Dysferlinopathy

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Camille Bouchard	--	1382	2023-09-21 09:45:04	\|
2	references update	Fanny Huang	Meta information modification	1382	2023-09-26 07:22:50	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12186011

Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the DYSF gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca²⁺ signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb–Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family. They are therefore grouped under the name dysferlinopathy.

dysferlinopathy dysferlin

1. Introduction

In the ClinVar database, there are 719 hereditary mutations in the DYSF gene that have been classified as either pathogenic or likely pathogenic ^[1] and that can cause a dysferlinopathy, such as Miyoshi Myopathy type 1 (MMD1) and Limb–Girdle Muscular Dystrophy type 2B (LGMD2B), now called Limb–Girdle Muscular Dystrophy R2 dysferlin-related (LGMDR2) ^[2]^[3]. LGMDR2 first affects proximal muscles (such as thighs), and MMD1 affects distal muscles initially (such as calves) ^[4]. The same mutations in the DYSF gene can cause either an MMD1 or an LGMDR2 presentation, leading to family members with the same mutation being affected in different muscles ^[5]^[6]. Since both clinical presentations can be acquired by the same mutations and progress the same, the term dysferlinopathy is used, as it is the same disease ^[7].

2. Signs and Symptoms

The age of onset for MMD1 and LGMDR2 is 20 ± 5 years and 21 ± 7 years, respectively, and patients present calf or thigh weakness and atrophy. In the following 5 years, the weakness and atrophy evolve to include the upper limbs ^[8]. Most patients (72%) present with lower limb weakness, which is proximal for 15%, distal for 32%, or both for 25% of patients. An upper limb weakness is also reported by 7% of patients. Their symptoms include muscle wasting (27%); pain, stiffness, or cramps (13%); or pseudohypertrophy (6%) ^[9]. Patients’ creatine kinase (CK) level is also on average 54 times higher than that of control groups ^[8], and they start using a cane to walk in their thirties and become wheelchair-bound in their forties or, on average, 21 years after onset ^[10]. The phenotype is located in the skeletal muscles, and the heart remains unaffected, with normal results for electrocardiogram and echocardiogram ^[11]. However, a 3-year study showed that up to 30% of patients have a reduced forced vital capacity (FVC) and that up to 58% of patients have a cardiac P-wave abnormality, which can be a risk factor for atrial flutter ^[12].

3. MRI Pattern

A minority of patients do not correlate with the typical phenotype, but it has been described as follows in Table 1 ^[13]:

Table 1. Muscles involved in dysferlinopathy.

In the upper limb girdle: the subscapularis muscle is the most affected, and the levator scapulae is the least affected.

Paraspinal muscles ≥ abdominal muscles

Gluteus minimus ≥ gluteus medius and maximus

Obturator externus ≥ gluteus maximus

Adductor magnus ≥ adductor longus

Rectus femoris is also involved when the vasti muscles are involved

Peroneus ≥ tibialis anterior

Symmetric involvement of left and right sides

≥: is equally or more involved than.

For dysferlinopathy, there is no significant difference between the right and left muscle fat fraction (FF) or the contractile cross-section area (cCSA); it is therefore considered symmetrical ^[14]. However, FF increases significantly with time after the onset and even more so in non-ambulant patients. The fastest increases in FF occur in the quadriceps, hamstrings, adductors, and posterior leg muscles. cCSA also decreases concomitantly with time. A three-year study concluded in 11.0% and 12.8% increases in cCSA, while 9.6% and 8.4% increases in FF were observed in ambulant and non-ambulant patients compared to the control group ^[14].

Another MRI study revealed that the most frequently affected muscles were the gastrocnemius medialis and soleus, with a similar pattern for both dysferlinopathy phenotypes ^[15]. It also confirmed the correlation between time since onset and the severity of muscle pathology. This study found asymmetry in 41.8% of patients. The study pointed out two commonly affected muscles in the arms, namely, the biceps brachii (for 57.1% of patients) and the forearm anterior muscles (for 53.8% of patients), and several affected muscles in the scapular girdle, namely, the subscapularis (80.8%), latissimus dorsi (75.3%), infraspinatus (73.8%), and supraspinatus (72.8%). As for the pelvic girdle and trunk region, the most affected muscles were the tensor fascia latae (95%), gluteus minimus (90.8%), obturator externus (86%), iliocostalis (93.1%), longissimus (86.2%), and multifidus (88.5%). The most commonly involved thigh muscles were the semimembranosus (95.4%), semitendinosus (90.2%), biceps femoris long head (93.5%), and adductor magnus (94.1%). In the lower leg, the affected muscles were the soleus (99.45%), gastrocnemius medialis (99.45%), and gastrocnemius lateralis (94.7%). The study concluded that spinal muscles were equally or more affected than abdominal ones and that the anterior muscles in the forearm were equally or more affected than the posterior ones. They also observed that all symptomatic patients had at least one affected posterior lower leg muscle and that severely affected patients had involvement of all lower leg muscles.

4. Muscle Biopsy

Patient muscle biopsy shows variability in muscle fibre sizes. Some fibres are necrotic, and others are regenerative ^[16]. Microscopic analyses show proliferating connective tissue. Other studies confirmed the abnormal variability in the size of fibres along with splitting fibres and scattered necrotic and regenerating fibres ^[17]. They also noticed a high quantity of internalized nuclei, as well as increased endomysial and perimysial connective tissue. They also found granular membrane attack complex (MAC) deposits on the surface of non-necrotic fibres, which was also described in previous studies ^[17]^[18]. An electron microscopy analysis of biopsies showed small defects of the plasma membrane, especially in hypercontracted or necrotic fibres. Small vesicles also formed layers to replace the sarcolemma on the surface of the muscle fibres. This study also showed the thickening or duplication of the basal lamina in 35% of dysferlin-deficient patient fibres compared to a control group. Their fibres also showed papillary projections surrounded by globular dense material. Their subsarcolemmal region also contained small vacuoles and an increase in rough endoplasmic reticulum.

Several other studies confirmed that typical patient biopsies contain necrotic fibres, regenerative ones, and connective or fat tissue ^[19]^[20]^[21]. One of them compared the phenotypes of early-onset (EO) and late-onset (LO) patients. Their results showed a non-significant trend for EO patients to have more perimysial inflammation, necrotic fibres, and fat and connective tissue accumulation ^[19]. Some results came from case studies and vary from patient to patient. DeLuna et al. also showed that dysferlin is upregulated in the activated satellite cells of dysferlinopathy patients, especially during differentiation into myotubes ^[22].

5. Diagnosis

Dysferlinopathy has common symptoms with other diseases such as polymyositis (PM) or other Limb–Girdle muscular dystrophies (LGMDs), and it can therefore be misdiagnosed ^[23]. In fact, they all present with a high creatine kinase level, and muscle inflammation and weakness.

Another possible but rare misdiagnosis for dysferlinopathy can be Charcot–Marie–Tooth disease (CMT), since both diseases involve a distal weakness phenotype ^[11]. One way to tell them apart is that CMT does not cause a high creatine kinase level nor the sarcolemma upregulation of major histocompatibility complex class I (MHC I) like dysferlinopathy does. An electromyographic (EMG) study makes it possible to differentiate dysferlinopathy from CMT ^[24].

A Western blot can show whether a patient has an absence of the dysferlin protein, but it cannot confirm a mutation. Genetic screening is necessary to confirm whether their DYSF gene contains two pathogenic or potentially pathogenic mutations. This can be carried out on either a blood or muscle sample ^[25]^[26]^[27]. More precisely, a Western blot with a dysferlin-targeting antibody can verify the presence or absence of the dysferlin protein in the tissues, such as a muscle biopsy, but this can also be a secondary decrease due to another protein, such as calpain-3 ^[28]. Direct sequencing or different hybridization methods can allow one to identify precise mutations in the gene ^[29].

6. Clinical Research

The evolution of 193 patients with dysferlinopathy over one year was evaluated at baseline, 6 months, and one year with tests such as the ACTIVLIM questionnaire, an adapted North Star Ambulatory Assessment (a-NSAA), the Motor Function Measure (MFM-20), timed function tests, the 6-minute walk test (6MWT), the Brooke scale, the Jebsen test, manual muscle testing, and hand-held dynamometry ^[30]. The conclusion was that it is possible to measure changes in dysferlinopathy patients within 6 months using a-NSAA, MFM-20, a timed 10 m walk, and timed up and go.

Also, a study was conducted to evaluate the impact of dysferlinopathy on patients’ function and quality of life ^[31]. This study could be used to assess the right tests to quantify patient needs in future research for a cure or for services to help patients improve their quality of life and daily functions.

References

ClinVar. Available online: https://www.ncbi.nlm.nih.gov/clinvar/?term=dysf%5Bgene%5D&redir=gene (accessed on 8 September 2023).
Liu, J.; Aoki, M.; Illa, I.; Wu, C.; Fardeau, M.; Angelini, C.; Serrano, C.; Urtizberea, J.A.; Hentati, F.; Ben Hamida, M.; et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 1998, 20, 31–36.
Straub, V.; Murphy, A.; Udd, B.; Corrado, A.; Aymé, S.; Bönneman, C.; de Visser, M.; Hamosh, A.; Jacobs, L.; Khizanishvili, N.; et al. 229th ENMC international workshop: Limb girdle muscular dystrophies–Nomenclature and reformed classification Naarden, The Netherlands, 17–19 March 2017. Neuromuscul. Disord. 2018, 28, 702–710.
Patel, N.J.; Van Dyke, K.W.; Espinoza, L.R. Limb-girdle muscular dystrophy 2B and miyoshi presentations of dysferlinopathy. Am. J. Med. Sci. 2017, 353, 484–491.
Illarioshkin, S.N.; Ivanova–Smolenskaya, I.A.; Greenberg, C.R.; Nylen, E.; Sukhorukov, V.S.; Poleshchuk, V.V.; Markova, E.D.; Wroge-mann, K. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 2000, 55, 1931–1933.
Weiler, T.; Bashir, R.; Anderson, L.V.B.; Davison, K.; Moss, J.A.; Britton, S.; Nylen, E.; Keers, S.; Vafiadaki, E.; Greenberg, C.R.; et al. Identical mutation in patients with limb girdle muscular dystrophy type 2B or miyoshi myopathy suggests a role for modifier gene(s). Hum. Mol. Genet. 1999, 8, 871–877.
Moore, U.; Gordish, H.; Diaz-Manera, J.; James, M.K.; Mayhew, A.G.; Guglieri, M.; Fernandez-Torron, R.; Rufibach, L.E.; Feng, J.; Blamire, A.M.; et al. Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease. Neuromuscul. Disord. 2021, 31, 265–280.
Woudt, L.; Di Capua, G.A.; Krahn, M.; Castiglioni, C.; Hughes, R.; Campero, M.; Trangulao, A.; González-Hormazábal, P.; Godoy-Herrera, R.; Lévy, N.; et al. Toward an objective measure of functional disability in dysferlinopathy. Muscle Nerve 2015, 53, 49–57.
Harris, E.; Bladen, C.L.; Mayhew, A.; James, M.; Bettinson, K.; Moore, U.; Smith, F.E.; Rufibach, L.; Cnaan, A.; Bharucha-Goebel, D.X.; et al. The Clinical Outcome Study for dysferlinopathy: An international multicenter study. Neurol. Genet. 2016, 2, e89.
Aoki, M.; Takahashi, T. Mutational and clinical features of Japanese patients with dysferlinopathy (Miyoshi myopathy and limb girdle muscular dystrophy type 2B). Rinsho Shinkeigaku 2005, 45, 938–942.
Socoliuc, C.G.; Oprişan, A.; Dobrescu, A.; Manole, E.; Bastian, A.E. The challenging diagnosis of dysferlinopathy. Rom. J. Neurol. 2021, 20, 264.
Moore, U.; Fernandez-Torron, R.; Jacobs, M.; Gordish-Dressman, H.; Diaz-Manera, J.; James, M.K.; Mayhew, A.G.; Harris, E.; Guglieri, M.; Rufibach, L.E.; et al. Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study. Muscle Nerve 2022, 65, 531–540.
Llansó, L.; Moore, U.; Bolano-Diaz, C.; James, M.; Blamire, A.M.; Carlier, P.G.; Rufibach, L.; Gordish-Dressman, H.; Boyle, G.; Hilsden, H.; et al. Expanding the muscle imaging spectrum in dysferlinopathy: Description of an outlier population from the classical MRI pattern. Neuromuscul. Disord. 2023, 33, 349–357.
Reyngoudt, H.; Smith, F.E.; Araújo, E.C.d.A.; Wilson, I.; Fernández-Torrón, R.; James, M.K.; Moore, U.R.; Díaz-Manera, J.; Marty, B.; Azzabou, N.; et al. Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy. J. Cachexia Sarcopenia Muscle 2022, 13, 1850–1863.
Diaz-Manera, J.; Fernandez-Torron, R.; Llauger, J.; James, M.K.; Mayhew, A.; Smith, F.E.; Moore, U.R.; Blamire, A.M.; Carlier, P.G.; Rufibach, L.; et al. Muscle MRI in patients with dysferlinopathy: Pattern recognition and implications for clinical trials. J. Neurol. Neurosurg. Psychiatry 2018, 89, 1071–1081.
Rekik, S.; Sakka, S.; Ben Romdhane, S.; Amer, Y.B.; Lehkim, L.; Farhat, N.; Ben Mahfoudh, K.; Authier, F.J.; Dammak, M.; Mhiri, C. Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity. Mol. Biol. Rep. 2020, 47, 5755–5761.
Selcen, D.; Stilling, G.; Engel, A.G. The earliest pathologic alterations in dysferlinopathy. Neurology 2001, 56, 1472–1481.
Spuler, S.; Engel, A.G. Unexpected sarcolemmal complement membrane attack complex deposits on nonnecrotic muscle fibers in muscular dystrophies. Neurology 1998, 50, 41–46.
Fernández-Eulate, G.; Querin, G.; Moore, U.; Behin, A.; Masingue, M.; Bassez, G.; Leonard-Louis, S.; Laforêt, P.; Maisonobe, T.; Merle, P.; et al. Deep phenotyping of an international series of patients with late-onset dysferlinopathy. Eur. J. Neurol. 2021, 28, 2092–2102.
Folland, C.; Johnsen, R.; Gomez, A.B.; Trajanoski, D.; Davis, M.R.; Moore, U.; Straub, V.; Barresi, R.; Guglieri, M.; Hayhurst, H.; et al. Identification of a novel heterozygous DYSF variant in a large family with a dominantly-inherited dysferlinopathy. Neuropathol. Appl. Neurobiol. 2022, 48, e12846.
Eryaşar, G.; Seçil, Y.; Beckmann, Y.; Kendir, A.İ.; Diniz, A.G.; Başoğlu, M. Two cases with dysferlinopathy. Turk. Norol. Derg. 2011, 17, 45–50.
de Luna, N.; Gallardo, E.; Illa, I. In vivo and in vitro dysferlin expression in human muscle satellite cells. J. Neuropathol. Exp. Neurol. 2004, 63, 1104–1113.
Contreras-Cubas, C.; Barajas-Olmos, F.; Frayre-Martínez, M.I.; Siordia-Reyes, G.; Guízar-Sánchez, C.C.; García-Ortiz, H.; Orozco, L.; Baca, V. Dysferlinopathy misdiagnosed with juvenile polymyositis in the pre-symptomatic stage of hyperCKemia: A case report and literature review. BMC Med. Genom. 2022, 15, 139.
Urtizberea, J.A.; Bassez, G.; Leturcq, F.; Nguyen, K.; Krahn, M.; Levy, N. Dysferlinopathies. Neurol. India 2008, 56, 289.
Fanin, M.; Angelini, C. Progress and challenges in diagnosis of dysferlinopathy. Muscle Nerve 2016, 54, 821–835.
Ho, M.; Gallardo, E.; McKenna-Yasek, D.; De Luna, N.; Illa, I.; Brown, R.H., Jr. A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann. Neurol. Off. J. Am. Neu-Rological Assoc. Child Neurol. Soc. 2002, 51, 129–133.
Ankala, A.; Nallamilli, B.R.; Rufibach, L.E.; Hwang, E.; Hegde, M.R. Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies. Muscle Nerve 2014, 50, 333–339.
Anderson, L.V.; Harrison, R.M.; Pogue, R.; Vafiadaki, E.; Pollitt, C.; Davison, K.; Moss, J.A.; Keers, S.; Pyle, A.; Shaw, P.J.; et al. Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dys-ferlinopathies). Neuromuscul. Disord. 2000, 10, 553–559.
Sinclair, A. Genetics 101: Detecting mutations in human genes. Can. Med. Assoc. J. 2002, 167, 275–279.
Moore, U.; Jacobs, M.; James, M.K.; Mayhew, A.G.; Fernandez-Torron, R.; Feng, J.; Cnaan, A.; Eagle, M.; Bettinson, K.; Rufibach, L.E.; et al. Assessment of disease progression in dysferlinopathy: A 1-year cohort study. Neurology 2019, 92, e461–e474.
Mayhew, A.G.; James, M.K.; Moore, U.; Sutherland, H.; Jacobs, M.; Feng, J.; Lowes, L.P.; Alfano, L.N.; Lofra, R.M.; Rufibach, L.E.; et al. Assessing the Relationship of Patient Reported Outcome Measures with Functional Status in Dysferlinopathy: A Rasch Analysis Approach. Front. Neurol. 2022, 13, 828525.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Clinical Neurology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Camille Bouchard

Jacques P. Tremblay

View Times: 104

Update Date: 26 Sep 2023

Table of Contents

Video Upload Options

Confirm