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Oculopharyngeal, distal, and congenital muscular dystrophies

Oculopharyngeal, distal, and congenital muscular dystrophies
Literature review current through: May 2024.
This topic last updated: Dec 21, 2022.

INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in a number of genes required for normal muscle function. Some of the genes responsible for these conditions have been identified. Muscle weakness is the primary symptom.

The pathogenesis, genetics, and clinical characteristics of oculopharyngeal, distal, and congenital muscular dystrophies are discussed here. Other muscular dystrophies are presented separately. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Emery-Dreifuss muscular dystrophy" and "Facioscapulohumeral muscular dystrophy" and "Limb-girdle muscular dystrophy" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

OCULOPHARYNGEAL MUSCULAR DYSTROPHY — Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy that is characterized by ocular and pharyngeal muscle involvement, leading to ptosis and dysphagia [1,2].

Clinical features — OPMD typically presents with ptosis, dysarthria, and dysphagia. It can also be associated with proximal and distal extremity weakness. The onset is usually in middle age with asymmetric involvement of the levator palpebrae muscles. Progressive extraocular weakness subsequently develops. In general, OPMD is a slowly progressive myopathy. However, ptosis can occlude vision, and severe dysphagia may lead to weight loss and death if not treated.

Differential diagnosis — OPMD is distinguished from facioscapulohumeral dystrophy (FSHD) by the different distributions of weakness. Extraocular weakness is far more severe in OPMD. (See "Facioscapulohumeral muscular dystrophy".)

OPMD is distinguished from myotonic dystrophy because myotonia is absent in the former. Ocular muscle involvement is rarely severe in early myotonic dystrophy. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

Differentiation from a mitochondrial myopathy may be more difficult. However, mitochondrial myopathies often have associated features such as retinitis pigmentosa, ataxia, elevated cerebrospinal fluid protein, cardiac conduction defects, and developmental delay that are absent in OPMD. (See "Approach to the metabolic myopathies".)

Laboratory studies — Muscle biopsy shows variation of fiber size and "rimmed" vacuoles. Serum creatine kinase (CK) levels may be elevated. In a study of 168 patients with genetically confirmed OPMD, muscle magnetic resonance imaging (MRI) showed fatty replacement in 97 percent of symptomatic patients [3]; early fat replacement involving the tongue, adductor magnus, and the soleus muscles may be useful in differentiating OPMD from mitochondrial and other myopathies.

Genetics — OPMD is a genetic myopathy with mainly autosomal dominant inheritance. The prevalence of autosomal dominant OPMD is relatively high in the Canadian province of Quebec, where it is estimated at 1:1000 individuals [2]. The prevalence of autosomal dominant OPMD in France is lower at 1:100,000 individuals. The estimated prevalence of autosomal recessive OPMD in Quebec and France is 1:10,000 [2]. A single founder chromosome appears to be responsible for OPMD in the French-Canadian population [4]. The disease has also been described in the Uzbek Jews living in Israel [5,6], and in Ashkenazi Jews [1] and Hispanic populations in the United States [7,8].

Most cases of OPMD are caused by a GCN trinucleotide repeat expansion (where "N" represents any A, C, G, or T nucleotide) in the first exon of the PABPN1 gene [9]. The normal PABPN1 gene contains 10 repeats [2]. In OPMD, autosomal dominant inheritance occurs with expanded alleles that range from 12 to 17 repeats. Autosomal recessive inheritance has been reported with alleles that have 11 repeats [10-12], as has at least one case of probable autosomal dominant inheritance [13]. The GCN repeat is relatively short, with small and relatively stable expansions. The polyadenylate binding protein nuclear 1 localizes to the nucleus, where it seems to be involved in messenger RNA (mRNA) polyadenylation [14]. Although data are not entirely consistent, one study from France of 354 unrelated index cases suggests that longer expansions are correlated with earlier diagnosis and greater disease severity [15]. In a Japanese patient, OPMD was caused by a PABPN1 c.35G>C pathogenic variant, which mimicked the effect of the GCN repeat expansion [16].

A severe form of OPMD with earlier onset and faster progression has been reported in patients who are homozygotes for the PABPN1 gene [17,18].

Ten families with severe, progressive muscular dystrophy, phenotypically very similar to OPMD but with much earlier onset, have been described; the condition was caused by heterozygous frameshift variants in the HNRNPA2B1 gene [19].

Treatment — Treatment is supportive. In a small number of patients, cricopharyngeal myotomy has been attempted with improvement of the dysphagia [20]. In a retrospective report of 24 patients with OPMD, botulinum toxin injections into the cricopharyngeal muscle improved swallowing in 59 percent; however, various adverse events like dysphonia (24 percent) and deterioration of swallowing function (14 percent) occurred in 44 percent of these patients [21]. Severe ptosis that occludes vision can be corrected surgically, but, unfortunately, postoperative complications are common and include sling infection or exposure, keratopathy, overcorrection or undercorrection, and lagophthalmos [22]. Approaches to prevent aspiration and ensure good nutrition can be life-saving in the population of patients with severe dysphagia [23].

DISTAL MUSCULAR DYSTROPHIES — Distal muscular dystrophies are a heterogeneous group of myopathies (table 1) that include the following types [24-31]:

Nonaka myopathy

Miyoshi muscular dystrophy 1

Miyoshi muscular dystrophy 3

Welander distal myopathy

Udd distal myopathy (tardive tibial muscular dystrophy)

Markesbery-Griggs late onset distal myopathy (zaspopathy)

Distal myotilinopathy

Laing distal myopathy (MPD1coll)

Distal myopathy with vocal cord and pharyngeal dysfunction (MPD2)

Distal myopathy 3, Finnish (MPD3)

Williams distal myopathy (MPD4)

Distal myopathy with pes cavus and areflexia (vacuolar neuromyopathy)

Distal myopathy with rimmed vacuoles due to SQSTM1 pathogenic variants

These disorders are characterized by weakness that starts distally in the arms and/or legs and gradually progresses to affect proximal muscles. Almost all forms of distal myopathy can present as early as the second decade, although the onset is usually between 40 and 60 years of age.

CONGENITAL MUSCULAR DYSTROPHIES — The term congenital muscular dystrophy (CMD) was initially applied to infants who were hypotonic and weak at birth and had findings consistent with muscular dystrophy on muscle biopsy. The recognition of multiple genetic forms of CMD and milder variants has broadened the definition to include muscular dystrophies with onset in the first two years after birth (table 2) [32-35]. Arthrogryposis (contracture of two or more joints at birth) is commonly observed in the newborn period. The serum creatine kinase (CK) concentration is usually elevated, and muscle biopsy is characteristically abnormal with extensive fibrosis, degeneration, and regeneration of muscle fibers and proliferation of fatty and connective tissue. In some cases, the clinical course is static but, in most patients, it progresses very slowly. However, actual improvement has been observed in a few cases.

The original classification of the CMDs was based mainly upon the presence or absence of structural central nervous system abnormalities detected by neuroimaging or at autopsy (table 3). The absence of structural changes distinguished "occidental" or "classic" CMD from "syndromic" forms of CMD such as Fukuyama muscular dystrophy, Walker-Warburg syndrome, or muscle-eye-brain disease. However, the distinction is not entirely precise, as structural lesions have been described in some cases of classic CMD [36]. Cognitive impairment is a frequent manifestation of CMD, particularly in patients with structural brain lesions, although it has also been detected in patients with CMD and normal brain magnetic resonance imaging (MRI) [37].

The syndromic CMDs are caused by defective post-translational modification of alpha-dystroglycan (dystroglycanopathies) and other proteins, and are caused by pathogenic variants in multiple genes (table 2). Dystroglycanopathies are characterized clinically by the involvement of multiple organ systems, severe brain malformations, and developmental delay [38].

Cardiac involvement ranges from absent or mild to severe, and is most often associated with dystroglycanopathies such as Fukuyama type, Walker-Warburg syndrome, and muscle-eye-brain disease [39]. Cardiac involvement is also seen in merosin-deficient CMD. In a database search of articles from PubMed, Embase, and Cochrane, cardiac abnormalities, primarily left ventricular dysfunction and arrhythmias, were reported in 41 percent of patients with merosin-deficient CMD [40].

Classic form — The identification of pathogenic variants within the laminin alpha-2 chain gene (LAMA2; merosin) led to the subclassification of classic CMD into merosin-deficient and merosin-positive groups. The chromosomal loci and the respective genes that have been identified for these disorders are listed in the table (table 2).

Merosin-deficient CMD (MDC1A; MIM 607855) is characterized by a combination of severe CMD, demyelination of the cerebral hemispheres (typically without structural CNS anomalies) and high CK levels. Affected patients usually present with severe neonatal hypotonia, contractures, feeding difficulties, and muscle weakness affecting the upper limbs more severely than the lower limbs, which leads to delayed acquisition of motor milestones such as sitting and walking independently. Facial weakness is often pronounced and, in the second decade of life, extraocular muscle weakness may be noted as well (usually involving upgaze). Approximately, 20 to 30 percent of patients develop seizure disorders, usually later in childhood, and 5 to 10 percent of patients exhibit cognitive deficits [41].

The associated mutated gene (LAMA2) was mapped to chromosome 6q22-23 and identified as encoding the alpha-2 chain of laminin, also known as merosin [42]. The laminin alpha-2 chain is a component of the DAP complex (figure 1). Disease-associated variants in the LAMA2 gene can cause either the severe early-childhood phenotype or milder and atypical phenotypes now collectively known as the LAMA2-related muscular dystrophies [43]. Staining of muscle biopsies from these patients with antimerosin antibodies shows a partial or absent pattern of the protein [44].

Merosin-positive CMD without structural brain abnormalities usually has a milder phenotype. This group is clinically and genetically heterogeneous, and includes classic CMD without distinguishing features, rigid spine syndrome associated with pathogenic variants in the selenoprotein N1 (SEPN1) gene, CMD with hyperextensible distal joints (Ullrich type), and CMD with intellectual disability or sensory abnormalities (table 2 and table 3).

Ullrich congenital muscular dystrophy and Bethlem myopathy — The presence of multiple proximal joint contractures and hyperextensible distal joints in a child with congenital generalized weakness is suggestive of Ullrich congenital muscular dystrophy (MIM 254090). The course is characterized by a progressive decline in motor and respiratory function in the first decade of life, with a majority confined to wheelchair by 11 years of age [45]. The phenotype was originally associated with recessive pathogenic variants in type VI collagen genes (COL6A1, COL6A2, and COL6A3), although dominant variants were subsequently reported [46-53].

Pathogenic variants in the same genes also cause Bethlem myopathy (MIM 158810), a relatively less severe disorder typically presenting with proximal weakness and flexion contractures involving primarily distal joints (eg, ankles and interphalangeal joints of the fingers) but also involving the knees, hips, elbows, shoulders, and neck [54-56]. Bethlem myopathy was originally associated with autosomal dominant pathogenic variants in COL6A1, COL6A2, and COL6A3 genes; patients with compound heterozygous COL6A2 pathogenic variants and recessive inheritance have been reported as well [57,58].

While Ullrich congenital muscular dystrophy and Bethlem myopathy were once believed to be separate entities, they are now considered to represent opposite ends of a phenotypic spectrum [51]. Genetic analysis of 49 patients with onset of symptoms during the first two years of life who had pathogenic variants in one of the COL6-encoding genes showed that homozygous stop-codon (nonsense) variants in the triple helix domains resulted in the most severe phenotypes in which ambulation was never achieved [59]. By contrast, dominant de novo in-frame exon skipping and glycine missense variants as well as compound heterozygous novel variants (nonsense/missense) were associated with a moderate-progressive or intermediate phenotypes [60].

Dystroglycanopathies — The dystroglycanopathies are associated with pathogenic variants in different genes that cause defective post-translational modification of alpha-dystroglycan (figure 1). They are both genetically and phenotypically heterogeneous. In current nomenclature, these phenotypes are referred to as the "MDDG" series and include a disease spectrum ranging from mild to severe forms of congenital muscular dystrophy to mild forms of limb-girdle muscular dystrophy. The dystroglycanopathies are characterized by a variety of developmental brain abnormalities, best identified on MRI, including lissencephaly, cerebellar cysts, pontine hypoplasia, and posterior concavity of the brainstem (bowing) [61].

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A or MDDGA) includes the more severe phenotypes historically known as Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy, and a milder phenotype called muscle-eye-brain disease (table 2). Congenital muscular dystrophy-dystroglycanopathy with or without intellectual disability (type B or MDDGB) is also genetically heterogeneous [62-69]. The type B phenotypes of congenital muscular dystrophy-dystroglycanopathy are less severe than the type A but more severe than the type C (limb-girdle muscular dystrophy-dystroglycanopathy) [70].

The phenotypes of congenital muscular dystrophy-dystroglycanopathy historically designated as Fukuyama, Walker-Warburg, and muscle-eye-brain disease (all now considered type A) are reviewed in the sections that follow.

Fukuyama type — The Fukuyama type of CMD (MIM 253800) is among the most common autosomal recessive disorders in Japan (0.7 to 1.2 per 10,000 births) [71], and is characterized by hypotonia, generalized weakness, severe developmental delay, febrile seizures and/or epilepsy, microcephaly, and elevated serum CK levels (table 3) [72].

The electroencephalogram is abnormal in this disorder and shows epileptiform activity. Cortical dysgenesis is detected by cerebral computed tomography (CT) or MRI. The specific lesions are pachygyria and polymicrogyria in the temporal and occipital regions. Transient T2 hyperintensities appear in the white matter, and hypoplasia of the pons and cerebellar cysts may occur [73]. Ocular involvement is limited to simple myopia without structural changes. In a registry from Japan of patients with Fukuyama CMD, myopia was the most frequently diagnosed abnormality (9 percent), followed by strabismus (6 percent) [74]. Overall, 16 percent of patients needed respiratory support and this percentage increased with age. Cardiac dysfunction was diagnosed in 16 percent of patients, and dysphagia was noted in 22 percent.

The locus for the mutated Fukuyama-type (MDDGA4) congenital muscular dystrophy gene (FKTN gene) is located on chromosome 9q31-33 [71,75]. The respective protein, fukutin, is secreted outside the cell and may be a component of the extracellular matrix reinforcing muscle membranes [73]. Pathologic studies of the brain have suggested that fukutin is a constituent of the basement membrane [76].

FKTN pathogenic variants have also been associated with severe dilated cardiomyopathy accompanied by a mild form of limb-girdle muscular dystrophy [77]. In addition, FKTN pathogenic variants have been identified in children with an LGMD phenotype and normal intelligence and brain structure designated muscular dystrophy-dystroglycanopathy (limb-girdle) type C4 (MDDGC4). (See "Limb-girdle muscular dystrophy".)

Walker-Warburg syndrome — Cerebro-ocular dysplasia or Walker-Warburg syndrome (WWS) is a type of CMD associated with ocular dysplasia, hydrocephalus, and cerebral malformations [78-81]. Ocular abnormalities include cataracts, optic nerve hypoplasia, corneal clouding, and retinal dysplasia or detachment. Serum CK concentration is mildly to moderately elevated in this disorder and the electrodiagnostic findings are myopathic. Brain MRI shows hypodense white matter, hypoplastic cerebellum and pons, ventricular dilatation (with or without hydrocephalus), and abnormal cortical development known as cobblestone type brain malformation (also called Type II lissencephaly). Other malformations include Dandy-Walker cyst, sometimes associated with posterior encephaloceles. The median survival is only four months.

The Walker-Warburg phenotype is associated with pathogenic variants in the POMT1, POMT2, FKTN, FKRP, POMGNT1, LARGE, ISPD, GTDC2, and DAG1 genes [63,64,82-93]. These pathogenic variants cause defective glycosylation of alpha-dystroglycan complex (figure 1) [84]. In current terminology (table 2), WWS associated with POMT1 pathogenic variants (MIM 236670) is designated as muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A1 (MDDGA1).

Other pathogenic variants in the POMT1 gene are linked to a milder phenotype of congenital muscular dystrophy with microcephaly and intellectual disability, but without the ocular manifestations or structural brain malformations of WWS [94]. In addition, POMT1 and POMT2 gene pathogenic variants have been identified in children with subtypes of autosomal recessive limb-girdle muscular dystrophy (MDDGC1 and MDDGC2). (See "Limb-girdle muscular dystrophy", section on 'Dystroglycanopathies'.)

Muscle-eye-brain disease — Muscle-eye-brain (MEB) disease has a milder phenotype than WWS [95]. The disorder is especially prevalent in Finland.

Patients with MEB typically present with hypotonia, severe progressive myopia from infancy, and developmental delay. Pale retina, low or flat electroretinogram, and visual failure related to retinal degeneration develop with advancing age. Seizures are common and cognitive impairment is often severe. At approximately five years of age, most patients decline motorically and develop contractures and spasticity [96].

Laboratory findings in MEB disease include an elevated serum CK level. Electromyography shows myopathic findings and the electroencephalogram is always abnormal. Brain MRI shows cobblestone lissencephaly, although it is less severe than in WWS; the brainstem in MEB disease is characteristically flat [97]. Ventriculomegaly and white matter hypodensities may also be seen [98]. Visual evoked potentials are delayed and giant (>50 microvolts) in most patients [95].

Muscle biopsy usually shows dystrophic changes, although these may be minimal. Immunohistochemistry shows normal dystrophin and other dystrophin-associated proteins except for deficient alpha-dystroglycan [99].

The clinical phenotype of MEB can be caused by gene pathogenic variants of POMGNT1 [100-103], FKRP [87], POMT2 [64,104], POMT1 [62], FKTN [105], and LARGE [65]. In current terminology (table 2), POMGNT1-related muscle-eye-brain disease (MIM 253280) is designated as muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A3 (MDDGA3).

Diagnosis — For patients with a clinical presentation that is suspicious for CMD, we suggest an evaluation that includes cranial MRI, eye examination, and molecular genetic testing with next generation sequencing techniques [106]. A muscle biopsy for histology and immunostaining is indicated if the molecular genetic testing is negative, but muscle biopsy is not needed if a genetic diagnosis is made.

The infant with any type of CMD typically presents in the newborn period as a floppy baby, often with arthrogryposis. The clinical features are similar to those of an infant with a severe congenital myopathy, a disorder that is more frequent than the rare congenital muscular dystrophies. (See "Approach to the infant with hypotonia and weakness" and "Congenital myopathies".)

MRI of the brain is useful to look for structural lesions or white matter abnormalities that accompany some CMDs. Examination of the eyes is important to exclude an ocular abnormality. The infant with a CMD has variably elevated serum CK levels.

Molecular genetic testing allows for confirmation of many forms of CMD, and testing is available for virtually all genes associated with CMD [32,107]; it has superseded muscle biopsy in most settings. However, no genetic diagnosis can be made in many cases, even with next generation sequencing techniques, suggesting that additional genetic causes of CMD remain to be identified [106].

The diagnosis can also be supported by muscle biopsy findings of wide-spread dystrophic changes or a myopathic pattern [108]. In infants lacking merosin, muscle immunohistochemical examination with antimerosin antibodies usually reveals complete or partial absence of this protein in the sarcolemma of the muscle fibers.

Patients with LMNA-related congenital muscular dystrophy may have prominent inflammatory changes on muscle biopsy and thus be misdiagnosed as having an inflammatory myopathy. In one series of 20 patients with early onset (age ≤2 years) inflammatory myopathy, heterozygous LMNA pathogenic variants were identified in 11 (55 percent) [109].

Management — No definitive treatment is available for these disorders. However, multiorgan complications are common, and multidisciplinary care emphasizing surveillance and prompt interventions may be beneficial for affected children [32].

Monitoring recommendations for CMD, usually performed at least annually, consist of the following [110]:

Cardiac evaluation at diagnosis for all infants with CMD and periodic electrocardiography and echocardiography for those with or at risk for cardiac involvement

Pulmonary function testing in sitting and supine positions

Polysomnography for those with sleep disturbance or pulmonary function testing <65 percent of predicted

Nutrition parameters and growth measurements

Assessment of swallowing and bulbar weakness

Range of motion and orthopedic assessments

General management principles include the following [38,39,110]:

Measures to control weight and avoid obesity

Physical therapy to improve mobility and avoid contractures

Mechanical assistive devices to increase mobility and ambulation

Surgery for orthopedic complications

When beneficial, use of assisted cough, noninvasive ventilation, or tracheostomy and mechanical ventilation

Social and emotional support

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Muscular dystrophy (The Basics)")

Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)")

SUMMARY

Oculopharyngeal muscular dystrophy (OPMD) – This is a rare, slowly progressive myopathy that is characterized by ocular and pharyngeal muscle involvement, leading to ptosis, dysarthria, and dysphagia. Most cases of OPMD are caused by a GCN trinucleotide repeat expansion (where "N" represents any A, C, G, or T nucleotide) in the first exon of the PABPN1 gene. Treatment is supportive. (See 'Oculopharyngeal muscular dystrophy' above.)

Distal muscular dystrophies – These disorders are a heterogeneous group of myopathies, as listed in the table (table 1). They are characterized by weakness that starts distally in the arms and/or legs and gradually progresses to affect proximal muscles. (See 'Distal muscular dystrophies' above.)

Congenital muscular dystrophies (CMDs) – This category includes a number of genetically determined conditions in which muscular dystrophy is evident at birth or within the first two years of life. The original classification of the CMDs was based mainly upon the presence or absence of structural central nervous system abnormalities detected by neuroimaging or at autopsy (table 3). The absence of structural changes distinguished "occidental" or "classic" CMD from "syndromic" forms of CMD such as Fukuyama muscular dystrophy, Walker-Warburg syndrome, or muscle-eye-brain disease. However, the distinction is not entirely precise. The syndromic CMDs are caused by defective post-translational modification of alpha-dystroglycan (dystroglycanopathies) and other proteins, and they are caused by pathogenic variants in multiple genes (table 2).

For patients with a clinical presentation that is suspicious for CMD, we suggest an evaluation that includes cranial MRI, eye examination, and molecular genetic testing with next-generation sequencing techniques [106]. A muscle biopsy for histology and immunostaining is indicated if the molecular genetic testing is negative. No definitive treatment is available for these disorders. However, multiorgan complications are common, and multidisciplinary care emphasizing surveillance and prompt interventions may be beneficial for affected children, as described above. (See 'Congenital muscular dystrophies' above.)

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Topic 6180 Version 32.0

References

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