Objective: To report a GYG1 mutation in a Peruvian family presenting as a non classified Spinocerebellar Ataxia (SCA) with added GEMIN5, DES and TPM3 mutations.

Background: SCA, a group of neurodegenerative ataxic disorders with autosomal dominant inheritance, are characterized by unsteadiness, lack of coordination and dysarthria. As we have already reported; GYG1 is mostly expressed in muscle, and is involved in enzymatic branching of glycogen synthesis; its mutations have been associated with ataxia and polyglucosan body myopathy [1]. GEMIN5, a component of the survival motor assembly neuron complex, in charge of spliceosome assembly and snRNP transport [2], its mutation, can cause cerebellar syndrome, ataxia, tremor, and hypotonia, and motor neuron disease in adults. Furthermore, DES (desmin) proteins form stable filamentous networks connecting myofibrils to each other and to the plasma membrane, mutations produce desmin-related myopathy, a familial cardiac and skeletal myopathy, with distal myopathies. Finally, TPM3 gene stabilizes cytoskeleton actin filaments in non-muscle cells. The mutation may lead to nemaline myopathy [3], characterized by variable muscle weakness [4] causing global hypotonia and diffuse axial weakness, including neck and limb girdle and foot dorsiflexion weakness [5].

Method: 4 members of a Peruvian family of 5, with extensive past familiar history of 13 affected members reported in the family tree presented to the clinic complaining of Parkinsonism symptoms [figure 1]. Symptoms included tremor, rigidity, spasticity, dysarthria, upper limb weakness, hyperekplexia and ataxia. Physical examination of the individuals showed left hand dystonia, bilateral Hoffman, positive Romberg, gait ataxia and tandem gait difficulty. Whole exome sequencing identified mutations in GYG1 in three patients who presented with similar clinical findings,  GEMIN5 in two of them, and DES, and TPM3 the latter one presenting also with diplopia, progressive loss of vision and vertigo [table1].

Results: Patients received physical therapy as well as treatment with AChEIs,  dopamine, GABA agonists, curcuminoids and antioxidants. They have been under close monitoring, two of them with progressive symptoms.

Conclusion: This is the first case report to demonstrate that GYG1 mutations can present as a Non classified SCA like symptoms in a Peruvian familiar cohort.

Table 1 Clinical Features and genetic Testing

Figure 1 Family tree

References: Escalante A,, Trillo w. et al. Non classified SCA-like presentation of GEMIN5 + GYG-1 mutation. Case report. Mov Disord. 2023;38(suppl 1). Available from: https://www.mdsabstracts.org/abstract/non-classified-sca- like-presentation-of-gemin5-gyg-1-mutation-case-report/.
2. Jiang D, et al. Gemin5 plays a role in unassembled-U1 snRNA disposal in SMN-deficient cells. FEBS Lett. 2018 Apr;592(8):1400-1411. Available from: https://pubmed.ncbi.nlm.nih.gov/29537490/
3. Kuruba B et al. Structural effects of disease-related mutations in actin-binding period 3 of tropomyosin. Molecules. 2021;26(22):6980. Available from: http://dx.doi.org/10.3390/molecules26226980
4. Lambert, M.R., Gussoni, E. Tropomyosin 3 (TPM3) function in skeletal muscle and in myopathy. Skelet Muscle. 2023 Nov 7;13(1):18. Available from: https://pubmed.ncbi.nlm.nih.gov/37936227/
5. Bevilacqua JA et al. Novel autosomal dominant TPM3 mutation causes a combined congenital fiber type disproportion-cap disease histological pattern. Neuromuscul Disord. 2022 Aug;32(8):687-691. Available from: https://pubmed.ncbi.nlm.nih.gov/35688744/

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MDS Abstracts - https://www.mdsabstracts.org/abstract/non-classified-spinocerebellar-ataxia-like-syndrome-due-to-gyg-1-gene-mutation-with-tpm3-gemin5-and-des-mutations-in-a-peruvian-family/