Microtubule-associated protein 1B dysregulates microtubule dynamics and neuronal mitochondrial transport in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.

Camptocormia in patients with multiple system atrophy at different disease durations: frequency and related factors.

BACKGROUND: Camptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated. METHODS: A total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3-5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used. RESULTS: In the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3-5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3-5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463). CONCLUSION: The frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease.

The Study of Subthalamic Deep Brain Stimulation for Parkinson Disease-Associated Camptocormia.

BACKGROUND Camptocormia is an axis symptom of Parkinson disease. It remains uncertain whether treatment with medications and surgery are effective. In this study, we assessed the efficacy of subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson disease-associated camptocormia and explored some of its mechanisms. MATERIAL AND METHODS Parkinson disease-associated camptocormia was diagnosed by the following procedures. All patients underwent bilateral STN DBS. The patents' camptocormia was rated by degree and MDS Unified Parkinson's Disease Rating Scale (UPDRS) item 3.13 before and after DBS surgery. Rehabilitation and psychological interventions were used after surgery, in addition to adjustments of medication and stimulus parameters. The treatment effects on camptocormia were assessed comparing medication-off (presurgery) versus stimulation-on (post-surgery). Ethical approval for this study was provided through the Center of Human Research Ethics Committee (No. 2019-35). This study trial was registered in Chinese Clinical Trial Registry (No. ChiCTR1900022655). All the participants provided written informed consent. RESULTS After DBS surgery, all of study patients' symptoms were improved, with different levels of improvement. The minimum and maximum improvement rates were 20% and 100% respectively. The score of item 3.13 of the MDS-UPDRS III and the degree of camptocormia were found to be obviously improved (P<0.05). CONCLUSIONS STN DBS can improve Parkinson disease-associated camptocormia; STN DBS assisted with rehabilitation and psychological intervention appears to be more effective.

Preoperative factors that predict fair outcomes following surgery in patients with proximal cervical spondylotic amyotrophy. A retrospective study.

STUDY DESIGN: Observational cohort study OBJECTIVES: To investigate preoperative factors that predict fair outcomes following surgery in patients with proximal cervical spondylotic amyotrophy (CSA) using electrophysiological and neurological findings. SETTING: Yamaguchi University METHODS: 54 patients with proximal CSA who underwent surgical treatment of the cervical spine were enrolled. Erb-point stimulated compound muscle action potentials (CMAP) were recorded from the deltoid and biceps brachii muscles. We computed the ratio of affected to normal side CMAP amplitudes in two muscles (deltoid and biceps brachii) and regarded the mean ratio (CMAP-R) as representing the severity of neural involvement. Pre- and postoperative strengths of the most atrophic muscles were evaluated using manual muscle testing. Improvements in strength were classified as excellent (5 grades recovered), good (more than one grade recovered), fair (no improvement), or poor (worsened). RESULTS: Surgical outcomes were excellent in 26 patients, good in five, fair in 16, poor in seven. Patients with fair outcomes had lower CMAP-R than those patients with excellent and good outcomes [P = 0.0099, odds ratio = 0.89 (95% confidence interval, 0.81-0.97; for a change of 10%)]. Eight patients (15%) had a C5 palsy. CONCLUSIONS: CMAP-R could be used as a reliable predictive factor related to a fair surgical outcome. We must pay attention to the incidence of C5 palsy after surgery.

Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA.

Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.

Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) is an autosomal recessive disease that develops early during infancy. The gene responsible for disease development is immunoglobulin helicase µ-binding protein 2 (IGHMBP2). IGHMBP2 is a ubiquitously expressed gene but its mutation results in the loss of alpha-motor neurons and subsequent muscle atrophy initially of distal muscles. The current SMARD1 mouse model arose from a spontaneous mutation originally referred to as neuromuscular degeneration (nmd). The nmd mice have the C57BL/6 genetic background and contain an A to G mutation in intron 4 of the endogenous Ighmbp2 gene. This mutation causes aberrant splicing, resulting in only 20-25% of full-length functional protein. Several congenital conditions including hydrocephalus are common in the C57BL/6 background, consistent with our previous observations when developing a gene therapy approach for SMARD1. Additionally, a modifier allele exists on chromosome 13 in nmd mice that can partially suppress the phenotype, resulting in some animals that have extended life spans (up to 200 days). To eliminate the intrinsic complications of the C57BL/6 background and the variation in survival due to the genetic modifier effect, we created a new SMARD1 mouse model that contains the same intron 4 mutation in Ighmbp2 as nmd mice but is now on a FVB congenic background. FVB-nmd are consistently more severe than the original nmd mice with respect to survival, weigh and motor function. The relatively short life span (18-21 days) of FVB-nmd mice allows us to monitor therapeutic efficacy for a variety of novel therapeutics in a timely manner without the complication of the small percentage of longer-lived animals that were observed in our colony of nmd mice.

Camptocormia as the presenting symptom in sporadic late onset nemaline myopathy: a case report.

BACKGROUND: Camptocormia has been reported in a plethora of diseases comprising disorders of the central nervous system, the peripheral nervous system, and the neuromuscular junction as well as hereditary and acquired myopathies. In sporadic late onset nemaline myopathy concomitant axial myopathy is common, but reports about camptocormia as the only presenting symptom in this condition are very rare. Notably, sporadic late onset nemaline myopathy is a potentially treatable condition in particular when associated with monoclonal gammopathy of unknown significance, HIV or rheumatological disorders. CASE PRESENTATION: We report the case of a 62-year-old female patient, who presented with slowly progressive camptocormia. Comprehensive work-up including neurological work-up, laboratory tests, MR-imaging, muscle biopsy and genetic testing led to the diagnosis of sporadic late onset nemaline myopathy. CONCLUSIONS: Our case report highlights that sporadic late onset nemaline myopathy has to be considered in patients presenting with isolated camptocormia and comprehensive work-up of camptocormia is mandatory to ascertain the individual diagnosis, especially in consideration of treatable conditions.

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss.

Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.

Emerging therapies and challenges in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368.

Body height loss characterizes camptocormia in Parkinson's disease.

Axial deformities such as camptocormia or Pisa syndrome in people with Parkinson's disease (PwP) are poorly understood. The scarcity of information may result from the shortage of reliable and responsive evaluation instruments. We evaluated the body height loss (BHL) as a new measure for PwP with axial deformities. 50 PwP with axial deformity defined by an UPDRS item 28 value of at least 2 were included in this mono-center study. We measured body height while lying supine and after 1 min of standing, providing a percentage value of BHL, and compared this measure to other clinical variables. BHL depended on the Hoehn and Yahr clinical stage and correlated with clinical scales for function and mobility, but not with timely measures of the axial disorder such as age at diagnosis or duration of disease. ANOVA showed that only lumbar flexion explained the variability of BHL (F = 21.0, p < 0.0001), but not kyphosis (F = 0.4, p = 0.74) or lateroflexion (F = 0.6, p = 0.6). Re-test reliability of BHL was good with к = 0.76 (p < 0.0001). BHL resulted from the lumbar spine and the hip joint and not from the thoracic spine or lateroflexion. This observation conforms to the concept of upper-type and lower-type camptocormia with only the latter leading to a BHL. The assessment of the BHL is shown to be a well defined, easy to perform, and reliable measure for the clinical evaluation of lower-type camptocormia.

Subthalamic deep brain stimulation and trunk posture in Parkinson's disease.

OBJECTIVES: We sought to assess the efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD)-associated trunk posture abnormalities retrospectively analyzing data from 101 patients reporting mild-to-severe trunk posture abnormalities of a cohort of 216 PD patients treated with STN-DBS at our center. METHODS: Abnormal trunk posture was rated on a scale of 0 (normal) to 4 (marked flexion with an extreme abnormality of posture) as per the grading score reported in the Unified Parkinson's Disease Rating Scale. The independent effect of STN-DBS on trunk posture was assessed comparing Medication-Off (presurgery) vs Stimulation-On/Medication-Off (post-surgery). The combined effect of STN-DBS plus levodopa was evaluated comparing Medication-On (presurgery) vs Stimulation-On/Medication-On (post-surgery). Analyses were conducted considering both the entire cohort of patients and the subgroup with camptocormia (CMC) and Pisa syndrome (PS). RESULTS: The independent effect of STN-DBS resulted in a 41.4% improvement in abnormal trunk posture severity (P < .001), with 78.2% of patients (n = 79) reporting an improvement of at least 1 point. The combined effect of STN-DBS and levodopa resulted in a 30.9% improvement (P = .061), with 54.5% of patients (n = 55) reporting an improvement of at least 1 point. The subanalysis of patients with CMC (n = 23) and PS (n = 5) showed a 42.7% improvement in abnormal posture severity when considering the independent effect of STN-DBS (P < .001) and 30.5% when considering the combined effect of STN-DBS and levodopa (P < .001). CONCLUSIONS: STN-DBS may have the potential for improving posture in patients with advanced PD.

Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy.

Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission.

Effectiveness of spinal cord stimulation for painful camptocormia with Pisa syndrome in Parkinson's disease: a case report.

BACKGROUND: Spinal cord stimulation (SCS) has recently been reported to be effective for truncal postural abnormalities such as camptocormia and Pisa syndrome in Parkinson's disease. In this case report, we describe a case of a woman with Parkinson's disease in whom SCS was effective for painful camptocormia with Pisa syndrome. CASE PRESENTATION: A 65-year-old woman was admitted to our hospital because of painful camptocormia. She had noticed resting tremor in the left upper limb and aprosody at 48 years of age. She was diagnosed as having Parkinson's disease (Hoehn & Yahr stage 1) at 53 years of age. Cabergoline was started during that same year, with subsequent addition of selegiline hydrochloride; the symptoms of parkinsonism disappeared. Wearing-off occurred when she was 57 years old, 3 years after starting carbidopa/levodopa, and truncal postural abnormalities-painful camptocormia with Pisa syndrome to the right-appeared at 58 years of age. These symptoms worsened despite adjustment of her oral medications, and deep brain stimulation (DBS) was performed when she was 60 years old. The truncal postural abnormalities improved after DBS, and she could travel abroad at 61 years of age. However, from 62 years of age, painful camptocormia with Pisa syndrome to the right reappeared. The pain was unsuccessfully treated with oral analgesics, radiofrequency coagulation of the dorsal and medial branches of the lumbar spinal nerve, and lumbar epidural block. Finally, SCS was performed for the pain relief. The pain disappeared immediately after SCS and her posture then gradually improved. Unified Parkinson's Disease Rating Scale score improved from 48 to 34 points and Timed Up and Go Test improved from 15 s to 7 s after SCS. CONCLUSIONS: This case suggests that SCS may be effective for improving painful truncal postural abnormalities and motor complications of Parkinson's disease. Pain relief or a direct effect on the central nervous system by SCS was considered to explain the alleviation of these symptoms.

A case report of thoracolumbar paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism.

BACKGROUND: Camptocormia is severe flexion of the thoracolumbar spine, exaggerated during standing and walking but minimized in supine position. Even though camptocormia is a relatively common condition during the course of Parkinson's disease, there is ongoing controversy concerning its mechanisms. The most widely accepted and yet still disputed one is dystonia. However, based on myopathic changes observed in the paraspinal muscle biopsies of some PD patients with camptocormia, the attempt to attribute camptocormia to myopathy has continued. This case presents evidence for paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism. CASE PRESENTATION: A patient presented with a relatively acute onset of camptocormia and new-onset back pain. Upon examination, she had asymmetric parkinsonism. Magnetic resonance imaging of the lumbar spine revealed alterations in muscle signal intensity in the right paraspinal muscles at the L1-2 level. In the presence of persistent back pain, repeat imaging done two months later showed diffuse enlargement and patchy enhancement of the paraspinal muscles on T1-weighted imaging from T4 through sacrum bilaterally. About fifteen months after the onset of camptocormia, she underwent ultrasound-guided gun biopsy of the paraspinal muscles for evaluation of focal atrophy of the back muscles on the right. The biopsy revealed unmistakable myopathic changes, marked endomysial and perimysial fibrosis of the muscles, and merely mild infiltration of inflammatory cells but no clues regarding the cause of myopathy. On account of persistent back pain and MRI results indicative of ongoing inflammation, she was prescribed glucocorticoid, which she refused to take. Now merely two and a half years after the onset of camptocormia, she is in Hoehn and Yahr stage 4. CONCLUSIONS: The coincidence of back pain with the appearance of camptocormia and the imaging and pathology findings supportive of myopathy give strong evidence for paraspinal myopathy as the cause of the deformity in this patient. When a patient presents with a relatively acute onset of camptocormia accompanied by back pain, the clinician should not overlook the possibility of myopathy of paraspinal muscles, which may be one of the few treatable causes of camptocormia.

Repetitive nerve stimulation as a diagnostic aid for distinguishing cervical spondylotic amyotrophy from amyotrophic lateral sclerosis.

PURPOSE: To identify and compare the features of compound muscle action potential (CMAP) decrements in repetitive nerve stimulation (RNS) in patients with cervical spondylotic amyotrophy (CSA) and in patients with amyotrophic lateral sclerosis (ALS). METHODS: The cohort consisted of 43 CSA (distal-type to proximal-type ratio: 27-16) and 35 ALS patients. Five muscles, including abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), middle deltoid (Del), and upper trapezius (Trap), were tested by 3-Hz RNS. Decrements greater than cutoff values (APB > 5.8%; ADM > 4.8%; BB > 5.2%; Del > 6%; Trap > 5.1%) determined using receiver operating characteristic (ROC) curves were defined as abnormal, and the conventional criterion (≥10%) was also considered. RESULTS: A significant CMAP decrement (>cutoff values) was recorded from at least one tested muscle in 91.4% of ALS patients, and was most common in the proximal muscle, a finding that differed significantly from CSA patients (32.6%, P < 0.05). The application of cutoff values greatly improved the sensitivity of RNS over the conventional criterion (≥10%) for the detection of ALS (P < 0.05). The specificity of this technique remained higher when performing RNS in the proximal muscles, especially in the upper trapezius (AUC = 0.864, sensitivity = 0.643, and specificity = 1.000). The decrement percentages were significantly greater in the proximal muscles of ALS patients than in those of the CSA patients (P < 0.05). In addition, illness duration was not correlated with decrement percentage in either patient group, and no difference in the frequency of decrement among different ALS diagnostic categories was observed (P > 0.05). CONCLUSIONS: The application of RNS, especially in proximal muscles, may provide a simple accurate and noninvasive supplementary test for distinguishing CSA from ALS, even in the early stage of these diseases. A combination of RNS, needle EMG, clinical features and cervical magnetic resonance imaging may yield sufficient diagnostic information to differentiate CSA and ALS.

A large animal model of spinal muscular atrophy and correction of phenotype.

OBJECTIVES: Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers. METHODS: Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed. RESULTS: Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology. INTERPRETATION: High SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset.

Camptocormia in Parkinson's disease: definition, epidemiology, pathogenesis and treatment modalities.

Camptocormia is an axial postural deformity characterised by abnormal thoracolumbar spinal flexion. The symptom usually presents while standing, walking or exercising and is alleviated while sitting, lying in a recumbent position, standing against a wall or using walking support. There is no consensus on the degree of thoracolumbar flexion to define camptocormia. However, most authors usually use an arbitrary number of at least 45° flexion of the thoracolumbar spine when the individual is standing or walking. Aetiologies of camptocormia are heterogeneous, and Parkinson's disease (PD) is one of its many causes. The prevalence of camptocormia in PD ranges from 3% to 18%. Central and peripheral mechanisms might both contribute to its pathogenesis. Although there is no established consensus for treatment of camptocormia in PD, there are non-pharmacological, pharmacological and surgical approaches that can be used.

[Life-threatening hypophosphatemia in 74-year-old woman with recurrent pneumonia and progressive muscular atrophy]. / Zagrazajaca zyciu hipofosfatemia u 74-letniej kobiety z nawracajacym zapaleniem pluc i postepujaca atrofia miesni.

UNLABELLED: Although hypophosphatemia can be a serious threat to health and life, it is a problem rarely taken into consideration in the differential diagnosis in the current clinical practice. The aim of the study was to present the description of hypophosphatemia issues in the context of the threat they may pose to the health and life when undiagnosed. CASE REPORT: 74-year-old internal charged woman , with progressive destruction for a few years, recurrent pneumonia, and a compression fracture of the spine, was admitted to hospital because of fainting and general deterioration. In the course of the performed diagnostics primary hyperparathyroidism was diagnosed with pre-existing inadequate severe hypophosphatemia. Because the presented clinical picture, only partially tie in symptomatology of primary hiperparathyroidism, the diagnostic process was targeted to search for other causes of both hypophosphatemia and symptoms reported by the patient. Finally, in addition to PHPT ( primary hyperparathyroidism) also vitamin D deficiency and tuberculosis was found. The fact that the treatment of infectious disease led to the phosphatemia standardization , and thus to significant improvement of the overall demonstrates, shows the significant contribution of tuberculosis in the pathogenesis of phosphate deficiency in this case. RESULTS: Our case is an example of confirming the need for a thorough and multidirectional analysis of the clinical picture, which is a prerequisite for a correct diagnosis.