Genetic test for Mendelian fatigue and muscle weakness syndromes

Main Article Content

Aysha Karim Kiani
Bruno Amato
Silvia Maitz
Savina Nodari
Sabrina Benedetti
Francesca Agostini
Lorenzo Lorusso
Enrica Capelli
Astrit Dautaj
Matteo Bertelli


Chronic fatigue, muscle weakness, genetic test


Several inherited disorders involve chronic fatigue, muscle weakness and pain. These conditions can depend on muscle, nerve, brain, metabolic and mitochondrial defects. A major trigger of muscle weakness and fatigue is exercise. The amount of exercise that triggers symptoms and the frequency of symptoms are highly variable. In this review, the genetic causes and molecular pathways involved in these disorders are discussed along with the diagnostic and treatment options available, with the aim of fostering understanding of the disease and exploring therapeutic options.


Download data is not yet available.


Metrics Loading ...
Abstract 315 | PDF Downloads 82


1. Cohen BH. Mitochondrial and metabolic myopathies. Continuum (Minneap Minn) 2019; 25: 1732-66.
2. Lebo RV, Anderson LA, DiMauro S, Lynch E, Hwang P, Fletterick R. Rare McArdle disease locus polymorphic site on 11q13 contains CpG sequence. Hum Genet 1990; 86: 17-24.
3. Santalla Hernández A, Nogales-Gadea G, Blázquez Encinar A, et al. Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update. 2017; 18: 819.
4. Nogales‐Gadea G, Brull A, Santalla A, et al. McArdle disease: update of reported mutations and polymorphisms in the PYGM gene. Hum Mutat 2015; 36: 669-78.
5. Llavero F, Arrazola Sastre A, Luque Montoro M, et al. McArdle disease: new insights into its underlying molecular mechanisms. Int J Mol Sci 2019; 20: 5919.
6. Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis 2018; 13: 1-7.
7. Fishbein WN, Armbrustmacher VW, Griffin JL. Myoadenylate deaminase deficiency: a new disease of muscle. Science 1978; 200: 545-8.
8. Sabina RL. Myoadenylate deaminase deficiency: a common inherited defect with heterogeneous clinical presentation. Neurol Clin 2000; 18: 185-94.
9. Rubio JC, Martín MA, Bautista J, Campos Y, Segura D, Arenaset J. Association of genetically proven deficiencies of myophosphorylase and AMP deaminase: a second case of ‘double trouble’. Neuromuscul Disord 1997; 7: 387-9.
10. Fishbein W, Griffin J, Armbrustmacher V. Stain for skeletal muscle adenylate deaminase. An effective tetrazolium stain for frozen biopsy specimens. Arch Pathol Lab Med 1980; 104: 462.
11. Fishbein WN. Indicator enzyme assays: I. Adenylate deaminase: Principles and application to human muscle biopsies and blood cells. Biochem Med 1979; 22: 307-22.
12. Lecky B. Failure of D-ribose in myoadenylate deaminase deficiency. Lancet 1983; 321: 193.
13. Wieser T. Carnitine palmitoyltransferase II deficiency. In: GeneReviews. Seattle (WA): University of Washington, 2004.
14. Deschauer M, Wieser T, Zierz S. Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects. Arch Neurol 2005; 62: 37-41.
15. Taroni F, Verderio E, Dworzak F, Willems PJ, Cavadini P, DiDonato S. Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 1993; 4: 314-20.
16. Bonnefont J-P, Demaugre F, Prip-Buus C, et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 1999; 68: 424-40.
17. Smeets RJ, Smeitink JAM, Semmekrot BA, et al. A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency. J Hum Genet 2003; 48: 8-13.
18. Olpin S, Afifi A, Clark S, et al. Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency. J Inherited Metab Dis 2003; 26: 543-57.
19. Blanc P, Carrier H, Thomas L, Chavaillon JM, Robert D. Acute rhabdomyolysis with carnitine-palmityl-transferase deficiency. Intensive Care Med 1982; 8: 307.
20. Ørngreen MC, Ejstrup R, Vissing J. Effect of diet on exercise tolerance in carnitine palmitoyltransferase II deficiency. Neurology 2003; 61: 559-61.
21. Engel AG, Shen X-M, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 2015; 14: 420-34.
22. Mallory LA, Shaw JG, Burgess SL, et al. Congenital myasthenic syndrome with episodic apnea. Pediatr Neurol 2009; 41: 42-5.
23. Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog Neurobiol 2001; 64: 393-429.
24. Senderek J, Müller JS, Dusl M, et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 2011; 88: 162-72.
25. Deinum J, Steenbergen-Spanjers GCH, Jansen M, et al. DBH gene variants that cause low plasma dopamine β hydroxylase with or without a severe orthostatic syndrome. J Med Genet 2004; 41: e38.
26. Kim CH, Zabetian CP, Cubells JF, et al. Mutations in the dopamine β‐hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet 2002; 108: 140-7.
27. van den Berg MP, Almomani R, Biaggioni I, et al. Mutations in CYB561 causing a novel orthostatic hypotension syndrome. Circ Res 2018; 122: 846-54.
28. Shirey-Rice JK, Klar R, Fentress HM, et al. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. Dis Model Mech 2013; 6: 1001-11.
29. Orphanet. Corticosteroid-binding globulin deficiency [ORPHA:199247]. Available at:
30. Preisler N, Orngreen MC, Echaniz-Laguna A, et al. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? Neurology 2012; 78: 265-8.
31. Sewry CA, Jimenez-Mallebrera C, Muntoni F. Congenital myopathies. Curr Opin Neurol 2008; 21: 569-75.