - Orphanet J. Rare Dis.
VL  - 13
IS  - 1
PB  - Biomed Central Ltd
PY  - 2018
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - 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 in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
AU  - Repp, B.
AU  - Mastantuono, E.
AU  - Alston, C.L.*
AU  - Schiff, M.*
AU  - Haack, T.B.*
AU  - Rötig, A.*
AU  - Ardissone, A.*
AU  - Lombès, A.*
AU  - Catarino, C.B.*
AU  - Diodato, D.*
AU  - Schottmann, G.*
AU  - Poulton, J.*
AU  - Burlina, A.*
AU  - Jonckheere, A.*
AU  - Munnich, A.*
AU  - Rolinski, B.*
AU  - Ghezzi, D.*
AU  - Rokicki, D.*
AU  - Wellesley, D.*
AU  - Martinelli, D.*
AU  - Wenhong, D.*
AU  - Lamantea, E.*
AU  - Ostergaard, E.*
AU  - Pronicka, E.*
AU  - Pierre, G.*
AU  - Smeets, H.J.M.*
AU  - Wittig, I.*
AU  - Scurr, I.*
AU  - de Coo, I.F.M.*
AU  - Moroni, I.*
AU  - Smet, J.*
AU  - Mayr, J.A.*
AU  - Dai, L.*
AU  - De Meirleir, L.*
AU  - Schuelke, M.*
AU  - Zeviani, M.*
AU  - Morscher, R.J.*
AU  - McFarland, R.*
AU  - Seneca, S.H.*
AU  - Klopstock, T.*
AU  - Meitinger, T.
AU  - Wieland, T.
AU  - Strom, T.M.
AU  - Herberg, U.*
AU  - Ahting, U.*
AU  - Sperl, W.*
AU  - Nassogne, M.C.*
AU  - Ling, H.*
AU  - Fang, F.*
AU  - Freisinger, P.*
AU  - van Coster, R.*
AU  - Strecker, V.*
AU  - Taylor, R.W.*
AU  - Häberle, J.*
AU  - Vockley, J.*
AU  - Prokisch, H.
AU  - Wortmann, S.B.
C1  - 53972
C2  - 45152
TI  - Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?
JO  - Orphanet J. Rare Dis.
VL  - 13
IS  - 1
PY  - 2018
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage. Our study is the first prospective, longitudinal investigation, exploiting detailed serial testing of predefined clinical and molecular outcome parameters (including serial CSF assessments) in a 29-year-old MNGIE patient undergoing 1 year of extensive HMD. We demonstrate that HMD only transiently restores increased serum and urine levels of thymidine and deoxyuridine, but fails to reduce CSF levels of the toxic metabolites and is ineffective to influence neurological function. These findings have direct important implications for clinical practice: They prevent a burdensome, long-term invasive, but ultimately probably ineffective procedure in future MNGIE patients.
AU  - Röeben, B.*
AU  - Marquetand, J.*
AU  - Bender, B.*
AU  - Billing, H.*
AU  - Haack, T.B.
AU  - Sanchez-Albisua, I.*
AU  - Schöls, L.*
AU  - Blom, H.J.*
AU  - Synofzik, M.*
C1  - 51691
C2  - 43383
CY  - London
TI  - Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function.
JO  - Orphanet J. Rare Dis.
VL  - 12
IS  - 1
PB  - Biomed Central Ltd
PY  - 2017
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - BACKGROUND: TTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far. METHODS: We performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness. RESULTS: We identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs. CONCLUSIONS: Our findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.
AU  - Koch, J.*
AU  - Freisinger, P.*
AU  - Feichtinger, R.G.*
AU  - Zimmermann, F.A.*
AU  - Rauscher, C.*
AU  - Wagentristl, H.P.*
AU  - Konstantopoulou, V.*
AU  - Seidl, R.*
AU  - Haack, T.B.
AU  - Prokisch, H.
AU  - Ahting, U.*
AU  - Sperl, W.*
AU  - Mayr, J.A.*
AU  - Maier, E.M.*
C1  - 44741
C2  - 36991
CY  - London
TI  - Mutations in TTC19: Expanding the molecular, clinical and biochemical phenotype.
JO  - Orphanet J. Rare Dis.
VL  - 10
IS  - 1
PB  - Biomed Central Ltd
PY  - 2015
SN  - 1750-1172
ER  - 

TY  - JOUR
AB  - BACKGROUND: Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families. METHODS: We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form. RESULTS: Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues. CONCLUSION: We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.
AU  - Haghighi, A.*
AU  - Haack, T.B.
AU  - Atiq, M.*
AU  - Mottaghi, H.*
AU  - Haghighi-Kakhki, H.*
AU  - Bashir, R.A.*
AU  - Ahting, U.*
AU  - Feichtinger, R.G.*
AU  - Mayr, J.A.*
AU  - Rotig, A.*
AU  - Lebre, A.S.*
AU  - Klopstock, T.*
AU  - Dworschak, A.*
AU  - Pulido, N.*
AU  - Saeed, M.A.*
AU  - Saleh-Gohari, N.*
AU  - Holzerova, E.*
AU  - Chinnery, P.F.*
AU  - Taylor, R.W.*
AU  - Prokisch, H.
C1  - 32498
C2  - 35077
TI  - Sengers syndrome: Six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients.
JO  - Orphanet J. Rare Dis.
VL  - 9
IS  - 1
PY  - 2014
SN  - 1750-1172
ER  -