Successful infliximab treatment in siblings with Netherton syndrome: Unveiling a novel SPINK5 gene variant and literature review.

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis. In this article, we present two siblings with NS who harbour a novel variant in the SPINK5 gene and were treated with infliximab infusions. Both patients exhibited the characteristic clinical triad of NS, and their whole exome sequencing analysis revealed a homozygous variant, c.1820+53G>A, in the SPINK5 gene. Notably, this is the first documented instance of homozygosity for this particular variant. Despite the absence of a specific treatment, both patients achieved total clearance of the skin lesions, and a significant decrease in total IgE levels was documented.

Case report: Revealing the rare-a Brody Disease patient from Turkey expanding the phenotype.

Brody Disease is an exceptionally rare, autosomal recessive myopathy attributed to the pathogenic variants in the ATP2A1, which encodes the sarcoplasmic/endoplasmic reticulum Ca (2+) ATPase type 1 protein SERCA1. It was first described by Brody IA in 1969. To date, only thirty-three Brody families with forty-seven patients have been reported in the literature, and the disease prevalence is considered as 1 in 10 million, demonstrating the peculiarity of the disease. Clinical characteristics of Brody Disease include muscle stiffness after exercise, myalgia, and muscle cramps. Brody Disease patients generally have disease onset in the first decade, and genetic diagnosis is delayed as a consequence of both the rareness and the mild course of the disease. Here, we report a Turkish Brody Disease patient with a homozygous c.428G>A p.Arg143Gln (NM_004320.4) missense mutation in the ATP2A1. The male patient, whose symptoms started at the age of 14-15, is now 36 years old. His clinical manifestations are athletic appearance, exotropia, slightly elevated creatine kinase (CK), mild progressive proximal muscle weakness in the lower extremities, muscle cramps, pain and stiffness. The patient described here has a very mild progression with an onset in the second decade, expanding the Brody Disease phenotype. The study also implies that in the era of emerging genetic therapies, the routine testing of patients with myopathies is a prerequisite since not only future therapies will be designed on molecular findings, but also currently available symptomatic and palliative treatment options will be more precisely applied.

Evaluation of the Hematological and Serum Biochemistry Parameters in the Pre-Symptomatic and Symptomatic Stages of ALS Disease to Support Early Diagnosis and Prognosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Since there are no pathognomonic tests for ALS prognoses; clinical diagnoses of the disease take time and are usually difficult. Prognostic biomarkers are urgently needed for rapid and effective ALS prognoses. Male albino rats were divided into ten groups based on age: 0 (40-45 days old), A (70-75 days old), B (90-95 days old), C (110-115 days old), and D (130-135 days old). Each group was divided into two subgroups according to its mutation status: wild type (SOD1WT) or mutated (SOD1G93A). Serum biochemistry and hematological parameters were measured in 90 rats to evaluate possible biomarkers for faster ALS diagnoses and prognoses. Weight loss, cholesterol, creatinine, glucose, total bilirubin (TBIL), blood urine nitrogen (BUN), c-peptide, glucagon, PYY, white blood cell (WBC), lymphocyte (LYM), monocyte (MID), granulocyte (GRAN), red cell distribution width with standard deviation (RDW-SD), red cell distribution width with the coefficient of variation (RDW-CV), platelet (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and procalcitonin (PCT) levels were changed in the SOD1G93A rats compared to the SOD1WT rats independently from aging. For the first time in the literature, we showed promising hematological and serum biochemistry parameters in the pre-symptomatic and symptomatic stages of ALS by eliminating the effects of aging. Our results can be used for early diagnoses and prognoses of ALS, improving the quality of life and survival time of ALS patients.

Impact of the Amyotrophic Lateral Sclerosis Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated With the Human Mutant SOD1G93A Protein Accumulation.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and ALS incidence is increasing worldwide. Patients with ALS have respiratory failure at the disease's end stages, leading to death; thus, the lung is one of the most affected organs during disease progression. Tissue stiffness increases in various lung diseases because of impaired extracellular matrix (ECM) homeostasis leading to tissue damage and dysfunction at the end. According to the literature, oxidative stress is the major contributor to ECM dysregulation, and mutant protein accumulation in ALS have been reported as causative to tissue damage and oxidative stress. In this study, we used SOD1G93A and SOD1WT rats and measured lung stiffness of rats by using a custom-built stretcher, where H&E staining is used to evaluate histopathological changes in the lung tissue. Oxidative stress status of lung tissues was assessed by measuring glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), catalase (CAT), and superoxide dismutase 1 (SOD1) levels. Western blot experiments were performed to evaluate the accumulation of the SOD1G93A mutated protein. As a result, increased lung stiffness, decreased antioxidant status, elevated levels of oxidative stress, impaired mineral and trace element homeostasis, and mutated SOD1G93A protein accumulation have been found in the mutated rats even at the earlier stages, which can be possible causative of increased lung stiffness and tissue damage in ALS. Since lung damage has altered at the very early stages, possible therapeutic approaches can be used to treat ALS or improve the life quality of patients with ALS.

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

Phenotypical spectrum of SACS variants: Neuromuscular perspective of a complex neurodegenerative disorder.

OBJECTIVES: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by the SACS gene variants. Main clinical features include early-onset and progressive cerebellar ataxia, spasticity, sensorimotor polyneuropathy. However, the phenotypic spectrum expanded with the increased availability of next-generation sequencing methods. MATERIALS AND METHODS: Herein, we describe the clinical features of nine patients from seven unrelated families with SACS variants from the cohort of the Neuromuscular Disorders Unit of the Neurology Department of the Istanbul University, Istanbul Faculty of Medicine. RESULTS: Seven patients were male. Seven patients in our cohort had disease onset in the first decade of life. Eight patients were born to consanguineous marriages. Distal weakness in the lower limbs was a prominent feature in all of our patients. Seven patients had ataxia, and six patients had spasticity. Interestingly, one patient showed an isolated Charcot-Marie-Tooth-like phenotype. Five patients showed sensorimotor demyelinating polyneuropathy in the nerve conduction studies. Linear pontine hypointensity was the most frequent cranial magnetic resonance imaging (MRI) abnormality. Two patients with a later disease onset had a homozygous c.11542_11544delATT (p.Ile3848del) variant. The rest of the identified variants were scattered throughout the SACS gene. CONCLUSIONS: Atypical clinical features in our patients highlight that the phenotypic spectrum of ARSACS can be observed in a wide range.

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.

A rare case of juvenile amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic motor neuron disease characterised by progressive weakness in striated muscles resulting from the destruction of neuronal cells. The term juvenile ALS (JALS) is used for patients whose symptoms start before 25 years of age. JALS may be sporadic or familial. CASE: Here, we present a sporadic case of JALS because of its rarity in children. The heterozygous p.Pro525Leu (c.1574C > T) variation was identified in the fused in sarcoma (FUS) gene. CONCLUSION: The p.Pro525Leu mutation in the FUS gene has been detected in patients with ALS, characterised by early onset and a severely progressive course.

Varied phenotypic spectrum presenting of paroxysmal exercise-induced dyskinesia: a Turkish family with SLC2A1 mutation.

INTRODUCTION: Paroxysmal exercise-induced dyskinesia (PED) is characterized by repeated episodes of involuntary movement disorders that are typically caused by prolonged walking or running and mostly caused by SLC2A1 gene mutations. Phenotypes vary from focal dystonia, ataxia, tremor, and complex non-kinesigenic movements to other movement disorders in patients with SLC2A1 mutation. Also, SLC2A1 mutations carriers may present with also other phenotypes such as epileptic seizure and migraine. CASE REPORTS: We report five patients with various phenotypic spectrums of PED in a Turkish family. Whole exome sequencing revealed a likely pathogenic synonymous variant p.Ser324Ser (c.972G > A) in the SLC2A1 gene (ENST00000426263.3) and the variant segregated in all affected family members. Also, other than PED, the phenotypical spectrum of affected individuals in this family includes epilepsy, mental retardation, and weakness. CONCLUSIONS: We concluded that family members with the same SLC2A1 gene mutation may show very heterogenous phenotypes. Clinicians should be aware of wide variety of symptoms of the patients with PED. We also emphasized that even if a mutation in the coding sequence does not make an amino acid change, it may cause the disease.

Assessment of the corticospinal fiber integrity in mirror movement disorder.

Mirror movements are unintended movements occurring on one side of the body that mirror the contralateral voluntary ones. It has been proposed that mirror movements occur due to abnormal decussation of the corticospinal pathways. Using detailed multidisciplinary approach, we aimed to enlighten the detailed mechanism underlying the mirror movements in a case subject who is diagnosed with mirror movements of the hands and we compared the findings with the unaffected control subjects. To evaluate the characteristics of mirror movements, we used several techniques including whole exome sequencing, computed tomography, diffusion tensor imaging and transcranial magnetic stimulation. Computed tomography showed the absence of a spinous process of C5, fusion of the body of C5-C6 vertebrae, hypoplastic dens and platybasia of the posterior cranial fossa. A syrinx cavity was present between levels C3-C4 of the spinal cord. Diffusion tensor imaging of the corticospinal fibers showed disorganization and minimal decussations at the lower medulla oblongata. Transcranial magnetic stimulation showed that motor commands were distributed to the motor neuron pools on the left and right sides of the spinal cord via fast-conducting corticospinal tract fibers. Moreover, a heterozygous missense variation in the deleted in colorectal carcinoma gene has been observed. Developmental absence of the axonal guidance molecules or their receptors may result in abnormalities in the leading of the corticospinal fibers. Clinical evaluations and basic neuroscience techniques, in this case, provide information for this rare disease and contribute to our understanding of the normal physiology of bimanual coordination.

Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2.

Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast.

Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.

Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.

Turkish families with juvenile motor neuron disease broaden the phenotypic spectrum of SPG11.

OBJECTIVE: Identification of causative mutations in 3 consanguineous families (with 4 affected members) referred to our center with young-onset motor neuron disease and overlapping phenotypes resembling autosomal recessive juvenile amyotrophic lateral sclerosis (ARJALS) and autosomal recessive hereditary spastic paraplegia (ARHSP). METHODS: Patients have a slowly progressive motor neuron disease with upper and lower motor neuron dysfunction. There is distal muscle weakness and atrophy associated with pyramidal signs. Whole-exome sequencing was performed on the patients and the unaffected parent samples to identify disease-causing mutations. Variants were prioritized according to their predicted pathogenicity and their relevance to the clinical phenotypes. RESULTS: Five distinct homozygous mutations within the SPG11 gene were identified, 3 of which were novel and truncating: c.7155T>G/p.Tyr2385Ter, c.2250delT/p.Phe750Leufs*3, and c.1966_1967delAA/p.Lys656Valfs*11. The copresence of 2 distinct homozygous missense variations was observed in 2 families: c.6224A>G/p.Asn2075Ser and c.7132T>C/p.Phe2378Leu. The segregation of these variations in the family members was validated by Sanger sequencing. CONCLUSIONS: Four patients with juvenile-onset motor neuron disease with consanguineous parents were found to carry homozygous mutations in the SPG11 gene. Our findings confirm the overlapping phenotypes of SPG11-based ARJALS and ARHSP, indicating that these 2 entities may be the extreme phenotypes of the same disease continuum with many common features. This, in turn, confirms the difficult differential diagnosis of these 2 diseases in the clinic.

Temporal expression analysis of angiogenesis-related genes in brain development.

BACKGROUND: The current knowledge on molecular pathogenesis of cerebral vascular malformations (CVM), which are believed to arise during development, is very limited. To unravel the molecular mechanisms involved in CVMs, a detailed understanding of the brain vascular development at molecular level is crucial. In this study, we aimed to explore the temporal and comparative expression profile of angiogenesis-related genes in the establishment of brain vasculature. METHODS: Expression of a total of 113 angiogenesis-related genes during murine brain development has been analyzed using low-density array systems designed for angiogenesis-related genes. Bai1 (brain specific angiogenesis inhibitor-1), a recently identified novel anti-angiogenic gene, has been selected for further characterization. RESULTS: We found that 62 out of 113 analyzed genes have expression in brain development at varying levels. Nineteen of these were differentially expressed between embryonic and postnatal stages (>1.5 fold). Bai1 is strongly expressed on growing blood vessels of cerebral cortex and hippocampus, partially expressed in the lateral regions of striatum, but mostly absent on the thalamus. CONCLUSION: By showing the comparative expression analysis of angiogenesis-related genes throughout brain development, the data presented here will be a crucial addition to further functional studies on cerebrovascular research.

Alfa-class prefoldin protein UXT is a novel interacting partner of Amyotrophic Lateral Sclerosis 2 (Als2) protein.

Mutations in Als2 gene cause several autosomal recessive forms of motor neuron diseases including Juvenile Amyotrophic Lateral Sclerosis (JALS), Juvenile Primary Lateral Sclerosis (PLSJ) and Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP). To find novel protein-protein interactions of Als2 protein we performed a yeast two hybrid screen and fished out the Ubiquitously Expressed Transcript (UXT) protein. UXT is a novel gene encoding for an α-class prefoldin type chaperone which acts as a co-activator for various transcriptional factors such as Nf-κB and AR. The interaction between Als2 and UXT was confirmed by co-immunoprecipitation. Co-localization between endogenous Als2 and UXT was mainly found in the cytoplasm of neuronal Neuro2a cells with immunofluorescence microscopy. Cell cycle arrest of Neuro2a cells showed that Als2 and Uxt transcriptional levels are synchronously changing. Our results suggest that Als2 is a binding partner of Uxt and Als2/Uxt interaction could be important for the activation of Nf-κB pathway. These results provides basis for future research to investigate the role of Nf-κB pathway in the development of motor neuron diseases.

Bell's palsy and choreiform movements during peginterferon alpha and ribavirin therapy.

Neuropsychiatric side effects of long-term recombinant interferon-alpha therapy consist of a large spectrum of symptoms. In the literature, cranial neuropathy, especially Bell's palsy, and movement disorders, have been reported much less often than other neurotoxic effects. We report a case of Bell's palsy in a patient with chronic hepatitis C during peginterferon-alpha and ribavirin therapy. The patient subsequently developed clinically inapparent facial nerve involvement on the contralateral side and showed an increase in choreic movements related to Huntington's disease during treatment.