Clinical features and molecular genetic investigation of infantile-onset ascending hereditary spastic paralysis (IAHSP) in two Chinese siblings caused by a novel splice site ALS2 variation.

OBJECTIVE: ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts, among which autosomal recessive Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare phenotype. In this study, we gathered clinical data from two Chinese siblings who were affected by IAHSP. Our aim was to assess the potential pathogenicity of the identified variants and analyze their clinical and genetic characteristics. METHOD: Here, Whole-exome sequencing (WES) was performed on proband to identify the candidate variants. Subsequently, Sanger sequencing was used to verify identified candidate variants and to assess co-segregation among available family members. Utilizing both silico prediction and 3D protein modeling, an analysis was conducted to evaluate the potential functional implications of the variants on the encoded protein, and minigene assays were performed to unravel the effect of the variants on the cleavage of pre-mRNA. RESULTS: Both patients were characterized by slurred speech, astasia, inability to walk, scoliosis, lower limb hypertonia, ankle clonus, contracture of joint, foot pronation and no psychomotor retardation was found. Genetic analysis revealed a novel homozygous variant of ALS2, c.1815G > T(p.Lys605Asn) in two Chinese siblings. To our knowledge, it is the first confirmed case of a likely pathogenic variant leading to IAHSP in a Chinese patient. CONCLUSION: This study broadens the range of ALS2 variants and has practical implications for prenatal and postnatal screening of IAHSR. Symptom-based diagnosis of IAHSP is frequently difficult for medical practitioners. WES can be a beneficial resource to identify a particular disorder when the diagnosis cannot be determined from the symptoms alone.

Anatomical Study of Cross-Transfer of the Contralateral C7 Nerve Through the Posterior Epidural Pathway of the Cervical Spine for the Treatment of Spastic Paralysis of the Upper Limbs.

BACKGROUND: This study explored the safety and feasibility of surgical treatment of spastic paralysis of the central upper extremity by contralateral cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine. METHODS: Five fresh head and neck anatomical specimens were employed to simulate contralateral cervical 7 nerve transfer through the posterior epidural pathway of the cervical spine. The relevant anatomical landmarks and surrounding anatomical relationships were observed under a microscope, and the relevant anatomical data were measured and analysed. RESULTS: The posterior cervical incision revealed the cervical 6 and 7 laminae, and lateral exploration revealed the cervical 7 nerve. The length of the cervical 7 nerve outside the intervertebral foramen was measured to be 6.4 ± 0.5 cm. The cervical 6 and cervical 7 laminae were opened with a milling cutter. The cervical 7 nerve was extracted from the inner mouth of the intervertebral foramen, and its length was 7.8 ± 0.3 cm. The shortest distance of the cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine was 3.3 ± 0.3 cm. CONCLUSIONS: Cross-transfer surgery of the contralateral cervical 7 nerve via the posterior epidural pathway of the cervical spine can effectively avoid the risk of nerve and blood vessel damage in anterior cervical nerve 7 transfer surgery; the nerve transfer distance is short, and nerve transplantation is not required. This approach may become a safe and effective procedure for the treatment of central upper limb spastic paralysis.

Lateral Decubitus Supraclavicular Brachial Plexus Block in Transverse Myelitis.

Transverse myelitis is a rare inflammatory condition typically presenting with symptoms like muscle weakness, sensory issues, and problems affecting bowel and bladder function. In this study, we describe the successful anesthesia management of an adult patient with transverse myelitis exhibiting spastic paralysis and compromised cardiopulmonary reserves, whose preferred resting position was lateral decubitus. Targeted anesthesia was administered via a supraclavicular approach to the brachial plexus block for wrist deformity fixation surgery, mitigating the pulmonary complications associated with general anesthesia, achieving earlier recovery, and avoiding the use of opioids. This case underscores the significance of customizing the patient's personalized positioning, while also highlighting the potential for effective regional anesthesia in atypical positions. We illustrate the successful use of supraclavicular brachial plexus block for left wrist deformity fixation and debridement surgery in the lateral decubitus, the most convenient position for the transverse myelitis patient with spastic paraplegia.

Royle's sympathectomy for spastic paralysis: Sorry saga or scientific awakening?

On October 20, 1924, at the Waldorf-Astoria Hotel in New York City, two medical graduates of the University of Sydney delivered the John B. Murphy Oration to the American College of Surgeons on the topic of sympathetic ramisection for the treatment of spastic paralysis. The surgery was regarded as a triumph. The triumph, however, was short-lived, when one of the speakers, John Irvine Hunter, a promising anatomist, died prematurely. Norman Royle, an orthopedic surgeon, continued the research program and continued to perform these operations. Within a few short years, however, the theory of the dual nerve supply of skeletal muscle, which underpinned the procedure, and the results of surgery for spastic paralysis came under question. Nevertheless, Royle's sympathectomy found another indication and became the treatment of choice for peripheral vascular disease for several decades thereafter. Although Hunter and Royle's original work was discredited, their research turned their sorry saga into a scientific awakening of the sympathetic nervous system.

Contralateral C7 nerve transfer via the prespinal route in treatment of spastic paralysis of upper limb after cerebral palsy.

BACKGROUND: Upper limb spasticity leads to different degrees of disabilities in cerebral palsy, which seriously affects the life of patients. Contralateral C7 nerve transfer has been shown to improve function and reduce spasticity in the affected upper limb with post-stroke hemiplegia. However, reports about the efficacy of this procedure in treating upper limb spasticity caused by hemiplegic cerebral palsy were limited. CASE DESCRIPTION: We reported two cases (a 23-year-old male and a 18-year-old female) who suffered from hemiplegic cerebral palsy with unilateral sustained upper limb spasticity and underwent contralateral C7 nerve transfer in adulthood. The scores of Fugel-Meyer and ROM of the affected upper limbs were observed before and after surgery. Compared with the preoperative, scores of the latest follow-up both were significantly improved. The muscle tension of the upper limbs decreased, and the symptoms of spasm were alleviated. CONCLUSIONS: Considering contralateral C7 nerve transfer could effectively relieve spasticity and improve upper limb activity, it can be recommended as one of the reliable methods to manage spasticity and dystonia of upper limbs in patients with hemiplegic cerebral palsy.

Spastic S-shaped sigmoid colon in hemorrhagic GIST.

We treated a 44-year-old man with abdominal pain and melena caused by the gastrointestinal stromal tumor. In this case, computed tomography revealed a spastic S-shaped sigmoid colon, indicating intestinal spastic paralysis secondary to intestinal bleeding. This finding prompted screening colonoscopy for gastrointestinal bleeding.

Personalized Treatment for Infantile Ascending Hereditary Spastic Paralysis Based on In Silico Strategies.

Infantile onset hereditary spastic paralysis (IAHSP) is a rare neurological disease diagnosed in less than 50 children worldwide. It is transmitted with a recessive pattern and originates from mutations of the ALS2 gene, encoding for the protein alsin and involved in differentiation and maintenance of the upper motoneuron. The exact pathogenic mechanisms of IAHSP and other neurodevelopmental diseases are still largely unknown. However, previous studies revealed that, in the cytosolic compartment, alsin is present as an active tetramer, first assembled from dimer pairs. The C-terminal VPS9 domain is a key interaction site for alsin dimerization. Here, we present an innovative drug discovery strategy, which identified a drug candidate to potentially treat a patient harboring two ALS2 mutations: one truncation at lysine 1457 (not considered) and the substitution of arginine 1611 with a tryptophan (R1611W) in the C-terminus VPS9. With a protein modeling approach, we obtained a R1611W mutant model and characterized the impact of the mutation on the stability and flexibility of VPS9. Furthermore, we showed how arginine 1611 is essential for alsin's homo-dimerization and how, when mutated to tryptophan, it leads to an abnormal dimerization pattern, disrupting the formation of active tetramers. Finally, we performed a virtual screening, individuating an already therapy-approved compound (MK4) able to mask the mutant residue and re-establishing the alsin tetramers in HeLa cells. MK4 has now been approved for compassionate use.

[Treatment of finger spasm after stroke with wheat grain moxibustion at Shixuan (EX-UE 11) combined with rehabilitation training: a randomized controlled trial].

OBJECTIVE: To compare the clinical effect of wheat grain moxibustion combined with rehabilitation training and simple rehabilitation training on finger spasm after stroke. METHODS: A total of 80 patients with finger spasm after stroke were randomly divided into an observation group and a control group, 40 cases in each group. The control group was given routine rehabilitation training, once a day, 30 min each time. The observation group was given wheat grain moxibustion at Shixuan (EX-UE 11) on the basis of the control group, 8~10 moxibustion cones at each point, once a day. Both groups were treated for 6 days as one course of treatment for 4 courses. The motor function of the affected hand (Fugl-Meyer assessment [FMA] score) and muscle tension (modified Ashworth scale [MAS] grading), surface EMG indexes (wrist dorsiflexor muscle and flexor carpal metacarpal muscle mean square [RMS] value), hand muscle strength (neurological deficit score [NDS]) and daily living ability (modified Barthel index [MBI] score) were compared between the two groups before and after treatment, and clinical efficacy was evaluated. RESULTS: After treatment, FMA and MBI scores in the 2 groups were increased compared with before treatment (P<0.05), and those in the observation group were higher than the control group (P<0.05). The RMS value of wrist dorsiflexor muscle and flexor carpal metacarpal muscle in relaxation and passive function testsand and NDS in the 2 groups were lower than those before treatment (P<0.05), and those in the observation group were lower than the control group (P<0.05). MAS grading in the 2 groups was improved compared with before treatment (P<0.05), and that in the observation group was better than the control group (P<0.05). The total effective rate of the observation group was 92.5% (37/40), which was higher than that of the control group (80.0%, 32/40, P<0.05). CONCLUSION: Wheat grain moxibustion at Shixuan (EX-UE 11) combined with rehabilitation training can improve the hand motor function and daily living ability of patients with finger spasm after stroke, improve the degree of spasm and the function of wrist dorsiflexor muscle and flexor carpal metacarpal muscle, the clinical effect is better than simple rehabilitation training.

Treatment of finger spasm after stroke with wheat grain moxibustion at Shixuan (EX-UE 11) combined with rehabilitation training: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the clinical effect of wheat grain moxibustion combined with rehabilitation training and simple rehabilitation training on finger spasm after stroke.@*METHODS@#A total of 80 patients with finger spasm after stroke were randomly divided into an observation group and a control group, 40 cases in each group. The control group was given routine rehabilitation training, once a day, 30 min each time. The observation group was given wheat grain moxibustion at Shixuan (EX-UE 11) on the basis of the control group, 8~10 moxibustion cones at each point, once a day. Both groups were treated for 6 days as one course of treatment for 4 courses. The motor function of the affected hand (Fugl-Meyer assessment [FMA] score) and muscle tension (modified Ashworth scale [MAS] grading), surface EMG indexes (wrist dorsiflexor muscle and flexor carpal metacarpal muscle mean square [RMS] value), hand muscle strength (neurological deficit score [NDS]) and daily living ability (modified Barthel index [MBI] score) were compared between the two groups before and after treatment, and clinical efficacy was evaluated.@*RESULTS@#After treatment, FMA and MBI scores in the 2 groups were increased compared with before treatment (P<0.05), and those in the observation group were higher than the control group (P<0.05). The RMS value of wrist dorsiflexor muscle and flexor carpal metacarpal muscle in relaxation and passive function testsand and NDS in the 2 groups were lower than those before treatment (P<0.05), and those in the observation group were lower than the control group (P<0.05). MAS grading in the 2 groups was improved compared with before treatment (P<0.05), and that in the observation group was better than the control group (P<0.05). The total effective rate of the observation group was 92.5% (37/40), which was higher than that of the control group (80.0%, 32/40, P<0.05).@*CONCLUSION@#Wheat grain moxibustion at Shixuan (EX-UE 11) combined with rehabilitation training can improve the hand motor function and daily living ability of patients with finger spasm after stroke, improve the degree of spasm and the function of wrist dorsiflexor muscle and flexor carpal metacarpal muscle, the clinical effect is better than simple rehabilitation training.

A patient with spastic paralysis finally diagnosed as V180I genetic Creutzfeldt-Jakob disease 9 years after onset.

Genetic Creutzfeldt-Jakob disease (gCJD) with a mutation in codon 180 of the prion protein gene (V180I gCJD) is the most common form of gCJD in Japan, but only a few cases have been reported in Europe and the United States. It is clinically characterized by occurring in the elderly and presenting as slowly progressive dementia, although it generally shows less cerebellar and pyramidal symptoms than sporadic CJD. Here, we report a patient with V180I gCJD who initially presented with slowly progressive spastic paralysis with neither cerebrospinal fluid (CSF) nor magnetic resonance imaging (MRI) abnormalities. His symptoms progressed gradually, and after 9 years, he displayed features more typical of CJD. Diffusion-weighted MRI revealed high-intensity signals in the cortical gyrus, and there was a marked increase of 14-3-3 protein and total tau protein in the CSF, but he was negative for the real-time quaking-induced conversion assay. Although the time course was more consistent with Gerstmann-Sträussler-Scheinker disease than CJD, genetic testing revealed V180I gCJD. This is the first report of a patient with V180I gCJD who initially presented with spastic paralysis, and also the first to reveal that it took 9 years from disease onset for cortical dysfunction to develop and for MRI and CSF abnormalities to be detectable. In conclusion, we should screen for V180I gCJD in elderly patients presenting with slowly progressive spastic paralysis.

[Therapeutic effect on post-stroke spastic paralysis of upper extremity treated with combination of kinematic-acupuncture therapy and rehabilitation training].

OBJECTIVE: To compare the clinical therapeutic effect on post-stroke spastic paralysis of the upper extremity between the combination of kinematic-acupuncture therapy and rehabilitation training and the combined treatment of the conventional acupuncture with rehabilitation training. METHODS: A total of 60 patients of post-stroke spastic paralysis of the upper extremity at the non-acute stage were randomized into an observation group (30 cases) and a control group (30 cases, 1 case dropped off). On the base of the routine western medication and rehabilitation treatment, the kinematic-acupuncture therapy was added in the observation group and the conventional acupuncture was used in the control group. Baihui (GV 20), Dazhui (GV 14), Jiaji (EX-B 2) from T1 to T8, Tianzong (SI 11), Jianzhen (SI 9), Jianyu (LI 15) and Quyuan (SI 13) were selected in both groups. The treatment was given once daily and the treatment for 14 days was as one course. The one course of treatment was required in this research. Separately, before treatment and in 7 and 14 days of treatment, the score of simplified Fugl-Meyer scale of the upper extremity (FMA-UE), the grade of the modified Ashworth scale (MAS) and the score of the modified Barthel index scale (MBI) were compared between the two groups. RESULTS: Compared before treatment, in 7 and 14 days of treatment, FMA-UE score was increased obviously in either group (P<0.01). In 14 days of treatment, FMA-UE score in the observation group was higher than that in the control group (P<0.05). In 7 and 14 days of treatment, MAS grades of shoulder joint, elbow joint, wrist joint and metacarpophalangeal joint were all improved markedly in the two groups (P<0.05). Compared with the grades in 7 days of treatment, MAS grades of elbow joint and metacarpophalangeal joint were improved markedly in 14 days of treatment in the two groups (P<0.05). Compared with the control group, MAS grades of elbow joint and metacarpophalangeal joint were improved more markedly in the observation group in 14 days of treatment (P<0.05). Compared with the score before treatment, MBI score was increased in 7 and 14 days of treatment respectively in the observation group (P<0.05, P<0.01). In 14 days of treatment, MBI score was increased in the control group (P<0.01). CONCLUSION: For the patients with post-stroke spastic paralysis of the upper extremity at the non-acute stage, the combined treatment with kinematic-acupuncture therapy and rehabilitation training obviously improves the motor function of the upper extremity and the muscle tone of elbow joint and metacarpophalangeal joint. The therapeutic effect of this combination is better than that of the combined treatment of the conventional acupuncture with rehabilitation training. Additionally, this combined therapy improves the ability of daily life activity.

Therapeutic effect on post-stroke spastic paralysis of upper extremity treated with combination of kinematic-acupuncture therapy and rehabilitation training / 中国针灸

OBJECTIVE@#To compare the clinical therapeutic effect on post-stroke spastic paralysis of the upper extremity between the combination of kinematic-acupuncture therapy and rehabilitation training and the combined treatment of the conventional acupuncture with rehabilitation training.@*METHODS@#A total of 60 patients of post-stroke spastic paralysis of the upper extremity at the non-acute stage were randomized into an observation group (30 cases) and a control group (30 cases, 1 case dropped off). On the base of the routine western medication and rehabilitation treatment, the kinematic-acupuncture therapy was added in the observation group and the conventional acupuncture was used in the control group. Baihui (GV 20), Dazhui (GV 14), Jiaji (EX-B 2) from T to T, Tianzong (SI 11), Jianzhen (SI 9), Jianyu (LI 15) and Quyuan (SI 13) were selected in both groups. The treatment was given once daily and the treatment for 14 days was as one course. The one course of treatment was required in this research. Separately, before treatment and in 7 and 14 days of treatment, the score of simplified Fugl-Meyer scale of the upper extremity (FMA-UE), the grade of the modified Ashworth scale (MAS) and the score of the modified Barthel index scale (MBI) were compared between the two groups.@*RESULTS@#Compared before treatment, in 7 and 14 days of treatment, FMA-UE score was increased obviously in either group (<0.01). In 14 days of treatment, FMA-UE score in the observation group was higher than that in the control group (<0.05). In 7 and 14 days of treatment, MAS grades of shoulder joint, elbow joint, wrist joint and metacarpophalangeal joint were all improved markedly in the two groups (<0.05). Compared with the grades in 7 days of treatment, MAS grades of elbow joint and metacarpophalangeal joint were improved markedly in 14 days of treatment in the two groups (<0.05). Compared with the control group, MAS grades of elbow joint and metacarpophalangeal joint were improved more markedly in the observation group in 14 days of treatment (<0.05). Compared with the score before treatment, MBI score was increased in 7 and 14 days of treatment respectively in the observation group (<0.05, <0.01). In 14 days of treatment, MBI score was increased in the control group (<0.01).@*CONCLUSION@#For the patients with post-stroke spastic paralysis of the upper extremity at the non-acute stage, the combined treatment with kinematic-acupuncture therapy and rehabilitation training obviously improves the motor function of the upper extremity and the muscle tone of elbow joint and metacarpophalangeal joint. The therapeutic effect of this combination is better than that of the combined treatment of the conventional acupuncture with rehabilitation training. Additionally, this combined therapy improves the ability of daily life activity.

[Observation on the curative effect of articular needling at Sifeng (EX-UE 10) on finger spastic paralysis after stroke].

OBJECTIVE: To observe the improved effects of articular needling at Sifeng (EX-UE 10) on finger spastic paralysis after stroke on the basis of conventional treatment. METHODS: Sixty-four patients were randomly divided into an observation group and a control group, 32 cases in each group. Both groups were treated with conventional drugs, and in the control group, conventional acupuncture was treated. On the basis of the treatment in the control group, articular needling at Sifeng (EX-UE 10) was applied in the observation group. The treatment was given once everyday for 6 days with one day interval, and a total of two weeks were needed. The finger scores in the Fugl-Meyer evaluation scale (FMA), the Brunnstrom motor function rating, and the modified Ashworth spasm rating were observed before and after treatment. RESULTS: After treatment, the Fugl-Meyer scores in the two groups were higher than those before treatment (P<0.01). The Fugl-Meyer score in the observation group was higher than that in the control group (P<0.01). The results of Brunnstrom motor function rating and the modified Ashworth spasm rating were improved in the two groups (P<0.01, P<0.05), and the observation group was superior to the control group (P<0.01). CONCLUSION: The articular needling at Sifeng (EX-UE 10) can effectively improve the condition of finger spastic paralysis.

Fire-needle acupuncture for upper limb spastic paralysis after stroke: Study protocol for a randomized controlled trial.

BACKGROUND: Fire-needle acupuncture, an important kind of acupuncture therapy, has been clinically used to treat upper limb spastic paralysis (ULSP) after stroke. Clinical experience has indicated that fire-needle acupuncture treatment takes less time, requires fewer visits, and has more rapid results and fewer side effects compared to chemical medicine alternatives. This study will evaluate the effects of fire-needle acupuncture for ULSP in the context of standardized clinical research and provide high-quality data to inform clinical procedures and future study design. METHODS/DESIGN: A randomized controlled trial will be carried out to evaluate the effects of fire-needle acupuncture therapy in patients with ULSP from stroke. ULSP patients (n = 120) will be recruited at Changhai Hospital in Shanghai, China. Patients will be randomly divided into three groups, including fire-needle acupuncture group (FAG), filiform-needle acupuncture group (FFAG) and rehabilitation treatment group (RTG). During the 3-week treatment, the FAG will be treated every two days, while FFAG and RTG will be treated 5 d in a row and then rest for 2 d. The Simplified Fugl-Meyer Motor Function Scale and Modified Ashworth Scale will be used as the primary outcome measures. Statistical analysis will be conducted by an independent statistician. DISCUSSION: Through this study, the utility of fire-needle acupuncture in treating ULSP after stroke will be tested, and some specific claims of fire-needle acupuncture therapy will be evaluated, such as relieving spasm and muscular tension, improving activities of daily living, rapidity of response and less frequency of treatment compared with other treatments. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR-IOR-17013875; registration date: 28 December 2016).

Observation on the curative effect of articular needling at Sifeng (EX-UE 10) on finger spastic paralysis after stroke / 中国针灸

OBJECTIVE@#To observe the improved effects of articular needling at Sifeng (EX-UE 10) on finger spastic paralysis after stroke on the basis of conventional treatment.@*METHODS@#Sixty-four patients were randomly divided into an observation group and a control group, 32 cases in each group. Both groups were treated with conventional drugs, and in the control group, conventional acupuncture was treated. On the basis of the treatment in the control group, articular needling at Sifeng (EX-UE 10) was applied in the observation group. The treatment was given once everyday for 6 days with one day interval, and a total of two weeks were needed. The finger scores in the Fugl-Meyer evaluation scale (FMA), the Brunnstrom motor function rating, and the modified Ashworth spasm rating were observed before and after treatment.@*RESULTS@#After treatment, the Fugl-Meyer scores in the two groups were higher than those before treatment (<0.01). The Fugl-Meyer score in the observation group was higher than that in the control group (<0.01). The results of Brunnstrom motor function rating and the modified Ashworth spasm rating were improved in the two groups (<0.01, <0.05), and the observation group was superior to the control group (<0.01).@*CONCLUSION@#The articular needling at Sifeng (EX-UE 10) can effectively improve the condition of finger spastic paralysis.

Fire-needle acupuncture for upper limb spastic paralysis after stroke: Study protocol for a randomized controlled trial / 中西医结合学报

BACKGROUND@#Fire-needle acupuncture, an important kind of acupuncture therapy, has been clinically used to treat upper limb spastic paralysis (ULSP) after stroke. Clinical experience has indicated that fire-needle acupuncture treatment takes less time, requires fewer visits, and has more rapid results and fewer side effects compared to chemical medicine alternatives. This study will evaluate the effects of fire-needle acupuncture for ULSP in the context of standardized clinical research and provide high-quality data to inform clinical procedures and future study design.@*METHODS/DESIGN@#A randomized controlled trial will be carried out to evaluate the effects of fire-needle acupuncture therapy in patients with ULSP from stroke. ULSP patients (n = 120) will be recruited at Changhai Hospital in Shanghai, China. Patients will be randomly divided into three groups, including fire-needle acupuncture group (FAG), filiform-needle acupuncture group (FFAG) and rehabilitation treatment group (RTG). During the 3-week treatment, the FAG will be treated every two days, while FFAG and RTG will be treated 5 d in a row and then rest for 2 d. The Simplified Fugl-Meyer Motor Function Scale and Modified Ashworth Scale will be used as the primary outcome measures. Statistical analysis will be conducted by an independent statistician.@*DISCUSSION@#Through this study, the utility of fire-needle acupuncture in treating ULSP after stroke will be tested, and some specific claims of fire-needle acupuncture therapy will be evaluated, such as relieving spasm and muscular tension, improving activities of daily living, rapidity of response and less frequency of treatment compared with other treatments.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry (identifier: ChiCTR-IOR-17013875; registration date: 28 December 2016).

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis.

Spinal cord ischemia and reperfusion (SCIR) injury can lead to neurologic dysfunction and paraplegia, which are serious complications after shock or thoracoabdominal aortic surgery. Autophagy is a fundamental cellular process in eukaryotes, and homeostasis of autophagic activities in the cytoplasm is critical for the maintenance of neuronal function. To date, no studies have addressed the involvement of autophagy in the regulation of motor neurons in the ventral horn of the spinal cord area following SCIR-induced spastic paralysis or the underlying mechanisms of this process. In this study, we investigated spastic paralysis in rats following SCIR injury. The number of autophagosomes increased 3 h following the injury, and subsequently decreased slowly to near-normal levels in the sham group as indicated by the autophagy markers microtubule-associated protein 1 light chain 3 (LC3), beclin-1, and p62. Furthermore, after treatment with the autophagy inhibitor 3-Methyladenine (3-MA) and autophagy activator rapamycin following SCIR, autophagy in the SCIR-3-MA group decreased significantly, while that in the SCIR-Rap group increased, compared with SCIR-DMSO controls group. Moreover, the assessment of motor neurons function, using Reuter's score and motor evoked potentials (MEP) and somatosensory evoked potentials (SEP), indicated that promoting autophagy reduced scores compared with SCIR controls, while inhibiting autophagy increased the scores, and hence motor neurons function. Autophagy in the SCIR model protected motor neurons function and morphology. These results would provide more evidences for better understanding function of autophagy in motor neurons degeneration and mechanisms underlying spastic paralysis. Autophagy would be a novel target for prevention and therapy in SCIR damage.