De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

Prepubertal Periodontitis in a Patient with Combined Classical and Periodontal Ehlers-Danlos Syndrome.

We report an extremely rare case of combined classical and periodontal Ehlers-Danlos syndrome (EDS) with early severe periodontitis and a generalized lack of attached gingiva. A German family with classical EDS was investigated by physical and dental evaluation and exome and Sanger sequencing. Due to the specific periodontal phenotype in the affected child, an additional diagnosis of periodontal EDS was suspected. Physical and genetic examination of two affected and three unaffected family members revealed a family diagnosis of classical EDS with a heterozygous mutation in COL5A1 (c.1502del; p.Pro501Leufs*57). Additional to the major clinical criteria for classical EDS-generalized joint hypermobility, hyperelastic skin, and atrophic scarring -the child aged four years presented with generalized alveolar bone loss up to 80%, early loss of two lower incisors, severe gingival recession, and generalized lack of attached gingiva. Due to these clinical findings, an additional diagnosis of periodontal EDS was suspected. Further genetic analysis revealed the novel missense mutation c.658T>G (p.Cys220Gly) in C1R in a heterozygous state. Early severe periodontitis in association with generalized lack of attached gingiva is pathognomonic for periodontal EDS and led to the right clinical and genetic diagnosis in the present case.

Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P.

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.

Schizophrenia and Hereditary Polyneuropathy: PMP22 Deletion as a Common Pathophysiological Link?

Background: Schizophrenic disorders are common and debilitating due to their symptoms, which can include delusions, hallucinations, and other negative symptoms. Organic forms can result from various cerebral disorders. In this paper, we discuss a potential association between schizophrenia and hereditary polyneuropathies (PNPs). Case presentation: We present the case of a 55-year-old female patient with chronically paranoid-hallucinatory schizophrenia, severe cognitive deficits since the age of 30, and comorbid repeated focal pressure neuropathies beginning at age 20. At the age of 35, genetic testing revealed a deletion on chromosome 17p12 covering the peripheral myelin protein 22 gene (PMP22), which led to the diagnosis of hereditary neuropathy with liability to pressure palsy (HNPP). Cerebral magnetic resonance imaging showed internal atrophy, magnetic resonance spectroscopy found alteration of the glutamate and myo-inositol levels in the anterior cingulate cortex, neuropsychological testing showed deficits in working memory and psychomotor speed, and electrophysiological testing detected signs of sensorimotor demyelinating PNP (accentuated in the legs). Conclusion: There may be an association between schizophrenia and HNPP. In observational studies, the deletion of interest (chromosome 17p12) was nearly 10 times more common in schizophreniform patients than in controls. This potential association could be pathophysiologically explained by the role of PMP22, which is mainly expressed in the peripheral nervous system. However, PMP22 mRNA and protein can also be found in the brain. PMP22 seems to play an important role in regulating cell growth and myelination, functions that are disturbed in schizophrenia. Such a connection obviously cannot be clarified on the basis of one case. Future studies should analyze whether patients with HNPP exhibit increased rates of psychotic disorders, and patients with schizophrenia and repeated focal pressure neuropathies should be examined for the PMP22 mutation. Alternatively, the co-occurrence of schizophrenia and HNPP could be coincidental.

New Variant of MELAS Syndrome With Executive Dysfunction, Heteroplasmic Point Mutation in the MT-ND4 Gene (m.12015T>C; p.Leu419Pro) and Comorbid Polyglandular Autoimmune Syndrome Type 2.

Background: Mitochondrial diseases are caused by dysfunctions in mitochondrial metabolic pathways. MELAS syndrome is one of the most frequent mitochondrial disorders; it is characterized by encephalopathy, myopathy, lactic acidosis, and stroke-like episodes. Typically, it is associated with a point mutation with an adenine-to-guanine transition at position 3243 of the mitochondrial DNA (mtDNA; m.3243A>G) in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene. Other point mutations are possible and the association with polyglandular autoimmune syndrome type 2 has not yet been described. Case presentation: We present the case of a 25-year-old female patient with dysexecutive syndrome, muscular fatigue, and continuous headache. Half a year ago, she fought an infection-triggered Addison crisis. As the disease progressed, she had two epileptic seizures and stroke-like episodes with hemiparesis on the right side. Cerebral magnetic resonance imaging showed a substance defect of the parieto-occipital left side exceeding the vascular territories with a lactate peak. The lactate ischemia test was clearly positive, and a muscle biopsy showed single cytochrome c oxidase-negative muscle fibers. Genetic testing of blood mtDNA revealed a heteroplasmic base exchange mutation in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4) gene (m.12015T>C; p.Leu419Pro; heteroplasmy level in blood 12%, in muscle tissue: 15%). The patient suffered from comorbid autoimmune polyglandular syndrome type 2 with Hashimoto's thyroiditis, Addison's disease, and autoimmune gastritis. In addition, we found increased anti-glutamic acid decarboxylase 65, anti-partial cell, anti-intrinsic factor, and anti-nuclear antibodies. Conclusion: We present an atypical case of MELAS syndrome with predominant symptoms of a dysexecutive syndrome, two stroke-like episodes, and fast-onset fatigue. The symptoms were associated with a not yet described base and aminoacid exchange mutation in the MT-ND4 gene (m.12015T>C to p.Leu419Pro). The resulting changed protein complex in our patient is part of the respiratory chain multicomplex I and might be the reason for the mitochondriopathy. However, different simulations for pathogenetic relevance are contradictory and rather speak for a benign variant. To our knowledge this case report is the first reporting MELAS syndrome with comorbid polyglandular autoimmune syndrome type 2. Screening for autoimmune alterations in those patients is important to prevent damage to end organs.

Heterozygous deletion of SCN2A and SCN3A in a patient with autism spectrum disorder and Tourette syndrome: a case report.

BACKGROUND: Mutations in voltage-gated sodium channel (SCN) genes are supposed to be of importance in the etiology of psychiatric and neurological diseases, in particular in the etiology of seizures. Previous studies report a potential susceptibility region at the chromosomal locus 2q including SCN1A, SCN2A and SCN3A genes for autism spectrum disorder (ASD). To date, there is no previous description of a patient with comorbid ASD and Tourette syndrome showing a deletion containing SCN2A and SCN3A. CASE PRESENTATION: We present the unique complex case of a 28-year-old male patient suffering from developmental retardation and exhibiting a range of behavioral traits since birth. He received the diagnoses of ASD (in early childhood) and of Tourette syndrome (in adulthood) according to ICD-10 and DSM-5 criteria. Investigations of underlying genetic factors yielded a heterozygous microdeletion of approximately 719 kb at 2q24.3 leading to a deletion encompassing the five genes SCN2A (exon 1 to intron 14-15), SCN3A, GRB14 (exon 1 to intron 2-3), COBLL1 and SCL38A11. CONCLUSIONS: We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment.

17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5.

Context: Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutations of the hepatocyte nuclear factor 1 homeobox ß gene (HNF1B). Although clinical characteristics and therapeutic management of MODY5 are increasingly better defined, adequate consideration of the frequent association of MODY5 with 17q12 deletion syndrome is often missing. Evidence Acquisition: We report two cases of patients with 17q12 deletion syndrome who presented to our clinic. Furthermore, we reviewed the existing literature to improve systematic diagnostic and therapeutic approaches. A PubMed search using the terms 17q12 deletion syndrome, diabetes mellitus type MODY5, and/or HNF1B was performed. Evidence Synthesis: Three hundred sixty-one cases of postnatal 17q12 deletion syndrome were assessed, and details on clinical manifestations, diagnostic approaches, and therapeutic management were reviewed and compared with the two cases at our clinic. Furthermore, data on pathogenic mechanisms and their clinical implications were evaluated. Conclusion: The 17q12 deletion syndrome usually comprises MODY5, structural or functional abnormalities of the kidneys, and neurodevelopmental or neuropsychiatric disorders. A complete deletion of HNF1B can be found in about 50% of patients with MODY5. A wide variety of additional clinical features, including genital and brain malformations, has been reported. Because HNF1B deletions are virtually always part of a 17q12 deletion syndrome and common genetic analyses for evaluation of MODY5 are unable to detect the deletion of a 1.4-Mb chromosomal region, initial attention to the syndromal features at the stage of diagnosis is of considerable importance for establishing correct diagnosis, subsequent therapy, and interdisciplinary patient care.

Personalized Clinical Decision Making Through Implementation of a Molecular Tumor Board: A German Single-Center Experience.

PURPOSE: Dramatic advances in our understanding of the molecular pathophysiology of cancer, along with a rapidly expanding portfolio of molecular targeted drugs, have led to a paradigm shift toward personalized, biomarker-driven cancer treatment. Here, we report the 2-year experience of the Comprehensive Cancer Center Freiburg Molecular Tumor Board (MTB), one of the first interdisciplinary molecular tumor conferences established in Europe. The role of the MTB is to recommend personalized therapy for patients with cancer beyond standard-of-care treatment. METHODS: This retrospective case series includes 198 patients discussed from March 2015 through February 2017. The MTB guided individual molecular diagnostics, assessed evidence of actionability of molecular alterations, and provided therapy recommendations, including approved and off-label treatments as well as available matched clinical trials. RESULTS: The majority of patients had metastatic solid tumors (73.7%), mostly progressive (77.3%) after a mean of 2.0 lines of standard treatment. Diagnostic recommendations resulted in 867 molecular diagnostic tests for 172 patients (five per case), including exome analysis in 36 cases (18.2%). With a median turnaround time of 28 days, treatment recommendations were given to 104 patients (52.5%). These included single-agent targeted therapies (42.3%), checkpoint inhibitors (37.5%), and combination therapies (18.3%). Treatment recommendations were implemented in 33 of 104 patients (31.7%), of whom 19 (57.6%) showed stable disease or partial response, including 14 patients (7.1% of the entire population) receiving off-label treatments. CONCLUSION: Personalized extended molecular-guided patient care is effective for a small but clinically meaningful proportion of patients in challenging clinical situations. Limited access to targeted drugs, lack of trials, and submission at late disease stage prevents broader applicability, whereas genome-wide analyses are not a strict requirement for predictive molecular testing.

Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.

The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.

BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Assessment of leech therapy for knee osteoarthritis: a randomized study.

BACKGROUND AND PURPOSE: Symptomatic treatment of osteoarthritis of the knee with leeches is presently undergoing a renaissance. Previous studies have shown methodical weaknesses. In the present study patients were blinded regarding the treatment, and a control group was included to explore possible differences in various subjective clinical scores and intake of pain medication over time between leech therapy and placebo control. PATIENTS AND METHODS: 113 patients with advanced osteoarthritis of the knee were included. The patients were randomized to a single treatment group, group I (single leech application, n = 38), a double treatment group, group II (double application, n = 35), and a control group (n = 40). The second treatment in group II took place after an interval of 4 weeks. The treatment in the control group was simulated with the help of an "artificial leech". Results were documented with the KOOS and WOMAC scores and also a visual analog scale (VAS) for pain. Changes in the use of pain medication were monitored over 26 weeks. RESULTS: An improvement in KOOS and WOMAC scores, and also in VAS, was found in all 3 groups following treatment. These improvements were statistically significant for treatment groups I and II during the complete follow-up period. The reduction in individual requirements for pain medication was also statistically significant. The greatest improvement was seen in the group treated twice with the leeches, with a long-term reduction of joint stiffness and improved function in the activities of daily living. INTERPRETATION: Leech therapy can reduce symptoms caused by osteoarthritis. Repeated use of the leeches appears to improve the long-term results. We have not determined whether the positive outcome of the leech therapy is caused by active substances released during the leeching, the placebo effect, or the high expectations placed on this unusual treatment form.