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BMJ Case Rep ; 16(2)2023 Feb 03.
Article in English | MEDLINE | ID: covidwho-2232658


We describe the first case of anti-CV2 paraneoplastic polyneuropathy associated with lung adenocarcinoma. Our patient presented with progressive unsteadiness and numbness involving bilateral upper and lower limbs. He had symmetrical length-dependent lower motor neuron pattern of weakness and numbness involving both small and large fibres with prominent sensory ataxia. An extended workup for the polyneuropathy involving a serum paraneoplastic antineuronal antibody panel showed a positive reaction for anti-CV2 antibody. CT scan of the thorax, abdomen and pelvis revealed a right upper lung nodule and histopathological examination of the nodule revealed lung adenocarcinoma. He was scheduled for chemotherapy following his discharge and there was improvement of his sensorimotor polyneuropathy following his chemotherapy.

Adenocarcinoma of Lung , Lung Neoplasms , Paraneoplastic Polyneuropathy , Male , Humans , Paraneoplastic Polyneuropathy/etiology , Hypesthesia , Adenocarcinoma of Lung/complications , Motor Neurons/pathology , Lung Neoplasms/pathology , Autoantibodies
Muscle Nerve ; 65(5): 498-507, 2022 05.
Article in English | MEDLINE | ID: covidwho-1813581


Spinal muscular atrophy (SMA) is a group of neurodegenerative disorders resulting from the loss of spinal motor neurons. 95% of patients share a pathogenic mechanism of loss of survival motor neuron (SMN) 1 protein expression due to homozygous deletions or other mutations of the SMN1 gene, with the different phenotypes influenced by variable copy numbers of the SMN2 gene. Advances in supportive care, disease modifying treatment and novel gene therapies have led to an increase in the prevalence of SMA, with a third of SMA patients now represented by adults. Despite the growing number of adult patients, consensus on the management of SMA has focused primarily on the pediatric population. As the disease burden is vastly different in adult SMA, an approach to treatment must be tailored to their unique needs. This review will focus on the management of the adult SMA patient as they age and will discuss proper transition of care from a pediatric to adult center, including the need for continued monitoring for osteoporosis, scoliosis, malnutrition, and declining mobility and functioning. As in the pediatric population, multidisciplinary care remains the best approach to the management of adult SMA. Novel and emerging therapies such as nusinersen and risdiplam provide hope for these patients, though these medications are of uncertain efficacy in this population and require additional study.

Muscular Atrophy, Spinal , Adult , Genetic Therapy , Homozygote , Humans , Motor Neurons/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/therapy , Phenotype , Survival of Motor Neuron 1 Protein/genetics
Am J Hum Genet ; 107(4): 763-777, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-758482


Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

Axons/metabolism , Charcot-Marie-Tooth Disease/genetics , Guanine Nucleotide Exchange Factors/genetics , Muscle Weakness/genetics , Muscular Atrophy, Spinal/genetics , Musculoskeletal Abnormalities/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Animals , Axons/pathology , COP-Coated Vesicles/metabolism , COP-Coated Vesicles/pathology , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression , Golgi Apparatus/metabolism , Golgi Apparatus/pathology , Guanine Nucleotide Exchange Factors/metabolism , Heterozygote , Humans , Male , Mice , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Motor Neurons/metabolism , Motor Neurons/pathology , Muscle Weakness/diagnosis , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/pathology , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/metabolism , Musculoskeletal Abnormalities/pathology , Mutation , Pedigree , Primary Cell Culture , Spinal Cord/abnormalities , Spinal Cord/metabolism