| Abstract|| |
Within the history of neuromuscular diseases (NMD), congenital myopathies (CM) represent a relatively new category introduced in the mid-nineteen hundreds upon advent and subsequent application of enzyme histochemistry and electron microscopy by establishing the three major CM, central core disease, nemaline myopathy, and centronuclear myopathy which later pluralized each when the molecular era began at the end of last century. Quickly, during the following 5 decades, many new CM entities were described, based on muscle biopsies and their CM-characteristic myopathology, the former a prerequisite to recognizing an individual CM, the latter of the nosological hallmark of the individual CM. When the molecular era ushered in immunohistochemistry the spectrum and nosography of CM altered in that some CM became allelic to other cohorts of NMD, e.g., congenital muscular dystrophies, other muscular dystrophies, distal myopathies based on different or identical mutations in the same gene. The nosological spectrum of a defective gene also enlarged by recognizing several entities with mutations in the same gene, and same or similar nosological conditions originated from mutations in different genes. Lately, however, CM were reported which lacked any individual myopathological hallmarks, but were clearly based on molecular defects, a fair number of them being newly identified ones. Few CM still remain without any molecular clarification. This nosographic development rendered the original definition of such new CM questionable and brought uncertainty to their classification and nomenclature.
Keywords: Congenital myopathies, electron microscopy, enzyme histochemistry, mutations
|How to cite this article:|
Goebel HH, Dittmayer C, Stenzel W. Congenital myopathies: The current status. Indian J Pathol Microbiol 2022;65, Suppl S1:271-6
| Introduction|| |
Congenital myopathies (CM) as a group of newly defined neuromuscular diseases arose with the introduction into myopathology of new techniques, enzyme histochemistry and electron microscopy, in the middle of last century, also generally termed “New Myopathies” ushered in by Shy and Magee in 1956 with the non-descript title “A new congenital non-progressive myopathy” which later was further named “Central core disease”, although these cores had already been recorded in the earlier original paper. It took another seven years when the second “new” congenital myopathy was reported, again from GM Shy's group: “Nemaline myopathy. A new congenital myopathy”. With the publication of “Myotubular myopathy”, today incorporated among the centronuclear myopathies, and “Familial centronuclear myopathy”, the classical triad of congenital myopathies had been established and a solid nomenclatorial haven for subsequent new congenital myopathic entities had been procured within a period of 12 years (1956-1967): a cohort of early-onset largely non-progressive (with exceptions) neuromuscular diseases marked by myopathological characteristics in skeletal muscle and, thus, detectable only by muscle biopsy (or autopsy). The number and spectrum of congenital myopathies enlarged considerably over the following years, which can be considered “the golden era” of the nosography of the CM. With the explosion of molecular genetics,” the silvery era” ensued, employing molecular techniques and, in myopathology, immunohistochemistry, the latter, however, not reaching the abundance in application and knowledge as, for instance, in muscular dystrophies or inflammatory myopathies. At the morphological level, the recently refined electron microscopy technique of combining serial sections with transmission and scanning methods, to construct three-dimensional images has most suitably been applied to lesions within muscle fibres, such as rods or necklaces [Figure 1] and [Figure 2].
|Figure 1: Array tomography for 3D light and electron microscopy in a case of nemaline myopathy. (a) Approximately 350 serial semithin sections (200 nm each) were prepared for light microscopy, and high-resolution micrographs were aligned with Fiji/TrakEM2 to generate a large reconstructed volume for visualization of rods in a large tissue context. (b) For 3D electron microscopy, 77 serial ultrathin sections (60 nm each) were prepared and recorded with a Zeiss Merlin scanning electron microscope using a BSD4-detector for backscattered electron detection. (c) Rods were segmented semi-automatically using IMOD for visualization within the context of the muscle fiber|
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|Figure 2: Oxidative enzyme histochemistry and 3D electron microscopic features of necklace fibers. (a) NADH-TR preparation shows radiating strands in a fiber with a necklace pattern; the vacuoles do not demonstrate oxidative activity. (b) Approximately 90 ultrathin sections were recorded with a Zeiss Ultra scanning electron microscope, and the volume was reconstructed and segmented similarly as described in [Figure 1]. (c) Visualization of the original image plane (horizontally) and the two reconstructed image planes together with electron lucent inclusions (yellow), electron dense lysosome-like inclusions (red), the centrally located nucleus (blue) and the sarcolemma (green)|
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However, certain CM marked by distinct myopathological features, especially inclusions, have been identified being allelic to neuromuscular conditions without such inclusions, e.g., reducing body myopathy and other FHL1 conditions or spheroid body myopathy and other MYOT entities.
A more detailed survey addressing individual components of the nosology of CM, such as clinical, imaging, ultrasonographic, genetic, myopathological, and therapeutic ones has recently been provided in an educational seminar. These articles entail diverse new developments in many aspects of the CM.
The “classical” congenital myopathies
In the premolecular era, the golden one, each of the three classical CM, central core disease (CCD), nemaline myopathy (NEM), centronuclear myopathy (CNM), were deemed to be one separate disease each because their myopathology, i.e., central (and excentric) cores in CCD, rods/nemaline bodies in NEM, single central myonuclei in CNM and fiber-type disproportion, i.e., predominance and smallness of type I myofibers, type I fiber hypotrophy alone or type I fiber uniformity, was identical in genetically different forms of each of these three CM. Genetic analyses, however, revealed mutations in different genes renaming, also onomatopoetically, these three once single conditions as numerous gene-related entities.
The molecular background of CCD are mutations in the RYR1 gene. Apart from classical autosomal-dominant inheritance, genetic studies revealed additional recessive mutations. The nosological spectrum was augmented to core or core-like conditions without further specific myopathological features. Biopsied muscles of recessively affected RYR1 patients, however, did not contain central cores, but core-like lesions, both at the light and electron microscopic levels [Table 1], and sometimes even dystrophic features, i.e., necrosis and regeneration of muscle fibers and endomysial fibrosis. While the myopathology of CCD is still confined to RYR1 mutations the genetic spectrum of core-like lesions or even myopathies varies and, now, is manifold: SELENON, TTN, MEGF10, FXR1, ACTN2. Another myopathological feature is type I fiber uniformity in CCD with or without cores, rarely, the cores appearing later during the course of CCD. However, while RYR1 mutations are responsible for CCD, RYR1 mutations have been identified in neuromuscular conditions, including CM, without central cores, but minicores in multiminicore disease and “dusty” cores, or any cores, in congenital fiber type disproportion, in centronuclear myopathy, in malignant hyperthermia without cores, and axial myopathy. These conditions are, therefore, lumped under the name of “ryanodinopathies”. A myopathological variant is multiminicore disease one form of which may be caused by mutations in the RYR1 gene, others by mutations in other genes, such as SELENON.
|Table 1: The Spectrum of Core-like Myopathies (CLM) and further CM with core-like lesions|
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Nemaline myopathy (NEM) is now a multigenetic group of genetically different conditions, so far numbering 14 (NEM 1-14, [Table 2]). They all are identified by the occurrence of rods in muscle fibers [Figure 1] and not infrequently by an additional type I fiber hypotrophy or fiber type disproportion. Only when mutations in the ACTA1 are present additional or alternate myopathological features may be found: intranuclear rods, with or without sarcoplasmic rods, aggregates of actin filaments, with or without sarcoplasmic or intranuclear rods. The mutant proteins are related to the Z-disk. Occasionally rods and cores may coexist in the same NEM and muscle fibers. An acquired adult form of nemaline myopathy, SLONM (sporadic late-onset nemaline myopathy), is not a hereditary CM, but an immune-related myopathy, occasionally associated with an MGUS neuropathy, perhaps, with a similar pathophysiology as that of rods in HIV myopathy, but a hereditary adult form of NEM also exists.
|Table 2: The Spectrum of Nemaline Myopathies and further CM with nemaline bodies|
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Likewise, centronuclear myopathy is now a multigenetic condition with mutations in several genes including MTM1 (X-linked recessive, formerly myotubular myopathy) [Table 3]. Recently, the myopathological spectrum has been expanded to include radiating strands and necklaces in muscle fibers, the latter ones also explored in 3D by the array tomography technique [Figure 2].
|Table 3: The Spectrum of Centronuclear Myopathies (CNM) and further CM with central nuclei|
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The clinical entity congenital fiber-type disproportion (CFTD), as a nosographic appendix to the triad of classical CM, is genetically heterogeneous entailing mutations in genes that are also involved in nemaline myopathies and others [Table 4]. Myopathologically, the pattern of fiber type disproportion is present without any further structural abnormalities, but this pattern may also be seen in biopsied muscles from patients with Duchenne muscular dystrophy (personal observation), myotonic dystrophy type I, certain congenital myopathies with additional features or without, and dermatomyositis (personal observation).
|Table 4: The Spectrum of Congenital Fiber Type Disproportion and further CM with fiber type disproportion|
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Further congenital myopathies with known mutations and disease-specific myopathological features
While the canon of CM in this category is not firm less than a dozen may be listed, hereunder. The myopathologically specific lesions, largely inclusions within muscle fibers, may have been onomatopoetic, i.e., transferring the name of the lesion to the name of the myopathy.
Cap myopathy is one such condition based on mutations in the ACTA1, TPM2 and TPM3 genes marked by subsarcolemmal regions of haphazardly arranged sarcomeric fragments which consist of central Z-disks and bilateral I-bands or emerging thin/actin filaments. Cap myopathy shares its three genes, mentioned before, with NEM and CFTD conditions suggesting some pathophysiological relationship among these entities.
Another form within the ACTA1 spectrum [Table 5] is cytoplasmic body myopathy, a separate disease in spite of the presence in many variegated neuromuscular diseases of cytoplasmic bodies.
A rare form is Zebra body myopathy linked to NEM – and cap myopathy – by ACTA1 mutation and the presence of both rods and zebra bodies in muscle fibers. However, zebra bodies have also been encountered at myotendinous junctions and in extraocular muscles.
While aggregates of thin or actin filaments accrue in combination with ACTA1 mutations, also designated as actinopathies, granular myosin protein, rarely as fragments of thick or myosin filaments, accumulates in hyaline body myopathy, also named myosin storage myopathy or myosinopathy, often beneath the sarcolemma or among myofibrils associated with mutations in the MYH7 gene. Autosomal-dominant and –recessive forms exist, and the heart may be affected as well.
CM related to the sarcotubular system are sarcotubular myopathy due to mutations in the TRIM32 gene, being allelic to LGMDR8, and tubular aggregate myopathies linked to mutations in STIM1, ORAI1 and CASQ1 genes. While the former is autosomal-recessive and shows non-rimmed vacuoles under the microscope, the latter follow autosomal-dominant traits and are marked myopathologically in myofibers by aggregates of tubules which may react with antibodies to SERCA1 and SERCA2. Tubular aggregates may non-specifically be encountered in other diseases, such as periodic paralyses, congenital myasthenic syndromes, glycogenosis type X.
Reducing body myopathy shows the peculiar feature of non-membrane-bound reducing bodies, i.e., inclusions in muscle fibers, often about the myonucleus and associated with cytoplasmic bodies, which give a bluish hue in the histochemical MAG (menadione-linked alpha-glycerophosphate dehydrogenase) preparation without substrate. It is X-linked and related to mutations in the FHL1 gene, but there are patients with FHL1 mutations without reducing bodies in their muscle fibers. The heart may also be affected. Reducing bodies of different ultrastructure, different origin, and different nosological connotation are seen in patients with post-infantile glycogen storage disease, type II.
Sarcoplasmic body myopathy has earlier been described from Sweden and additionally recently from Spain as an autosomal–dominant myopathy due to mutations in the MB gene, hence, also called myoglobinopathy. Its myopathological hallmark are autofluorescent ultrastructurally electron dense finely granular inclusions in muscle fibers resembling lipopigments, especially those in vitamin E deficiency, where, however, the lipopigments are also seen in Schwann cells.
Spheroid body myopathy and Mallory body-like myopathy have been eliminated from the canon of separate CM and are now listed as myopathological and genetic variants of myofibrillar or protein aggregate myopathies because the former has been found to be a myotilinopathy, the latter a selenoproteinopathy.
Triadin myopathy is a recently described CM, myopathologically marked by minute vacuoles and absence of triadin, by immunohiostochemistry, in muscle fibers, and, by electron microscopy, absence of triadin elements at the junction of the terminal sacs and the T-tubules of the sarcotubular triads.
Another recently reported congenital myopathy contained myopathological “corona” muscle fibres in two siblings due to compound heterozygous mutations in the SCN4A gene. These “corona” fibers displayed myonuclei arranged in a circular or coronal fashion central to the subsarcolemmal region surrounding core-like lesions and a dearth of mitochondria therein. These features distinguished the “corona” fibers from the myopathology of necklace fibres and that encountered in the myopathy/”muscular dystrophy” marked by mutations in the CHKB gene.
Further congenital myopathies with specific myopathological features, but without known mutations
There are certain structures within muscle fibers, largely defined at the electron microscopic level, such as honeycomb structures or concentric laminated bodies which are not assigned to or characteristic of individual myopathies/CM, but would qualify as CM by the definition of CM. Others may be of dubious nosological connotation, fingerprint bodies, cylindrical spirals, hexagonal crystalline inclusions having been reported in respective myopathies because their anatomically specific structures appeared sufficiently numerous within the muscle fibers to justify their onomatopoetic status. Some papers recording these latter structures just use them in conjunction with the term myopathy giving the impression – at least to the authors – that their reported myopathy deserves the name of the most conspicuous morphological element in the biopsied skeletal muscle.
Fingerprint bodies are the myopathological hallmark of fingerprint body myopathy, but numerous fingerprint bodies have also been reported in myotonic dystrophy, the criteria of myotonic dystrophy overriding those of fingerprint myopathy of which fingerprint bodies are the only myopathological criterion. The combination with rods has been described in a nemaline myopathy, similar to the association of zebra bodies with rods which has made zebra bodies a companion or “cousin” of rods and, perhaps, thereby eliminated zebra body myopathy as a separate entity.
While concentric laminated bodies (CLB) have been recorded in passing and, thus, reported not as a main myopathological hallmark, cylindrical spirals, appearing somewhat similar to CLB in ultrastructure, have not infrequently occurred in publication titles., Taratuto et al. reported an autosomal-dominant myopathy with cylindrical spirals, but patients also had a mutation in the FSHD/DUX4 gene. Cylindrical spirals have also been viewed as similar to tubular aggregates because they have both been found reacting with antibodies against SERCA1 and SAR1 and deposited together in the same muscle fibers, closely attached to each other.
At several occasions crystalline or paracrystalline inclusions have incidentally been encountered in muscle fibres of unrelated patients. However, one type, that in hexagonal crystalloid body myopathy, has been documented several times, and in families, too. These inclusions may conspicuously be labelled with an antibody against caveolin 3, but the entire spectrum of molecular or proteomic data has not yet been identified.
Further congenital myopathies without specific myopathological features and with known mutations
The annually published Gene Table of “Neuromuscular Disorders” lists additional CM of recent published appearance, the term “congenital myopathy” having been used in the title or the text, according to mutated genes.
Few genes related to CM have further been listed under allelic non-CM conditions in the Gene Table 2021, such as SYN2 (EDMD5), POGLUT1 (LGMDR21), ECEL1 (distal arthrogryposis type 5).
Finally, CM with new gene mutations have lately been published as abstracts [Table 6] presented at recent Word Muscle Society meetings, but not – yet ? – listed in the latest annual Gene Table for 2021. Unfortunately, such abstract-only CM have not been entered in the Pubmed registry, but they are regularly published in “Supplement” issues of “Neuromuscular Disorders”. These CM and those mentioned in the preceding paragraph elude precise morphology-related names and other specific features, apart from their individual mutations. Hence, a modified nomenclature may be used based on the respective genes involved – and already used in the recent Gene Table, e.g., CM related to PAX7 and CM related to SCNA4.
|Table 6: Recently reported CM the genes of which are not present in the 2021 Gene Table|
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Management and treatment
While management is well established for patients with CM causal therapy is “in its infancy” entailing pharmacological and genetic approaches – enzyme replacement therapy has only been initiated in myotubular CM – but has not reached the level of success as, for instance, in early onset spinal muscular atrophy or Werdnig-Hoffmann disease.
| Conclusion|| |
The panoply of recently described CM which myopathologically lack specific features, but are molecularly clearly defined may require a new nomenclature, at least those without well-known individual myopathology, such as central core disease or hyaline body myopathy. These new CM could easily be designated as CM+defective gene, e.g., CM-MYH7 or CM-FHL1, similar to the nomenclature of CDG (congenital disorders of glycosylation), e.g., PM22-CDG. 3D Microscopy [Figure 1] and [Figure 2] used FIJI/TRAKEM2 and EMOD.
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Conflicts of interest
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Hans H Goebel
Department of Neuropathology, Charite, Chariteplatz 1, Berlin - 10117
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]