Combination therapy for Sneddon syndrome to reduce the incidence of cerebrovascular complications.

BACKGROUND: Sneddon syndrome is an occlusive vasculopathy that presents clinically with generalized livedo racemosa on the skin and transient ischemic attacks, strokes, and cognitive or motor deficits in the central nervous system. Antiplatelet or anticoagulant therapy is recommended. Due to the limited therapeutic efficacy and the resulting serious complications, we propose combination therapy with additional infusion cycles of alprostadil and captopril and report initial long-term results. PATIENTS AND METHODS: We performed a systematic retrospective analysis of all patients with primary Sneddon syndrome who received combination therapy in our clinic between 1995 and 2020. Therapeutic outcomes were evaluated using descriptive statistics compared to historical controls receiving monotherapy. We also analyzed the event rate of complications when combination therapy was discontinued. RESULTS: During the 99.7 patient-years of follow-up, there were no transient ischemic attacks and the stroke rate dropped to 0.02 per patient-year. In comparison, the rates of transient ischemic attacks and strokes in the historical controls ranged from 0.08 to 0.035 per patient-year. After discontinuation of alprostadil therapy, eight events occurred in three patients. CONCLUSIONS: Combination therapy reduces the long-term incidence of ischemic events in patients with primary Sneddon syndrome.

Personality factors in patients with myasthenia gravis: A prospective study.

INTRODUCTION: In myasthenia gravis (MG), depression and anxiety have frequently been reported as comorbidities. However, little is known about personality characteristics in MG patients. We aimed to characterise personality traits in MG and to correlate them with disease severity and disease course. METHODS: The Big Five Inventory data questionnaire was used to investigate personality traits in 44 MG patients and 45 healthy controls similar in age and gender. In 28 MG patients, a caregiver was also available for patient assessments to limit bias associated with social desirability in patients' responses. Patients were assessed with regard to premorbid personality (before manifestation of MG) and to present condition. In addition, anxiety and depression scales (Hospital Anxiety and Depression Scale and Beck Anxiety Inventory) were applied. RESULTS: Compared to controls, MG patients showed significantly higher levels of neuroticism, whereas openness and extraversion were significantly lower. Agreeableness and conscientiousness did not differ between groups. Neuroticism was influenced by disease severity such as generalization of weakness, presence of thymoma, and bulbar involvement as well as disease duration. Neuroticism correlated with premorbid level of neuroticism but also with depression and anxiety scores. CONCLUSION: A personality profile of increased neuroticism and lower openness and extraversion in MG patients may contribute considerably to the perception of disease severity. It may also be related to frequent comorbidities such as anxiety and depression. Although premorbid levels of neuroticism were increased, this characteristic may also increase considerably during the course of the disease. The data indicate that muscle weakness in MG is accompanied or even complicated by psychological aspects. Therefore, a psychological and behavioral intervention in addition to the specific pharmacological therapy might be of particular value.

Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies.

BACKGROUND AND OBJECTIVES: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). METHODS: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. RESULTS: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. DISCUSSION: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.

Prognostic factors in ALS: a comparison between Germany and China.

OBJECTIVE: Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients. METHODS: Comparison of prognostic factors was based on two hospital-based registries. The registry of the German Network for Motor Neuron Diseases contains 3100 patients with ALS. The Chinese registry comprises 2101 patients who were collected between 2003 and 2015 in the metropolitan area of Beijing. RESULTS: Disease progression was slower in China [median loss of 0.50 points (IQR 0.26-0.87 points) versus 0.55 points (IQR 0.28-1.00 points) of ALS functional rating scale revised (ALS-FRS-R) score per month; p < 0.0001]. Survival of patients with ALS was similar in Germany and China (p > 0.05). We found that younger age of onset (p < 0.0001), spinal onset (p < 0.0001), high BMI (p < 0.0001) and low progression rate (p < 0.0001) were positive prognostic factors in China as well as in Germany. INTERPRETATION: Prognostic factors, which are known to modify the course of disease in Caucasians, apply to Chinese patients as well. The results indicate that despite the apparent differences regarding genotype and clinical phenotype, findings from interventional studies in Caucasians aiming at disease-modifying prognostic factors (such as body weight) may be transferred to Chinese patients.

Comprehensive analysis of the mutation spectrum in 301 German ALS families.

OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families. RESULTS: 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes. CONCLUSIONS: We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Hot-spot KIF5A mutations cause familial ALS.

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases.

Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.

The cerebro-morphological fingerprint of a progeroid syndrome: white matter changes correlate with neurological symptoms in xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: We present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy ((1)H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, (1)H MRS demonstrated that the hippocampal formation was metabolically altered. CONCLUSIONS: The most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Electrophysiological assessment of the deltoid muscle after minimally invasive treatment of proximal humerus fractures - a clinical observation.

The minimal anterolateral acromial approach offers a less invasive access to the proximal humerus. Functional impairment following this procedure may be caused by paresis of the deltoid muscle as a result of iatrogenic injury to the axillary nerve. It was addressed whether electromyography (EMG) of the deltoid muscle gives evidence for an axillary nerve lesion in association with the minimal anterolateral acromial approach.Twenty-three patients (14 men, 9 women; average age 58 years) with proximal humerus fractures were included in this clinical observation. Follow-up was performed 6 weeks (6w), 6 months (6m) and 12 months (12m) postoperatively. EMG changes indicating either lesion of the axillary nerve or direct muscle trauma were distinguished in "acute", "chronic" and "combined" and semi quantified in "slight", "moderate" and "severe". Patients were examined clinically (standard neurological examination and Constant Score).Three cases of incomplete axillary nerve lesion with limited functional impairment were detected. Subclinical EMG signs of neural impairment of the deltoid muscle were observed frequently (6w, N = 8; 6m, N = 8; 12m, N = 7). Functional outcome did not show an association with EMG.Most patients presented with subclinical and most likely trauma- related neurogenic lesions of the deltoid muscle following the anterolateral acromial approach. Despite the fact that the axillary nerve does not function normally following this less-invasive approach for fixation of proximal humerus fractures, this does not appear to affect the clinical outcome. Prospective studies with larger sample sizes are required to determine the effect of axillary nerve retraction in the more commonly used deltopectoral approach.

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue.

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.

Amygdala size reduction is associated with memory deficits in complicated hereditary spastic paraparesis: an MRI study.

Neuroimaging findings in hereditary spastic paraparesis (HSP), especially in complicated HSP (cHSP), are heterogenous. This study aimed to investigate possible in vivo morphological alterations of the whole brain and the amygdala in cHSP as a correlate of cognitive impairment in contrast to pure variants (pHSP). Amygdalar and whole brain volumes of 33 HSP patients (21 pHSP and 12 cHSP) were measured using three-dimensional magnetic resonance imaging (MRI) data sets by region of interest-based volumetry. A neuropsychological test battery was also performed. A significant reduction in whole brain volume compared with the controls, as well as significant correlations with reduced amygdalar volume and a worse neuropsychological test performance was observed only in cHSP patients. Our findings of disproportional amygdalar atrophy only in cHSP substantiate the association of morphologically assessable cerebral degeneration with cognitive impairment in cHSP.

Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?

BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.

Hypercapnia is a possible determinant of the function of the blood-cerebrospinal fluid barrier in amyotrophic lateral sclerosis.

Elevated cerebrospinal fluid (CSF)/serum quotients of albumin (Q(Alb)) may occur in motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS), but the pathophysiologic mechanisms underlying these alterations are unclear. Evidence from animal experiments suggests that the arterial carbon dioxide level might affect the Q(Alb), i.e. the function of the blood-CSF barrier (BCB). We therefore compared basic CSF parameters in different forms of MND (ALS, n = 105; lower motor neuron diseases, n = 12; and upper motor neuron diseases, n = 7) and investigated the relationship between elevated Q(Alb) and the arterial partial pressure of carbon dioxide (pCO(2)) in ALS where respiratory insufficiency leads to hypercapnia in the course of the disease. Pathologic elevations of Q(Alb) occurred in 32 of 124 MND patients. In ALS, Q(Alb) significantly correlated with the arterial pCO(2) (r = 0.454; P = 0.001; n = 45). These data indicate that BCB dysfunction is a frequent finding in different forms of MND and may reflect distinct pathophysiological mechanisms. In ALS, an important underlying mechanism might be the influence of the arterial pCO(2) which may alter the CSF flow.

Whole brain-based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging.

Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.

Cardiac involvement in a female carrier of Duchenne muscular dystrophy.

A 42 year-old female carrier of Duchenne muscular dystrophy (DMD) was referred with suspected subacute myocarditis and non-sustained ventricular tachycardia. Echochardiography and cardiac catheterization revealed severely reduced left ventricular function (LVF). Coronary artery disease was excluded. Cardiac magnetic resonance imaging showed transmural, intramural and subepicardial late gadolinium enhancement. Myocardial biopsy excluded viral infection and showed severe myopathic changes with abnormal expression of dystrophin and utrophin. Moleculargenetic analysis of the DMD gene revealed frameshift duplication of exon 2. The patient received conventional heart failure therapy, implantable cardioverter/defibrillator-implantation and prednisolone to attenuate cardiac degradation. 6 months later she had improved clinically though LVF was still severely reduced.

Concentrations of beta-amyloid precursor protein processing products in cerebrospinal fluid of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders with heterogeneous clinical presentation but common neuropathological characteristics and pathophysiological substrates, which led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. For both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are reported. In a pilot study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS + FTLD. Changes in Abeta pattern could be described, allowing separation of patients with pure FTLD from ALS + FTLD. Combination of sAPP and Abeta values improves group differentiation. These findings may provide information on pathophysiological processes in the ALS-FTLD disease spectrum and could have impact in neurochemical diagnosis. We propose to expand this study to larger patient groups comprising followed up cases with known neuropathology.

Frontotemporal cognitive function in X-linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients.

A cross-sectional neuropsychological study of cognitive functions in 20 male patients with genetically proven spinal and bulbar muscular atrophy (SBMA) was performed, with a comparison of their cognitive performance with that of 20 age- and education-matched control subjects. Neuropsychological assessment covered executive functioning, memory, and attentional control. The SBMA patients revealed deficits in verbal and non-verbal fluency as well as concept formation. Additionally, they showed significant memory deficits in all of the investigated domains of working memory, short-term and long-term memory. With respect to attentional control, the SBMA patients underperformed in relevant subtests, although performance differences did not reach significance overall. We conclude that fronto-temporal cognitive functions are impaired in SMBA, although at a subclinical level. Thus, functional deficits in SBMA are not confined to motor neurons but also affect extramotor networks.

Histopathological analysis of skeletal muscle in patients with Parkinson's disease and 'dropped head'/'bent spine' syndrome.

BACKGROUND: 'Dropped head' and 'bent spine' phenomena are recognized clinical presentations of neuromuscular disorders. Similar symptoms are known in patients with parkinsonian syndromes, but their pathophysiology remains unclear. One hypothesis is a relation between the movement disorder and the skeletal muscle pathology. METHODS: We describe detailed histopathological data from 19 consecutive skeletal muscle biopsies in patients with idiopathic Parkinson's disease (PD) and concomitant 'dropped head' or 'bent spine' syndrome. A biochemical analysis of the respiratory chain complexes was also performed, and clinical, electrophysiological, and imaging data were analyzed. RESULTS: The subjects developed neuromuscular symptoms 2.7 +/- 2.4 years after onset of PD. We found no correlation with the age at onset of the disease, disease duration, or severity. We found no evidence for dystonia nor did we find any relationship between their anti-parkinsonian medication, and possible drug side effects. Muscle biopsies were abnormal in all patients. Based on histopathological criteria we divided the muscle pathology into three different groups, i.e. necrotizing myopathy, inflammatory myopathy, and myopathy with mitochondrial abnormalities. Biochemical analysis of respiratory chain complexes revealed abnormalities in nine patients. CONCLUSIONS: 'Dropped head' and 'bent spine' symptoms in association with PD appear to be accompanied by a wide spectrum of histopathological abnormalities in skeletal muscle. A muscle biopsy should be performed to identify potentially treatable conditions (i.e. inflammatory myopathies).