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\(\textbf {Background:}\) Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like \(\textit {SCA8, SCA10, SCA12}\) and \(\it {SCA36}\). Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the \(\it C9orf72\) gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. \(\textbf {Methods:}\) We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the \(\it C9orf72\) gene. \(\textbf {Results:}\) Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in \(\it C9orf72\). The analysis of the fragile X mental retardation 1 gene \(\textit {(FMR1)}\) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). \(\textbf {Conclusions:}\) Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller \(\it FMR1\) gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for \(\it C9orf72\) expansion in ataxia patients.

Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in \(\it ECM1\). Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the \(\it ECM1\) gene and summarize the current knowledge on \(\it ECM1\) mutations and possible genotype-phenotype correlations.

von Willebrand, Vitamin D and platelet diagnostics: The table shows the results for each patient, listed to patient ID according to Table 1, with unit and normal measurement range in brackets depending on the respective laboratory where the analysis was performed. For Vitamin D and functional platelet analysis, normal ranges differ among those depending on the commercial test used. Bold red values show deviation from the normal range. Stroked out values are not available in the specific laboratory of examination (n.a.d. = no applicable disease). (DOCX 111 kb)

Background The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations. Results 22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 % for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity. Conclusion The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.

Blood count and plasmatic coagulation laboratory results: The table shows the results for each patient, listed to patient ID according to Table 1, with unit and normal measurement range. Bold red values show deviation from the normal range. Stroked out values are not available in the specific laboratory of examination. (DOCX 74 kb)

Item does not contain fulltext BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

\(\textbf {Background:}\) Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) \(\textit {in vitro}\), its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of \(\it apoE\) on disease course of EAE and MS. \(\textbf {Methods:}\) \(MOG_{35-55}\) induced EAE in female and male \(\it apoE\)-deficient mice was assessed clinically and histopathologically. \(\it apoE\) expression was investigated by qPCR. The association of the MS severity score (MSSS) and \(\it APOE\) rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. \(\textbf {Results:}\) EAE disease course was slightly attenuated in male \(\it apoE\)-deficient \(\it (apoE^{-/-})\) mice compared to wildtype mice (cumulative median score: \(\it apoE^{-/-}\) = 2 [IQR 0.0–4.5]; wildtype = 4 [IQR 1.0–5.0]; \(\it n\) = 10 each group, \(\it p\) = 0.0002). In contrast, EAE was more severe in female \(\it apoE^{-/-}\) mice compared to wildtype mice (cumulative median score: \(\it apoE^{-/-}\) = 3 [IQR 2.0–4.5]; wildtype = 3 [IQR 0.0–4.0]; \(\it n\) = 10, \(\it p\)= 0.003). In wildtype animals, \(\it apoE\) expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; \(\it p\)< 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. \(\textbf {Conclusions:}\) \(\it apoE\) exerts moderate sex-specific effects on EAE severity. However, the results in the \(\it apoE\) knock-out model are not comparable to effects of polymorphic variants in the human \(\it APOE\) gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.

\(\bf Background:\) Atopic dermatitis (AD) is a chronic inflammatory skin disorder caused by complex interaction of genetic and environmental factors. Besides mutations in the filaggrin gene, leading to impaired skin barrier function, variation in genes encoding additional skin proteins has been suggested to contribute to disease risk. Laminin 5, playing an important role in skin integrity, is composed of three subunits encoded by the \(\it {LAMA3}\), \(\it {LAMB3}\) and \(\it {LAMC2}\) genes in which biallelic mutations cause epidermolysis bullosa junctionalis. We aimed at evaluating the role of variation in the \(\it {LAMA3}\), \(\it {LAMB3}\) and \(\it {LAMC2}\) genes for AD pathogenesis. \(\bf Methods:\) 29 single nucleotide polymorphisms (SNPs) were genotyped in the three genes in a German AD case-control cohort comprising 470 unrelated AD patients and 320 non-atopic controls by means of restriction enzyme digestion. Allele, genotype and haplotype frequencies were compared between cases and controls using chi-square testing and the Haploview software. \(\bf Results:\) Several SNPs in the \(\it {LAMA3}\) gene showed significant association with AD in our cohort (p