Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease whose pattern of weakness is predominantly distal. Limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) is another neuromuscular disease, which presents an autosomal recessive inheritance and is marked by proximal muscle weakness. Even if uncommon, comorbid inherited pathologies must be considered in cases of atypical presentations, especially in those with family history of consanguinity. Case Presentation: Herein, we report the unique case of a patient diagnosed with both DM1 and LGMD2B/R2: a 38-year-old woman in follow-up of DM1 in a neuromuscular disease service presenting prominent proximal weakness. The patient’s parents were consanguineous, and creatine kinase levels were elevated. A multi-gene panel test was performed and revealed the diagnosis of LGMD2B/R2. Conclusion: Genetic diseases with atypical presentations should raise the possibility of a second disorder, prompting an appropriate investigation. Overlooking a second diagnosis can implicate in not offering adequate genetic counseling, support, or specific treatment.

Established Facts

  • Muscular dystrophies are genetic disorders that manifest mainly as weakness in different and specific patterns of involvement, and the co-occurrence of two different dystrophies in a single patient is a rare event.

Novel Insights

  • This is the first case in the literature describing the co-occurrence of myotonic dystrophy type 1 (DM1) and limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) in a single patient. Atypical presentations of rare disorders should prompt investigation for alternative diagnoses. The co-occurrence of two dystrophies is rare but not negligible.

Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant disorder caused by the expansion of an unstable CTG trinucleotide repeat in the 3′-untranslated region of the gene DMPK (myotonic dystrophy protein kinase) [Udd and Krahe, 2012]. In the classical adult onset of DM1, clinical manifestations are characterized by slowly progressive distal muscle weakness, facial weakness, and myotonia. It is a multisystemic disease, presenting with subcapsular cataracts, endocrinopathy, cardiac conduction disturbances, tachyarrhythmias, and pneumonia due to aspiration in more advanced cases [Udd and Krahe, 2012]. Prevalence varies according to geographic area, but ranges from 1:100,000 in areas of Japan to 1:10,000 in Iceland, with a European-estimated prevalence of approximately 9:100,000 [Turner and Hilton-Jones, 2010]. The diagnosis is confirmed with genetic testing. Electromyography may be helpful with suggestive findings before performing DNA testing, and serum creatine kinase (CK) levels are generally mildly elevated in symptomatic patients, while they are expected to be normal in asymptomatic individuals. Muscle biopsy is not mandatory, but, if performed, demonstrates a grossly altered histological appearance [Turner and Hilton-Jones, 2010].

Limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) is a rare autosomal recessive dystrophy which affects a structural protein known as dysferlin (DYSF gene) and classically presents with both hip and shoulder proximal muscle weakness, more often starting in the hips and posteriorly progressing to other corporal segments. LGMD2B/R2 is the most common subtype of autosomal recessive LGMD with adult onset in Brazil, representing 30.5% of LGMD cases [Winckler et al., 2019]. Mean age at onset is 23 years, usually presenting with a slow course of progression; median age of walking aid dependency is 42 years [Winckler et al., 2019]. Heart can be involved, but it is not common, whereas respiratory involvement is present in approximately 16% of the patients [Winckler et al., 2019]. Regarding complementary tests, CK levels are commonly substantially increased, electromyography may be helpful with typical myopathic changes, muscle biopsy can show inflammation and degeneration, and definitive diagnosis is achieved by molecular genetic testing [Iyadurai and Kissel, 2016; Taghizadeh et al., 2019].

Here, we present the case of a patient with previously confirmed diagnosis of DM1 presenting atypical symptoms of predominantly proximal muscular weakness and parental consanguinity. Further investigation confirmed the additional diagnosis of LGMD2B/R2.

A 38-year-old woman in follow-up after a confirmed diagnosis of DM1 (DMPK – 19q13.2-q13.3; allele 1: 5 repeats; allele 2: >50 repeats) at the Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil, presented with a history of progressive proximal muscular weakness. At the time of the first diagnosis of DM1, the patient was 28 years old and presented with recurrent falls, although no proximal weakness was reported. In the following 2 years, progressive thigh pain and weakness while climbing stairs was developed. The patient got pregnant at 30 years of age, during which time proximal leg weakness continued to get worse, leading to walking difficulties. Two years later, she started to experience upper extremity proximal weakness when trying to hold the baby in her arms. The patient denied tremors or dysphagia.

Regarding family history, the patient’s parents were found to be consanguineous. Detailed family history is presented in Figure 1. Physical examination at the age of 35 years demonstrated a muscle power grade 2/5 in both proximal upper and lower limbs, according to the Medical Research Council (MRC) scale. Distal muscle power, otherwise, was graded 5/5 on upper extremities and 4/5 on lower extremities. Other findings were myopathic gait, globally reduced deep tendon reflexes, myotonia on thenar musculature percussion and moderate atrophy on humeral musculature. There was no detectable alteration in cranial nerves function on examination. CK levels were 880 U/L (reference range 29–168 U/L) at the time of assessment. A previous echocardiogram demonstrated patent foramen ovale with minimal flow and no hemodynamic repercussions. Furthermore, the patient was in use of levothyroxine for hypothyroidism, and an ophthalmologic evaluation revealed subcapsular cataract.

Fig. 1.

Representation of patient’s family history.

Fig. 1.

Representation of patient’s family history.

Close modal

A neuromuscular genetic panel with 131 genes aimed for limb-girdle dystrophies was performed and revealed two pathogenic variants in DYSF: NM_003494.3 c.4200dup;p.(Ile1401 Hisfs*8) and c.701G>;p.(Gly234Glu). It is not known if this is in cis or trans, which needs a segregation study to be identified. Based on the findings, LGMD2B/R2 diagnosis was established. Interestingly, although born to consanguineous parents, the patient was compound heterozygous, which was an unexpected finding. The patient has been informed about the novel diagnosis, and follow-up has been maintained. Genetic counseling was offered, along with the possibility of segregating both variants in the parents.

Muscular dystrophies represent a heterogeneous group of genetic diseases that share phenotypic features and degenerative changes on muscle biopsy. Clinically, the age of onset, severity, and degree of systemic involvement depend on the subtype of disease, but progressive muscle weakness is the major finding. Respiratory, cardiac, and swallowing musculature can be affected [Carter et al., 2018]. Differential diagnosis must be made between the different diseases inside the group [Klein et al., 2008] and with other muscular pathologies such as inflammatory myopathies, myasthenia gravis, nemaline, mitochondrial myopathies, and spinal muscular atrophy. The recent advances in gene identification and in research for therapies, such as in supportive medicine, have improved the patient’s quality of life and are expected to change the scenario in the following years [Mercuri et al., 2019].

In adults, myotonic dystrophy is the most common type of muscular dystrophy [Carter et al., 2018]. The main clinical characteristic is a pattern of distal weakness of slow progression. Otherwise, limb-girdle muscular dystrophies as a group represent the fourth most common cause of genetic muscle disease [Bockhorst and Wicklund, 2020]. They present, differently from the myotonic dystrophy, a typical proximal distribution of weakness, and LGMD2B/R2 follows an autosomal recessive pattern of inheritance.

Herein, we reported the unique case of a Brazilian adult woman with DM1 who developed important proximal muscular weakness and was additionally diagnosed with LGMD2B/R2, confirmed by identification of mutations in the DYSF gene. It represents a rare case of the co-occurrence of two dystrophies on the same patient. Although we expected an autosomal recessive mutation because of the history of consanguinity, our patient was compound heterozygous, making the consanguinity probably only a coincidence in our case.

There are other cases in the literature reporting the association of more than one inherited disorder. Starosta [Starosta et al., 2022] described a case of a child diagnosed with Pompe disease and sickle cell anemia. Lerario [Lerario et al., 2016] reported a boy with Down syndrome and increased CK levels that yielded a co-diagnosis of Becker muscular dystrophy. Xia [Xia et al., 2021] reported variants in two genes in a patient presenting with both manifestations of spinal muscular atrophy and Duchenne muscular dystrophy. Hannah-Schmouni [Hannah-Shmouni et al., 2021] reported 8 cases with concomitant diagnosis of two genetic disorders, all of them presenting atypical phenotypes for their primary diagnosis. Particularly, the first case reported the co-occurrence of MD1 and facioscapulohumeral muscular dystrophy that was suspected by an increasing difficulty in climbing stairs and a significant scapular winging on physical examination. Locci [Locci et al., 2021] described the co-occurrence of DMPK expansion and CLCN1 mutation in a patient with myotonia, speculating that the CLCN1 mutation could have attenuated the severity of DM1 phenotype in this case. We were not able to find another report on the co-occurrence of both MD1 and LGMD2B/R2 on a single patient. Thus, this represents the first case described in the literature.

Although the co-occurrence of two different genetic conditions is infrequent, clinicians should not overlook that possibility when facing a case with atypical presentation. Differential diagnosis with other genetic or acquired conditions must always be considered when the clinical presentation is not fully compatible with the diagnosis and before considering an expansion of phenotype. Overlooking a second diagnosis results in inadequate genetic counseling, support, or specific treatment.

Co-occurrence of different genetic disorders is unusual, but not so uncommon as physicians may imagine. A study that analyzed 802 patients with whole-exome sequencing (WES) performed in two national research programs in Canada [Balci et al., 2017] revealed that eight (3.5%) of them had two or more genetic diagnosis explaining their clinical phenotype. A larger analysis that evaluated 7,698 patients who underwent exome sequencing in the USA [Smith et al., 2019], showed that 2% had findings in at least two genes with significant clinical correlation, and this was more common in patients with history of consanguinity in the family and in patients with greater clinical complexity. Therefore, dual diagnosis should be suspected when a disease presents atypical signs and symptoms, even when dealing with rare genetic conditions such as muscular dystrophies. Cases in which multiple organ systems are being affected or there is an unusual pattern of muscular involvement should raise the suspicion for co-occurring disorders. In this article, we reported the rare case with a confirmed combination of DM1 and LGMD2B/R2 in a single Brazilian patient. Detailed family history should always be obtained, and the precise diagnosis can have an important impact on patient management.

This consists of a retrospective and observational case report, approved for Ethics Committee approval GPPG/HCPA 2017-0340. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

The authors declare that no funding was received.

Lucas Augusto Hauschild, Karina Carvalho Donis, and Jonas Alex Morales Saute designed the study. Lucas Augusto Hauschild wrote the manuscript. Lucas Augusto Hauschild, Taciana Seixas Maia da Silva, Pablo Brea Winckler, and Laércio Moreira Cardoso-Júnior reviewed the literature. Jonas Alex Morales Saute, Pablo Brea Winckler, and Karina Carvalho Donis edited the final manuscript.

All data generated or analyzed during this study are included in the final published article.

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