Orphan disease: features of difficult to diagnose and genetically verified muscular dystrophy based on DNA sequencing results (clinical case)

Currently, orphan diseases are rarely diagnosed due to low patient awareness, heterogeneity of symptoms, low publication activity of specialists who may encounter orphan pathology, and limited availability of molecular genetic technologies for verifying the human genome/exome. The clinical case is presented in the form of a detailed interdisciplinary examination of the patient within the framework of the genetic, neurological, radiological and neurophysiological profiles. At the same time, the work shows the clinical and laboratory-instrumental diversity of signs of a hereditary pathological process with neurogenic and myogenic manifestations. The peculiarity of the clinical case of the orphan disease is the rarity of its occurrence, as a consequence of the impossibility of diagnosing it by routine methods.

The patient was diagnosed with myofibrillar myopathy (type 1) taking into account the identified criteria: onset at theageof 20-40, burdenedgenealogical history onthefather’s side, progressive muscle weakness, distal muscle group of the legs, hypotrophy, paresis, initial cardiosclerosis, incomplete right bundle branch block, supraventricular extrasystoles, ischemic episodes (according to Holter), significant restructuring of motor unit potentials according to the myogenic type, a decrease in the average duration to 50 % of the norm in the calf muscles, myotonic discharges according to electroneuromyography, signs of myofibrillar muscular dystrophy of the legs with manifestation of a defect in the proteins desmin and αB-crystallin. During the work, a patient was found to have a pathogenic variant of the nucleotide sequence of the DES gene, encoding the desmin protein, is a structural protein of the cytoskeleton, and forming intermediate filaments of muscle cells.

Due to the fact that in most cases there is insufficient information about myofibrillar myopathy and the diagnosis of the disease is untimely without the use of specific methods, including medical genetic ones, the diagnosis is established several years later. The effective use of medical genetic technologies and the correct interpretation of the results depend on the coordinated work of a team of professionals.

1. Medical Genetics: National Guidelines / edited by EK Ginter, VP Puzyrev, SI Kutsev. Moscow: GEOTAR-Media 2022:896 p. (Series “National Guidelines”) - ISBN 978-5- 9704-6307-9. (In Russ.).

2. Nazarenko LP, Nazarenko MS. Epidemiology of hereditary diseases in healthcare practice: evolution from theory to technology and vice versa. Medical Genetics. 2020; 19(7): 15-16. (In Russ.). doi: 10.25557/2073-7998.2020.07.15-16

3. Klocheva EG, Goldobin VV, Alexandrov MV, et al. Clinical case of late manifestation of Wilson’s disease. Medical alphabet. 2022; (32): 47–52. (In Russ.). doi: 10.33667/2078-5631-2022-32-47–52

4. Novikov PV. The problem of rare (orphan) diseases in the Russian Federation: Medical and normative legal aspects of its solution. Therapeutic Archive. 2014; 86(12): 3-12. (In Russ.).

5. Novitsky VV, Goldberg ED, Urazova OI. Pathophysiology: Textbook: in 2 vols. 4th ed., revised. and add. Moscow: GEOTAR-Media, 2009; 1: 848. (In Russ.).

6. van Spaendonck-Zwarts KY, van der Kooi AJ, van den Berg MP, et al. Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D. Neth Heart J. 2012; 20(5): 219-28. doi: 10.1007/s12471-011-0233-y

7. Dalakas MC, Park KY, Semino-Mora C, et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med. 2000; 342(11): 770-80. doi: 10.1056/NEJM200003163421104

8. Dalakas MC, Dagvadorj A, Goudeau B, et al. Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations. Neuromuscul Disord. 2003; 13(3): 252-8. doi: 10.1016/s0960-8966(02)00271-7

9. Brodehl A, Hedde PN, Dieding M, et al. Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants. J Biol Chem. 2012; 287(19): 16047-57. doi: 10.1074/jbc.M111.313841

10. Illarioshkin SN, Seliverstov YuA, Klyushnikov SA. Problems of early diagnosis of hereditary neurological diseases. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2021; 66(4): 8-15. (In Russ.). doi: 10.21508/1027-4065-2021-66-4-8-15

11. Schroder R, Goudeau B, Simon MC, et al. On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. Hum. Mol. Genet. 2003; 12(6): 657-669. doi: 10.1093/hmg/ddg060

12. Goldfarb LG, Olivé M, Vicart P, Goebel HH. Intermediate filament diseases: desminopathy. Adv Exp Med Biol. 2008; 642: 131–64. doi: 10.1007/978-0-387-84847-1_11

13. Ryzhkova OP, Kardymon OL, Prokhorchuk EB, et al. Guidelines for the interpretation of human DNA sequence data obtained by massively parallel sequencing (MPS) methods (2018 revision, version 2). Medical Genetics. 2019; 18(2): 3-23. (In Russ.). doi: 10.25557/2073-7998.2019.02.3-23

14. Zamaraeva DV, Trunina II, Kotlukova NP, et al. The manifestation of genetic-related cardiomyopathy after myocarditis (a clinical case). Clinical and Experimental Surgery. Petrovsky Journal. 2020; 8(3): 110–8. (In Russ.). doi: 10.33029/2308-1198-2020-8-3-110-118

15. Valikova TA, Alifirova VM, Bychkova IV, Sabashkina KYu. The clinical case of Stark–Kaeser type scapuloperoneal syndrome. Bulletin of Siberian Medicine. 2015; 14(6): 115-118. (In Russ.). doi: 10.20538/1682-0363-2015-6-115-118

16. Aseeva AS, Lebedeva DI, Belova EV. A rare case of myofibrillar myopathy. Ural Medical Journal. 2014; 9(123): 8-12. (In Russ.).

17. Myasnikov RP, Shcherbakova NV, Kulikova ОV, et al. Des gene mutation in a family of proband with myofibrillary myopathy and non-compaction cardiomyopathy, resulted in cardiac transplantation. Russ J Cardiol. 2017; 10(150): 9–16. (In Russ.). doi: 10.15829/1560-4071-2017-10-9-16