TY - JOUR AB - Pathogenic variants in COL4A1, encoding the alpha chain of type IV collagen, have been associated with cerebrovascular pathology as well as malformations of cortical development, thereby causing structural epilepsy. This case illustrates successful resective epilepsy surgery in a 12-month-old girl with left occipital focal cortical dysplasia (FCD) associated with a heterozygous splice-donor variant in COL4A1. She presented with drug-resistant focal epilepsy with daily seizures from the age of 2 months, refractory to several combinations of antiseizure medications, as well as mild right-sided hemiparesis and developmental delay. All presurgical diagnostic modalities, including ictal and interictal electroencephalography (EEG), magnetic resonance imaging (MRI) and ictal fluorodeoxyglucose-positron emission tomography (FDG-PET), showed congruent findings, pointing towards one single left occipital epileptogenic zone (EZ). We performed a left occipital lobectomy, using intraoperative electrocorticography to confirm the boundaries of the EZ. After surgery the patient has remained seizure-free, and both cognitive and motor development have since improved. Histopathology of the resected brain tissue showed FCD Type Ia. Resective epilepsy surgery can have a very good outcome, also in patients with genetic mutations in COL4A1, constituting a less invasive option than the previously used more radical surgical procedures such as hemispherectomy. AU - Fearns, N.* AU - Wagner, M. AU - Borggräfe, I.* AU - Kunz, M.* AU - Rémi, J.* AU - Vollmar, C.* C1 - 69847 C2 - 55279 CY - Rudigerstr 14, D-70469 Stuttgart, Germany TI - Good outcome of resective epilepsy surgery in a one-year-old child with drug-resistant focal epilepsy with a novel pathogenic COL4A1 mutation. JO - Neuropediatrics PB - Georg Thieme Verlag Kg PY - 2024 SN - 0174-304X ER - TY - JOUR AB - Biallelic variants in PTRHD1 have been linked to autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism with only a limited number of patients reported so far. Here, we describe the clinical and genetic findings of another female individual of Austrian origin who also experienced infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, all of which are in concordance with the known phenotypic spectrum. In addition, she developed genetic generalized epilepsy around the age of 4 years, persisting into adulthood. Using diagnostic exome sequencing, we identified the homozygous missense variant c.365G>A, p.(Arg122Gln) in PTRHD1 (NM_001013663). In conclusion, we confirm previous reports suggesting an association between biallelic PTRHD1 variants and parkinsonism with neurodevelopmental abnormalities. Moreover, we hypothesize that generalized epilepsy may be part of the phenotypic spectrum. AU - Gebert, J.* AU - Brunet, T.* AU - Wagner, M. AU - Rath, J.* AU - Aull-Watschinger, S.* AU - Pataraia, E.* AU - Krenn, M.* C1 - 69905 C2 - 55324 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 209-212 TI - A Homozygous PTRHD1 missense variant (p.Arg122Gln) in an individual with intellectual disability, generalized epilepsy, and juvenile parkinsonism. JO - Neuropediatrics VL - 55 IS - 3 PB - Georg Thieme Verlag Kg PY - 2024 SN - 0174-304X ER - TY - JOUR AB - In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES.Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project.Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion.Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of "molecular or genetic autopsy" allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years. AU - Jacob, M.* AU - Brugger, M.* AU - Andres, S.* AU - Wagner, M. AU - Graf, E.* AU - Berutti, R. AU - Tilch, E. AU - Pavlov, M. AU - Mayerhanser, K.* AU - Hoefele, J.* AU - Meitinger, T.* AU - Winkelmann, J. AU - Brunet, T.* C1 - 70373 C2 - 55545 CY - Rudigerstr 14, D-70469 Stuttgart, Germany TI - Genome sequencing for cases unsolved by exome sequencing: Identifying a single-exon deletion in TBCK in a case from 30 years ago. JO - Neuropediatrics PB - Georg Thieme Verlag Kg PY - 2024 SN - 0174-304X ER - TY - JOUR AU - Borggraefe, I.* AU - Wagner, M. C1 - 68250 C2 - 54786 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 295-296 TI - Precision therapy in KCNQ2-related epilepsy. JO - Neuropediatrics VL - 54 IS - 5 PB - Georg Thieme Verlag Kg PY - 2023 SN - 0174-304X ER - TY - JOUR AB - Mitchell syndrome is a very rare genetic disorder due to a specific de novo gain-of-function variant in acyl-CoA oxidase 1 (ACOX1). So far, only five patients with this disease have been described worldwide. We present here two additional unrelated German patients found to carry the same heterozygous ACOX1 N237S variant through exome sequencing (ES). Both patients showed neurodegenerative clinical features starting from ∼4 to 5 years of age including progressive hearing loss, ataxia, ichthyosis, as well as progressive visual impairment leading to amaurosis, and died at the ages of 16 and 8 years, respectively. The first patient was clinically suspected to have anti-myelin oligodendrocyte glycoprotein-antibody-associated myelitis, but the disease course overall deteriorated despite extensive immunomodulatory therapy. The second patient was originally suspected to have a mitochondrial disorder due to intermittent elevated blood lactate. Since Mitchell syndrome has only been identified in 2020, the diagnosis in this second patient was only established through re-evaluation of ES data years after the original analysis. Comparison of all seven reported patients suggests that Mitchell syndrome often (but not always) clinically mimics autoimmune-inflammatory disease. Therefore, in patients with autoimmune central nervous system disease who do not respond adequately to standard therapies, re-evaluation of this diagnosis is needed and genetic analyses such as trio ES should be considered. AU - Thiels, C.* AU - Lücke, T.* AU - Rothoeft, T.* AU - Lukas, C.* AU - Nguyen, H.P.* AU - von Kleist-Retzow, J.C.* AU - Prokisch, H. AU - Grimmel, M.* AU - Haack, T.* AU - Hoffjan, S.* C1 - 68645 C2 - 54848 CY - Rudigerstr 14, D-70469 Stuttgart, Germany TI - ACOX1 gain-of-function variant in two German pediatric patients, in one case mimicking autoimmune inflammatory disease. JO - Neuropediatrics PB - Georg Thieme Verlag Kg PY - 2023 SN - 0174-304X ER - TY - JOUR AB - ASXL3 loss-of-function variants represent a well-established cause of Bainbridge-Ropers syndrome, a syndromic neurodevelopmental disorder with intellectual and motor disabilities. Although a recent large-scale genomics-based study has suggested an association between ASXL3 variation and cerebral palsy, there have been no detailed case descriptions. We report, here, a female individual with a de novo pathogenic c.1210C > T, p.Gln404* nonsense variant in ASXL3, identified within the frame of an ongoing research project applying trio whole-exome sequencing to the diagnosis of dystonic cerebral palsy. The patient presented with a mixture of infantile-onset limb/trunk dystonic postures and secondarily evolving distal spastic contractures, in addition to more typical features of ASXL3-related diseases such as severe feeding issues, intellectual disability, speech impairment, and facial dysmorphic abnormalities. Our case study confirms a role for ASXL3 pathogenic variants in the etiology of cerebral-palsy phenotypes and indicates that dystonic features can be part of the clinical spectrum in Bainbridge-Ropers syndrome. ASXL3 should be added to target-gene lists used for molecular evaluation of cerebral palsy. AU - Švantnerová, J.* AU - Minár, M.* AU - Radová, S.* AU - Kolníková, M.* AU - Vlkovič, P.* AU - Zech, M. C1 - 65759 C2 - 52902 SP - 361-365 TI - ASXL3 de novo variant-related neurodevelopmental disorder presenting as dystonic cerebral palsy. JO - Neuropediatrics VL - 53 IS - 5 PY - 2022 SN - 0174-304X ER - TY - JOUR AU - Trieschmann, G.* AU - Wach, K.* AU - Abel, M.* AU - Tilgner, E.* AU - Berweck, S.* AU - Zech, M. C1 - 65663 C2 - 52874 SP - 386-387 TI - A novel homozygous PDE 10A variant leading to infantile onset hyperkinesia. JO - Neuropediatrics VL - 53 IS - 5 PY - 2022 SN - 0174-304X ER - TY - CONF AB - Background/Purpose: No causal treatment for mitochondrial disease exists. Exome sequencing allows to identify specific mitochondrial defects (theoretically) amenable to dietary intervention. The mitochondrial transporters aspartate glutamate carrier 1 (AGC1) and mitochondrial pyruvate carrier 1 (MPC1) are tightly linked to glucose catabolism. Successful pathomechanism-based treatment of such defects with ketogenic diet (KD) was reported in two patients with AGC1-deficiency and a MPC1-deficient mouse model. Methods: The Munich exome database was queried for AGC1- and MPC1-deficient patients. Clinical and neuroradiological details were collected and literature cases reviewed. Results: Six MPC1-deficient individuals (4 reported, 2 novel) were identified and outcome on KD reported in 2 (1 novel). The phenotype beside developmental impairment (6/6) and elevated serum lactate (6/6) was variable with epilepsy (3/6), microcephaly (3/6), and the first report of one patient with splenomegaly, diabetes mellitus and bone fractures. In contrast to the previously reported infant, our severely affected patient improved distinctly on KD, with seizure freedom and developmental progress. Thirteen AGC1-deficient individuals (8 reported, 5 novel) were identified. Seven of 13 received KD. All had infantile-onset epilepsy, severe developmental impairment and muscular hypotonia. MRI revealed brain atrophy (9/9) and reduced myelination (7/9), MRS showed reduced n-acetyl-aspartate (5/6). Elevated serum lactate was found in 8 of 13. In six of seven patients, KD showed impressive improvement on seizure frequency, development, and neuroradiological features. Conclusion: Treatment with KD is beneficial in patients with AGC1 and MPC1 deficiency. This underlines the importance for early genetic diagnostics in patients with epilepsy especially with additional markers raising suspicion of mitochondrial disease. AU - Bölsterli, B.K.* AU - Boltshauser, E.* AU - Distelmaier, F.* AU - Geis, T.* AU - Klabunde-Cherwon, A.* AU - Kottke, R.* AU - Makowski, C.* AU - Mayr, J.A.* AU - O’Gorman Tuura, R.L.* AU - Prokisch, H. AU - Steinbruecker, K.* AU - Steinfeld, R.* AU - Syrbe, S.* AU - Wagner, M. AU - Ziegler, A.* AU - Wortmann, S.* C1 - 66658 C2 - 53047 SP - S1-S53 TI - Mitochondrial transporter defects: Successful treatment with ketogenic diet therapy JO - Neuropediatrics PY - 2021 SN - 0174-304X ER - TY - JOUR AB - Mitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L. AU - Schmid, S.J.* AU - Wagner, M. AU - Goetz, C.* AU - Makowski, C.* AU - Freisinger, P.* AU - Berweck, S.* AU - Mall, V.* AU - Burdach, S.* AU - Juenger, H.* C1 - 55917 C2 - 46777 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 197-201 TI - A de novo dominant negative mutation in DNM1L causes sudden onset status epilepticus with subsequent epileptic encephalopathy. JO - Neuropediatrics VL - 50 IS - 3 PB - Georg Thieme Verlag Kg PY - 2019 SN - 0174-304X ER - TY - JOUR AB - Variants in the inositol 1,4,5-trisphosphate receptor type 1 ( ITPR1 ) gene have been recently identified as a cause of Gillespie's syndrome, a rare inherited condition characterized by bilateral iris hypoplasia, congenital muscle hypotonia, nonprogressive cerebellar ataxia, and intellectual disability. Here, we describe the clinical and genetic findings in a patient who presented with iris hypoplasia, mild gait ataxia, atrophy of the anterior cerebellar vermis but no cognitive deficits. Whole-exome sequencing (WES) uncovered a heterozygous ITPR1 p.Glu2094Lys missense variant, affecting a highly conserved glutamic acid residue for which other amino acid substitutions have already been reported in Gillespie's syndrome patients. Our data expand both the phenotypic and genetic spectrum associated with Gillespie's syndrome and suggest a mutation hotspot on Glu2094. AU - Stendel, C.* AU - Wagner, M. AU - Rudolph, G.* AU - Klopstock, T.* C1 - 56619 C2 - 47207 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 382-386 TI - Gillespie's syndrome with minor cerebellar involvement and no intellectual disability associated with a novel ITPR1 mutation: Report of a case and literature review. JO - Neuropediatrics VL - 50 IS - 6 PB - Georg Thieme Verlag Kg PY - 2019 SN - 0174-304X ER - TY - JOUR AB - Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reportedmissensemutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature. AU - Alhaddad, B.* AU - Schossig, A.* AU - Haack, T.B. AU - Kovács-Nagy, R.* AU - Braunisch, M.C.* AU - Makowski, C.* AU - Senderek, J.* AU - Vill, K.* AU - Müller-Felber, W.* AU - Strom, T.M. AU - Krabichler, B.* AU - Freisinger, P.* AU - Deshpande, C.* AU - Polster, T.* AU - Wolf, N.I.* AU - Desguerre, I.* AU - Wörmann, F.* AU - Rötig, A.* AU - Ahting, U.* AU - Kopajtich, R. AU - Prokisch, H. AU - Meitinger, T. AU - Feichtinger, R.G.* AU - Mayr, J.A.* AU - Jungbluth, H.* AU - Hubmann, M.* AU - Zschocke, J.* AU - Distelmaier, F.* AU - Koch, J.* C1 - 53868 C2 - 45005 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 330-338 TI - PRUNE1 deficiency: Expanding the clinical and genetic spectrum. JO - Neuropediatrics VL - 49 IS - 5 PB - Georg Thieme Verlag Kg PY - 2018 SN - 0174-304X ER - TY - JOUR AB - Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondria) dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings. AU - Kovács-Nagy, R.* AU - Morin, G.* AU - Al Nouri, M.* AU - Brandau, O.* AU - Saadi, N.W.* AU - Nouri, M.A.* AU - van den Broek, F.* AU - Prokisch, H. AU - Mayr, J.A.* AU - Wortmann, S.B. C1 - 54758 C2 - 45830 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 373-378 TI - HTRA2 defect: A recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients. JO - Neuropediatrics VL - 49 IS - 6 PB - Georg Thieme Verlag Kg PY - 2018 SN - 0174-304X ER - TY - JOUR AB - Recently, heterozygous de novo mutations in SCL1A2 have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in SCL1A2 (c.1421+1G>C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism. AU - Wagner, M. AU - Gusic, M. AU - Günthner, R.* AU - Alhaddad, B.* AU - Kovács-Nagy, R.* AU - Makowski, C.* AU - Baumeister, F.A.M.* AU - Strom, T.M. AU - Meitinger, T. AU - Prokisch, H. AU - Wortmann, S.B. C1 - 51898 C2 - 43547 CY - Stuttgart SP - 59-62 TI - Biallelic mutations in SLC1A2; an additional mode of inheritance for SLC1A2-related epilepsy. JO - Neuropediatrics VL - 49 IS - 1 PB - Georg Thieme Verlag Kg PY - 2018 SN - 0174-304X ER - TY - JOUR AB - Many genetic and nongenetic causes for developmental delay in childhood could be identified. Often, however, the molecular basis cannot be elucidated. As next-generation sequencing is becoming more frequently available in a diagnostic context, an increasing number of genetic variations are found as causative in children with developmental delay.We performed trio exome sequencing in a girl with developmental delay and minor dysmorphological features. Using a filter for de novo variants, the heterozygous missense variant c.812A>T, p.(G1u217Val) was found in the candidate gene POU3F2 in our patient.POU3F2 plays an important role in neuronal differentiation and hormonal regulation. To date, it has not been associated with monogenic disorders. Studies on Pou3f2 knockout mice highlighted the importance of this protein in the development of the brain. Furthermore, microdeletions with an overlapping region including only POU3F2 and FBXL4 were linked to developmental delay in six unrelated families. Therefore, POU3F2 is a strong candidate gene for developmental delay, although functional assays proving this assumption still have to be done. AU - Westphal, D.S. AU - Riedhammer, K.M.* AU - Kovács-Nagy, R. AU - Meitinger, T. AU - Hoefele, J.* AU - Wagner, M. C1 - 54728 C2 - 45784 CY - Rudigerstr 14, D-70469 Stuttgart, Germany SP - 401-404 TI - A de novo missense variant in POU3F2 identified in a child with global developmental delay. JO - Neuropediatrics VL - 49 IS - 6 PB - Georg Thieme Verlag Kg PY - 2018 SN - 0174-304X ER - TY - JOUR AB - 3-MEthylGlutaconic aciduria, Deafness, Encephalopathy, neuroradiological evidence of Leigh-like disease (MEGDEL syndrome) was initially described in four children with additional features of defective oxidative phosphorylation. Loss of functional variants in the SERAC1 gene was later reported in relation with this disorder of phospholipid remodeling. We describe a girl born after a pregnancy complicated by intrauterine growth retardation. In the neonatal period, she presented hypotonia, lethargy, weak reflexes, transient hypoglycemia, and elevated transaminases. Magnetic resonance imaging (MRI) performed at 12 days of life showed bilateral basal ganglia alterations suggestive of Leigh syndrome. She progressed with failure to thrive, severe delay of developmental milestones, axial hypotonia, spastic tetraparesis and dystonic movements. Investigations disclosed hyperlactacidemia, and the urinary organic acids revealed high levels mainly of 3-methylglutaconic acid. Muscle biopsy showed decreased activity of several complexes of the respiratory chain. Compound heterozygosity for two previously unreported variants in SERAC1 leads to the diagnosis of MEGDEL syndrome. Unlike other patients, this child presents very early MRI alterations and manifests no deafness. AU - Sequeira, S.* AU - Rodrigues, M.* AU - Jacinto, S.* AU - Wevers, R.A.* AU - Wortmann, S.B. C1 - 51189 C2 - 42805 CY - Stuttgart SP - 382-384 TI - MEGDEL syndrome: Expanding the phenotype and new mutations. JO - Neuropediatrics VL - 48 IS - 5 PB - Georg Thieme Verlag Kg PY - 2017 SN - 0174-304X ER - TY - JOUR AB - Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. In the traditional diagnostic approach (“biopsy first”) the evaluation of the affected individual and his body fluids, combined with the analysis of the respiratory chain enzymes in muscle based the subsequent Sanger sequencing of single candidate genes (“from function to gene”). Within the past few years, next-generation sequencing techniques of leucocyte-derived DNA (e.g., exome sequencing), with a diagnostic yield of more than 40%, have become the first line routine technology. This implicates that the invasive muscle biopsy is performed less often, especially in children. Furthermore, in this “genetics-first” approach the detection of new candidate genes precedes functional evaluations (“from gene to function”) leading to reverse phenotyping of affected individuals. Here, we line out the value of muscle and other tissue biopsies in this “genetics-first” era. We describe when and why it is still needed. We create awareness of pitfalls in the genetic diagnostics of mitochondrial diseases still necessitating tissue biopsies. Finally, we discuss why tissue biopsies are required for confirmatory diagnostics, or for getting a biochemical diagnosis in patients with hidden variants not detectable by standard genetics. AU - Wortmann, S.B. AU - Mayr, J.A.* AU - Nuoffer, J.M.* AU - Prokisch, H. AU - Sperl, W.* C1 - 51411 C2 - 43211 CY - Stuttgart SP - 309-314 TI - A guideline for the diagnosis of pediatric mitochondrial disease: The value of muscle and skin biopsies in the genetics era. JO - Neuropediatrics VL - 48 IS - 4 PB - Georg Thieme Verlag Kg PY - 2017 SN - 0174-304X ER - TY - JOUR AB - We aimed to translate the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire into German and to evaluate its reliability and validity by studying the association between CPCHILD scores and gross motor function as measured by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The original CPCHILD questionnaire and manual were translated and back translated. It was administered to primary caregivers of persons with CP (GMFCS levels III-V) and was completed a second time 2 weeks after the first to measure test-retest reliability (n = 17). Primary caregivers of 68 children with CP; GMFCS level III (n = 14), level IV (n = 28), and level V (n = 26) completed the questionnaire. Mean total CPCHILD scores across GMFCS levels were 67.1 ± 14.9 for GMFCS level III, 56.6 ± 11.8 for level IV, and 44.3 ± 12.9 for level V. Good correlation (r =  - 0.56) was observed between GMFCS and total scores test-retest reliability showed intraclass correlation coefficients between 0.4 and 0.9. The German CPCHILD yielded similar test-retest reliability and score distributions across the GMFCS level as the original version. The best correlations were observed for domains that are close to the functional deficits. AU - Jung, N.H.* AU - Brix, O.* AU - Bernius, P.* AU - Schroeder, A.S.* AU - Kluger, G.J.* AU - Beyerlein, A. AU - Weir, S.* AU - von Kries, R.* AU - Narayanan, U.G.* AU - Mall, V.* AU - Berweck, S.* C1 - 31002 C2 - 34074 CY - Stuttgart SP - 289-293 TI - German translation of the caregiver priorities and child health index of life with disabilities questionnaire: Test-retest reliability and correlation with gross motor function in children with cerebral palsy. JO - Neuropediatrics VL - 45 IS - 5 PB - Georg Thieme Verlag Kg PY - 2014 SN - 0174-304X ER - TY - JOUR AB - Mitochondrial NADH: ubiquinone oxidoreductase (complex I) deficiency accounts for most defects in mitochondrial oxidative phosphorylation. Pathogenic mutations have been described in all 7 mitochondrial and 12 of the 38 nuclear encoded subunits as well as in assembly factors by interfering with the building of the mature enzyme complex within the inner mitochondrial membrane. We now describe a male patient with a novel homozygous stop mutation in the NDUFAF2 gene. The boy presented with severe apnoea and nystagmus. MRI showed brainstem lesions without involvement of basal ganglia and thalamus, plasma lactate was normal or close to normal. He died after a fulminate course within 2 months after the first crisis. Neuropathology verified Leigh disease. We give a synopsis with other reported patients. Within the clinical spectrum of Leigh disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI. The diagnosis should not be missed in spite of the normal lactate and lack of thalamus and basal ganglia changes on brain MRI. AU - Herzer, M. AU - Koch, J.* AU - Prokisch, H. AU - Rodenburg, R.* AU - Rauscher, C.* AU - Radauer, W.* AU - Forstner, R.* AU - Pilz, P.* AU - Rolinski, B.* AU - Freisinger, P.* AU - Mayr, J.A.* AU - Sperl, W.* C1 - 5930 C2 - 27503 CY - Stuttgart SP - 30-34 TI - Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect. JO - Neuropediatrics VL - 41 IS - 1 PB - Thieme PY - 2010 SN - 0174-304X ER - TY - JOUR AU - Baumeister, F.A.M.* AU - Auer, D.P.* AU - Hörtnagel, K. AU - Freisinger, P.* AU - Meitinger, T. C1 - 2758 C2 - 22914 SP - 221-222 TI - The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome. JO - Neuropediatrics VL - 36 PY - 2005 SN - 0174-304X ER - TY - JOUR AB - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a genetic disorder featuring diffuse MRI white matter abnormalities and a discrepantly mild clinical picture. it is related to different mutations in MLC1 gene encoding a putative membrane protein of still unknown function. We report on a genetically proven MLC patient who presented with a peculiar clinical course characterized by a prolonged comatose state following a minor head trauma at 12 years of age. The disturbance of consciousness lasted for over four months and then gradually improved. Proton MR spectroscopic imaging studies showed a moderately severe depletion of N-acetylaspartate restricted to the white matter with sparing of the cortical grey matter. The full recovery from coma suggests a transitory functional impairment of the structures implicated in the maintenance of consciousness. AU - Bugiani, M.* AU - Moroni, I.* AU - Bizzi, A.* AU - Nardocci, N.* AU - Bettecken, T. AU - Gärtner, J.* AU - Uziel, G.* C1 - 23558 C2 - 36649 SP - 211-214 TI - Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. JO - Neuropediatrics VL - 34 IS - 4 PB - Georg Thieme Verl. PY - 2003 SN - 0174-304X ER -