Objective: To present the first genetically characterized non-linear summative damage characterized case resulting in early-onset parkinsonism associated with congenital myasthenia

Background: The GAK (Cyclin G Associated Kinase) gene is involved in vesicle trafficking and clathrin-mediated endocytosis. Its mutations are related to autosomal recessive early-onset Parkinson’s disease 15 (PARK15). This rare disorder presents with Parkinsonian and pyramidal symptoms, including tremors, bradykinesia, rigidity, spasticity, and hyperreflexia. GAK interacts with cyclin G and CDK5, influencing neuronal function and protein homeostasis, thus contributing to Parkinson’s pathogenesis.

SCN4A (Sodium Voltage-Gated Channel Alpha Subunit 4) mutations lead to congenital myasthenic syndrome and periodic paralysis, a congenital sodium channelopathy affecting muscle function. The presence of both mutations may result in early-onset parkinsonism and myasthenic symptoms.

Method: We present the case of a 52-year-old female who developed progressive parkinsonian-type and neuromuscular symptoms following a SARS-CoV-2 infection. We conducted a thorough clinical examination, electrophysiological, laboratory, and genetic studies to assess the extent and nature of her condition.

Results: The patient presented with generalized weakness, intention tremor with onset in the lower limbs, distal predominant cramps, paresthesias, and dysesthesias. Other symptoms included recurrent headache, insomnia, acute weight loss, and muscle atrophy, and memory loss.

Physical examination revealed somnolence, hypo-reactive pupils, bilateral Marinescu’s reflex, muscle strength 3/5 X4, positive repetitive nerve stimulation test, deep tendon reflexes 2/4 X4, atrophy in the thenar and interosseous muscles, myotonic phenomenon, and fasciculations. Whole exome sequencing revealed non-linear summative heterozygous mutations of the SCN4A (50%) gene and GAK (47%) gene mutations.

Conclusion: This is the first case report of non-linear summative genetic damage between GAK and SCN4A mutations in a complex neuromuscular disorder, demonstrating overlapping features of congenital myopathy/myasthenic syndrome and early-onset parkinsonism in a Peruvian woman worldwide. The post-infectious worsening of symptoms suggests that SARS-CoV-2 acted as a significant disease-modifying factor, exacerbating pre-existing underlying genetic vulnerabilities.

References: 1.- GAK Gene, Cyclin G Associated Kinase [Internet]. LifeMap Sciences; 2024 Dec 25 [cited 2025 Mar 13]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=GAK
2.- SCN4A Gene, Sodium Voltage-Gated Channel Alpha Subunit 4 [Internet]. LifeMap Sciences; 2024 Dec 25 [cited 2025 Mar 13]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=SCN4A
3.- SCN4A-related congenital myopathy in a Han Chinese patient: A case report and literature review [Internet]. National Library of Medicine PubMed; 2023 Dec 11 [cited 2025 Mar 14]. Available from: https://pubmed.ncbi.nlm.nih.gov/38187266/
4.- Molecular-genetic studies of inherited myotonic conditions in Costa Rica [Internet]. University of Costa Rica; 2021 Nov 05 [cited 2025 Mar 14]. Available from: https://www.redalyc.org/journal/446/44670274019/html/
5.- Novel compound heterozygous mutations in SCN4A as a potential genetic cause contributing to myopathic manifestations: A case report and literature review [Internet]. National Library of Medicine PubMed; 2024 Mar 22 [cited 2025 Mar 14]. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10988054/
6.- Kosmanopoulos GP, Donohue JK, Hoke M, Thomas S, Peyton MA, Vo L, Crawford TO, Sadjadi R, Herrmann DN, Yum SW, Reilly MM, Scherer SS, Finkel RS, Lewis RA, Pareyson D, Pisciotta C, Walk D, Shy ME, Sumner CJ; Inherited Neuropathies Consortium – Rare Disease Clinical Research Network; McCray BA. TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations. Brain. 2025 Jan 7;148(1):238-251. doi: 10.1093/brain/awae201. PMID: 38917025.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-unique-genetic-duality-gak-and-scn4a-mutations-in-myasthenic-syndrome-and-early-onset-parkinsonism-in-a-peruvian-woman-a-case-report/