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Neurological Sciences : Official... Jun 2024Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS)...
Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.
PubMed: 38943019
DOI: 10.1007/s10072-024-07674-7 -
Nature Medicine Jun 2024There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We...
There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .
PubMed: 38942994
DOI: 10.1038/s41591-024-03078-4 -
Boletin Medico Del Hospital Infantil de... 2024Transverse myelitis (TM) is a demyelinating inflammatory disease that presents with motor, sensory, and autonomic dysfunction, which may be acute or subacute....
BACKGROUND
Transverse myelitis (TM) is a demyelinating inflammatory disease that presents with motor, sensory, and autonomic dysfunction, which may be acute or subacute. COVID-19-associated TM has been described in a scarce number of patients.
CLINICAL CASE
A 15-year-old previously healthy male patient with respiratory disease before his neurological deterioration presented to the emergency room after developing a complete medullary syndrome located at the cervical-dorsal level, with ascending and symmetric paraparesis that rapidly progressed to paraplegia, with sensory dysfunction from the T3 level, sphincter dysfunction and sudden ventilatory deterioration that required mechanical ventilation. Magnetic resonance imaging was compatible with acute TM. Inflammatory and non-inflammatory etiologies were discarded. In addition, a positive severe acute respiratory syndrome coronavirus 2 test was obtained. Treatment included steroid pulses and plasmapheresis, with an insidious evolution.
CONCLUSION
COVID-19 is an infrequent cause of TM and should be suspected when other etiologies have been ruled out.
Topics: Humans; Myelitis, Transverse; COVID-19; Male; Adolescent; Magnetic Resonance Imaging; Plasmapheresis; Respiration, Artificial; Paraplegia; Paraparesis
PubMed: 38941642
DOI: 10.24875/BMHIM.23000179 -
Movement Disorders Clinical Practice Jun 2024
PubMed: 38940375
DOI: 10.1002/mdc3.14153 -
Journal of Integrative Neuroscience Jun 2024
Topics: Humans; Spastic Paraplegia, Hereditary
PubMed: 38940092
DOI: 10.31083/j.jin2306115 -
Molecular Genetics & Genomic Medicine Jun 2024Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11...
BACKGROUND
Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).
METHODS
The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.
RESULTS
CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.
CONCLUSION
We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
Topics: Humans; Female; Adult; Spastic Paraplegia, Hereditary; Exons; Proteins; Codon, Nonsense; Corpus Callosum; Sequence Deletion; Phenotype
PubMed: 38938072
DOI: 10.1002/mgg3.2475 -
Journal of Orthopaedic Surgery and... Jun 2024The incidence of cervical spinal brucellosis is low, only a few case reports have been published, and case series are not widely reported in the medical literature....
BACKGROUND
The incidence of cervical spinal brucellosis is low, only a few case reports have been published, and case series are not widely reported in the medical literature. Therefore, clinical features, management, and outcomes of cervical spinal brucellosis are relatively unknown. In this series, the authors report 15 cases of patients with cervical spinal brucellosis, including clinical characteristic, imaging findings, management plans, the institution's experience, and outcomes at 1 year postoperatively.
METHODS
The study reviewed the clinical and radiographic records of 15 patients who received antimicrobial pharmacotherapy, and anterior cervical debridement and fusion for cervical spinal brucellosis. The data collected included patient demographic characteristics, spinal level affected, abscess, neurology, pathological reports, duration and type of antimicrobial regimens, details of orthopedic management, and complications incurred during the procedure.
RESULTS
Neck pain (100%) and limb paralysis (86.7%) were the most common clinical presentations, and the disease had a rapid progression. The C6-7 segment was the most commonly affected segment, followed by C4-5 and C5-6. Imaging commonly revealed epidural or paravertebral abscesses (80%). There was a significant improvement in the VAS, JOA, and NDI scores three months after surgery, and the scores continued to improve until the final follow-up. There was a statistically significant difference between the pre- and postoperative scores (P < 0.05). The ESR and CRP levels returned to normal within three months postoperatively, being 7.7 ± 4.5 mm/h and 7.55 ± 3.48 mg/L, respectively. There were statistically significant differences between the pre- and postoperative levels (P < 0.05). The positive rate of bacterial culture testing of pus or lesion tissues was only 40%, but blood cultures revealed an even lower positivity rate (33.3%). The average antimicrobial pharmacotherapy regimen duration was 6.1 ± 1.9 months. All patients achieved intervertebral bone fusion within 8 months (4.8 ± 1.4 months) after surgery and were cured with non-recurrence.
CONCLUSIONS
Spinal brucellosis rarely affects the cervical region, but its impact is more dangerous due to potential complications such as paraplegia or tetraplegia arising from epidural abscesses that compress the spinal cord. Surgical debridement, along with essential antimicrobial therapy, is an effective strategy and can lead to satisfactory prognosis in managing cervical spinal brucellosis.
Topics: Humans; Male; Brucellosis; Retrospective Studies; Female; Middle Aged; Adult; Cervical Vertebrae; Follow-Up Studies; Treatment Outcome; Aged; Spinal Fusion; Debridement; Cohort Studies; Anti-Bacterial Agents; Time Factors
PubMed: 38937747
DOI: 10.1186/s13018-024-04868-9 -
Aktuelle Urologie Jun 2024Integrity, control and regulation of the urinary tract are subject to a complex neuronal regulation, in which portions of the sympathetic, parasympathetic and somatic...
Integrity, control and regulation of the urinary tract are subject to a complex neuronal regulation, in which portions of the sympathetic, parasympathetic and somatic nervous system are involved. The spinal cord plays a central role in regulation and serves as a transmitter for the motor and sensory pathways. Bladder dysfunction followed by renal dysfunction was the most frequent cause of death in patients with spinal cord injuries/diseases (paraplegia) as recently as half a decade ago. Thanks mainly to diagnostic and therapeutic advances made in neuro-urology, urological problems are no longer life-limiting. A vital role is played not only by the actual function of the urinary tract but also by the complex interactions in patients living with paraplegia. Issues such undertreated hyperactivity of the detrusor muscle with autonomous dysregulation, incontinence with secondary skin changes, or insufficient hand function to perform intermittent catheterisation must be evaluated in an interdisciplinary approach. Spinal cord injury/disease implies numerous functional disorders and secondary impairments of the organism. In addition to bladder function, sexual dysfunction also plays a crucial role. Especially in younger patients who sustain paraplegia before or during the family planning phase, this disruption and limitation is an essential reason for reduced quality of life. Neurogenic intestinal function plays an additional crucial role with regard to quality of life and management of everyday life. In recent years, the range of neuro-urological topics has expanded significantly. The focus of our work shifted from being merely on the urinary tract and urodynamics. In particular, the diagnostic investigation and treatment of neurogenic intestinal dysfunction is increasingly in the hands of neuro-urologists. The complex presentation of paraplegia involves an interaction of bladder, intestinal and sexual dysfunction in a way that these influence one another. Therefore, the sustained care and re-integration of these patients essentially includes lifelong and regular neuro-urological care in a paraplegia centre. Last but not least, it is exactly these neuro-urological topics such as urinary tract infections, urinary and intestinal incontinence and faecal impaction, which most commonly lead to re-hospitalisation.
PubMed: 38936415
DOI: 10.1055/a-2252-0323 -
Journal of Movement Disorders Jun 2024
PubMed: 38932635
DOI: 10.14802/jmd.24022 -
Journal of Cardiothoracic Surgery Jun 2024For acute type A aortic dissection involving the aortic root with root diameter no more than 45 mm, there are various aortic root repair techniques. In this study, a...
BACKGROUND
For acute type A aortic dissection involving the aortic root with root diameter no more than 45 mm, there are various aortic root repair techniques. In this study, a novel surgical technique using a pericardial autograft for aortic root repair was introduced. We described its surgical steps in detail and compare its clinical outcomes with direct suture technique.
METHODS
Between July 2017 and August 2022, 95 patients with acute type A aortic dissection who underwent aortic root repair were enrolled, including aortic root repair using pericardial autograft (group A, n = 49) or direct suture (group B, n = 46). The patient's clinical data were retrospectively analyzed, and a 5-year follow-up was conducted.
RESULTS
The 30-day mortality, re-exploration for bleeding, postoperative new-onset renal failure requiring continuous renal replacement therapy, stroke, and paraplegia occurred in 3%, 4%, 11%, 5%, and 2% of the overall patients, respectively. There was no significant difference in the 30-day mortality and complication rate between the two groups. The 30-day mortality and re-exploration for bleeding marked the primary endpoint events. Logistic regression analysis indicated that there was a significant correlation between the primary endpoint events and surgical technique (odds ratio, 0.002; 95% confidence interval, 0-0.159; P = 0.026). The aortic valve insufficiency of the two groups were significantly improved after operation (group A, P < 0.001; group B, P < 0.001). During follow-up, there was no significant difference in short-term survival between the two groups after surgery (log-rank P = 0.75), and all patients were free from reoperation for aortic disease.
CONCLUSIONS
Patients who underwent aortic root repair using pericardial autograft tended to have reduced 30-day mortality and a lower risk of re-exploration for bleeding. Using pericardial autograft for aortic root repair is a safe and useful approach for patients with acute type A aortic dissection involving the aortic root.
Topics: Humans; Aortic Dissection; Male; Female; Retrospective Studies; Middle Aged; Pericardium; Treatment Outcome; Autografts; Aortic Aneurysm, Thoracic; Aged; Acute Disease; Postoperative Complications; Blood Vessel Prosthesis Implantation; Transplantation, Autologous; Follow-Up Studies
PubMed: 38926836
DOI: 10.1186/s13019-024-02909-2