The congenital muscular dystrophies

Abstract

Background

Congenital muscular dystrophies (CMDs) are genetically and clinically heterogeneous inherited conditions. Onset is typically within the first year of life. Most CMDs are autosomal recessive, except for de novo dominant mutations in LMNA‐related muscular dystrophy and some collagen‐6‐associated disorders.

Results

CMD is characterized by progressive muscular weakness, hypotonia, multiple contractures with a variable degree, spinal stiffness, delay in motor milestones acquisition, and histologically dystrophic lesions. Also, some forms of CMD may feature structural and myelination abnormalities on brain magnetic resonance imaging, intellectual impairment, and structural abnormalities of the eye. Muscle biopsy specimens exhibit a dystrophic pattern, but the appearance is quite variable depending on the different stages and severity of the disorder. The prevalence of CMD is estimated to be one in 100 000 people. Over the last few years, with advances in molecular genetic diagnostics, knowledge about neuromuscular disorders, particularly CMDs, has increased dramatically. Thus, the incidence may be higher than originally thought.

Conclusion

This article reviews the recent achievements related to the clinical, diagnostic, pathogenic, and therapeutic aspects of CMDs.

Introduction

Congenital muscular dystrophies (CMDs) are a group of inherited disorders that predominantly affect skeletal muscle. They are characterized by early‐onset hypotonia, mild to severe muscular weakness (at birth or in infancy), delayed or arrested fine and gross motor milestones, diminished deep tendon reflexes, and multiple joint contractures. ¹ , ² , ³ , ⁴ , ⁵ Creatine kinase (CK) is usually but not invariably elevated.

Muscle biopsy typically shows a dystrophic myopathic pattern with considerable variation in fiber size, endomysial and paramysial proliferation, degeneration/regeneration, increased adipose tissue, and fibrosis. ² , ³ , ⁶ , ⁷ , ⁸ The histological appearance may vary due to the disorder's specific stages, the disease severity, or both. Muscle biopsy early in the course of the disease may reveal a myopathic pattern without overt dystrophic features, suggesting congenital myopathy, metabolic myopathy, or a neurogenic disorder (Figure 1). ¹ , ²

Figure 1.

Adiposis, fibrosis, and loss of muscle tissue. Hematoxylin and eosin ×10. Courtesy of Dr. Beril Talim.

The occurrence is still poorly understood, although a few publications have reported incidence or prevalence in relatively small areas, with the overall prevalence of CMDs estimated at 0.5–2.5 per 100 000. ³ , ⁴ , ⁶ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³

With the notable exceptions of de novo dominant mutations in lamin A (LMNA)‐related MD and a proportion of severe collagen‐6‐related disorders (COL6‐RD), most CMDs have an autosomal recessive inheritance pattern. ¹⁴ In most instances, disruption of muscle extracellular matrix proteins and their interaction with the sarcolemmal membrane causes CMD. ¹⁵ Although symptoms may stabilize or even improve slightly in the short term, weakness and complications such as contractures, deformities, scoliosis, respiratory distress, cardiac involvement, feeding problems, and failure to thrive eventually worsen. ³ , ¹⁶ , ¹⁷ , ¹⁸ Here, we briefly review the types of CMDs, the related genes, the diagnostic approach, and recently available treatments.

History

Although CMDs were first described in the early 20th century, ⁸ , ¹⁹ they remained poorly differentiated until relatively recently. Batten first recognized CMD in 1903–1904 and described the features of the severe form of congenital myopathy. The term “congenital muscular dystrophy” was originally proposed by Howard in 1908. Subsequently, some distinct forms of CMD emerged based on clinical or ethnic characteristics. ⁸ , ¹⁸ , ²⁰ , ²¹ , ²² Between 1930 and 1990, several CMDs were named: congenital sclerotic atonic muscular dystrophy by Ullrich (in 1930), Fukuyama CMD (FCMD) by Fukuyama (in 1960), rigid spine syndrome by Dubowitz (in 1970), muscle–eye–brain disease (MEB) by Santavari (in 1977), and finally “Walker–Warburg syndrome (WWS)” by Dobbins (in 1986). In 1993, a form of CMD called “Western type of congenital muscular dystrophy” with similar manifestations of FCMD but in a different region was identified.

After 1993, the introduction of molecular diagnostic testing began to revolutionize the diagnosis of CMD. In 1994, merosin‐negative CMD or merosin‐deficient CMD was identified using genetic linkage and mutation analysis. ²³ , ²⁴ Now, this is called LAMA2 deficiency. In 1998, the genes responsible for FCMD and rigid spine CMD were identified. In 2001, a genotype/phenotype correlation of Ullrich CMD was found. In 2003, a new form of CMD with severe central nervous system (CNS) involvement was identified with a mutation in the LARGE gene, and in 2005, WWS with a mutation in another gene, POMT2, was identified. In the meantime, a mild form of WWS presenting like a limb‐girdle muscular dystrophy (LGMD) was identified. ²⁵ With the recent progress in molecular and genetic identification, 35 genes involved in CMD have been identified. However, with the increasing number of phenotypic spectrums, the boundaries between congenital myopathies, CMDs, and LGMDs have blurred. ⁸ , ¹² , ¹⁸ , ²¹ Intellectual impairment can be a component of α‐dystroglycan (α‐DG) glycosylation deficiencies. ⁹ , ¹⁰

Classification

Different approaches have been proposed for the classification of CMDs. The type and location of the abnormal or absent muscle protein determine the classification of CMD. ¹⁰ , ¹¹ These include: (1) disturbances in the structural proteins of the basement membrane or extracellular matrix of muscle fibers, including LAMA2‐related dystrophy (LAMA2‐RD), COL6‐related dystrophy (Ullrich CMD, intermediate, Bethlem myopathy), and integrin α7‐deficient CMD; (2) α‐DG glycosylation defects, including dystroglycanopathies (DGPs): from the most severe end of the spectrum, muscular dystrophy dystroglycanopathy A1 (MDDGA1), including WWS, MEB disease, and FCMD, to moderate MDDGB1, to MDDGC1, which is limb‐girdle MD, the milder end; (3) endoplasmic reticulum (ER) protein defects, including Selenon‐related myopathy (SEPN1); (4) nuclear envelope proteins, including LMNA‐related CMD; (5) proteins involved in ER to Golgi apparatus trafficking, including CMD with fatty liver and infantile‐onset cataract; and (6) other CMDs/CMD‐plus conditions, including mitochondrial CMD (megaconial), CMD with cerebellar involvement, CMD with extrapyramidal signs, CMD with cataracts and ID, Marinesco–Sjogren syndrome, mucolipidosis type IV, and MD/hearing loss/ovarian insufficiency syndrome. ² , ³ , ⁴ , ⁷ , ¹³ , ¹⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ (Figure 2).

Figure 2.

Classification scheme for congenital muscular dystrophy. BMD, Becker muscular dystrophy; CMD, congenital muscular dystrophy; DMD, Duchenne muscular dystrophy; EDMD, Emery–Dreifuss muscular dystrophy; LGDM, limb‐girdle muscular dystrophy.

Disturbances in structural basement membrane or extracellular matrix proteins

Collagen VI‐RD: Ullrich CMD and Bethlem myopathy

Collagen VI is a microfibrillar component found throughout the extracellular matrix of skeletal, smooth, and cardiac muscles, the skin's connective tissue, fibroblasts, and blood vessels. The extracellular matrix plays a structural role in supporting the stability and regeneration of muscle cells and allows muscle cells to adhere to the matrix. Consequently, COL6 could be pivotal in repair processes, such as wound healing and tissue and architecture development. Collagen VI consists of three chains COL6A1, COL62, and COL6A3. A mutation in the gene of any of these chains may lead to its abnormality, deficiency, or absence. Collagen VI‐RD includes various severe, moderate, and milder phenotypes, including Ullrich CMD and Bethlem myopathy; a range of transitional severity between Ullrich and Bethlem is the intermediate phenotype. Collagen VI‐RD is one of the most common CMDs, accounting for 30% of patients. Both autosomal dominant and recessive mutations can cause Ullrich CMD, but Bethlem myopathy is usually dominant. There are some clinical overlaps between both phenotypes. Bethlem myopathy is a milder version in the spectrum of collagen myopathies. ¹ , ⁸ , ¹¹ , ¹⁵ , ¹⁸ , ²¹ , ³¹ Delayed gross motor milestones, generalized muscle weakness, and typical hyperlaxity of distal joints associated with proximal joint contractures characterize the distinct phenotype of Ullrich CMD (Figure 3). The lack of collagen in the brain in a normal state results in normal intelligence without brain involvement. Other features include the prominent calcaneus, kyphoscoliosis, congenital/acquired hip dislocation, keloid formation, hyperkeratosis pilaris, soft palms, and soles. In milder Bethlem myopathy, onset is usually later in early adulthood but may also occur in neonates and progress slowly. Another variant with severity between Ullrich and Bethlem is the intermediate phenotype. These patients walk after the first decade of life but cannot run and develop progressive respiratory failure. Cardiac function is expected to be normal in Collagen VI‐related dystrophies. CK level may be normal to mildly elevated. ¹² , ¹⁸ , ²¹ , ³² , ³³ , ³⁴

Figure 3.

(A) Proximal contractures, distal laxity. (B) Fat pad under soles. From the personal archive (H. T.).

LAMA2‐RD CMD (CMD with α2‐laminin (merosin) deficiency, merosin‐deficient CMD, merosin‐deficient CMD type 1A [MDC1A])

Laminin is an extracellular protein that binds α2‐laminin to α‐DG, which is essential for proper basement membrane function. The normal function of laminin depends on binding to cell surface receptors. Integrin–laminin receptors are involved in cell adhesion, migration, and differentiation. ¹⁸ , ³⁵ , ³⁶ The α2‐laminin subunit is expressed in the basement membrane of muscle fibers, brain vessels, skeletal muscle, and peripheral nerve Schwann cells. ³⁷ Hence, a deficiency in α2‐laminin (merosin) leads to disrupted stability of the basal lamina, increased sensitivity to mechanical stress, and damage to the myofibers inside the muscle. Based on the residual amount of merosin in muscle biopsy samples, the spectrum of LAMA2‐RD phenotypes can be varied, ranging from severe early‐onset CMD due to loss of function mutation (90% of cases) to milder, later‐onset LGMDs due to in‐frame mutation in childhood (complete deficiency vs. partial deficiency). ³ , ²⁹ , ³⁶ , ³⁸ Most patients with the typical LAMA2‐RD phenotype achieve trunk control, but only a few children gain the ability to stand with support, and even fewer (<10%) can walk (Figure 4). Cognition is usually normal in both severe and mild forms. However, up to 30% of patients may experience epilepsy after the age of 6 years, which is not drug‐resistant. ³ , ⁸ , ²⁶ , ³⁶ , ³⁹

Figure 4.

(A) Typical clinical appearance of merosin deficiency. (B) T2 cranial magnetic resonance imaging denoting white matter involvement. From the personal archive (H. T.).

After 6 months of age, most LAMA2‐RD CMD patients show a specific pattern of diffuse white matter changes with increased signal intensity on T2‐weighted images on brain magnetic resonance imaging (MRI). Blood–brain barrier disruption associated with laminin α2 deficiency increases water content, resulting in abnormal white matter signal intensity. However, no correlation was found between the degree of white matter abnormality on MRI and the clinical status and degree of laminin α2 deficiency (partial or total). Cerebellar hypoplasia has been observed in patients with and without intellectual involvement. Also, these patients suffer from demyelinating motor neuropathy with decreased nerve conduction velocity. ⁸ , ²¹ , ³⁷ , ⁴⁰

Integrin α7‐deficient CMD

Integrin α7β1 is a laminin receptor located on the cell surface and connects the cell surface and the basal lamina. Integrin α7 deficiency (ITGA7 gene) CMD has been documented in only a few individuals worldwide, including one neonate. The phenotype is variable, and the disease is characterized by mild muscle weakness, microcephaly, ID, seizures, hemivertebra, and torticollis, with a mild increase in CK and dystrophic pattern in muscle biopsy. ¹² , ²¹ , ⁴¹ , ⁴²

Integrin α9‐deficient CMD

The integrin α9 subunit is expressed in different cells. Few publications have described mutations in integrin α9, suggesting that it is rare. ⁴²

Defects of α‐DG glycosylation

DGPs (MDDGs: WWS, MEB, FCMD, CMD variant 1C)

α‐DG, the most important part of the dystrophin–glycoprotein complex, affects the attachment of the cytoskeleton to the extracellular matrix. It also plays a role in neuronal migration, cortical integrity, and normal growth of retinal vessels. Thus, defects in the α‐DG lead to abnormalities of skeletal muscle, retina, brain, and myocardium. Genotype–phenotype correlation is complex because the same gene is often associated with different phenotypes, and the severity depends mainly on the level of glycosylation defect rather than the gene involved. So far, more than 20 genes involved in secondary DGPs have been identified, the most common of which are POMT1, POMT2, POMGnT1, POMGnT2, FKTN, FKRP, and LARGE ³ , ²⁶ , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ (Table 1). MDDGs are divided into three categories: MDDGA1, MDDGB1, and MDDGC1. The most severe form is MDDGA1, caused by POMT1 gene mutation, which includes WWS and WWS‐like, MEB, and FCMD. Severe structural abnormalities of the brain, cerebellum, and eyes, muscle weakness, and intellectual disabilities are characteristic of these cases. ² , ³ , ¹¹ , ¹² , ²⁶ , ⁴⁴ , ⁴⁷ , ⁴⁸ , ⁴⁹

Table 1.

CMD summary.

Place of involvement	CMD subgroup/name	Involved gene	Distinctive feature
Basal membrane or extracellular matrix proteins	LAMA2‐RD	LAMA2	Brain MRI abnormalities, peripheral neuropathy
	COL6‐RD (Bethlem, Ullrich, intermediate)	COL6A1, COL6A2, COL6A3	Proximal contractures and distal laxity, hyperkeratosis
	Integrin α7‐deficient CMD	ITGA7	Respiratory involvement
	Integrin α9‐deficient CMD	ITGA9
DGP	Primary DGP	DAG1	MEB, WWS
	Secondary DGP	POMT1, POMT2, POMGnT1, POMGnT2, FKTN, FKRP, LARGE1, ISPD, TMEM5, B3GALNT2, B4GAT1, DPM1, DPM2, DPM3, POMK, POMK/SGK196, GMPPB, DOLK	MEB, WWS, CMD‐CRB, CMD‐MR, CMD without MR, FCMD, dilated cardiomyopathy
Endoplasmic reticulum	SELENON‐related myopathy	SEPN1	Rigid spine, scoliosis
Nuclear envelope proteins	LMNA‐related CMD	LMNA	Cardiac involvement
Endoplasmic reticulum or Golgi	CMD + fatty liver + cataract	TRAPCC11, GOSR2	Fatty acid + cataract CNS involvement
Other CMDs	Megaconial CMD	CHKB	GDD, ASD, ichthyosis, dilated cardiomyopathies
	MD with extrapyramidal signs	MICU1	Extrapyramidal signs, episodic fatigue
	MD + cerebellar involvement	MSTO1	Ataxia, pigmental retinopathy
	MD with cataract and ID	INPP5K	Short stature, heart involvement
	Marinesco–Sjogren	SIL‐1	Cataract, pyramidal sign
	Mucolipidosis type IV	MCOLN1	Corneal clauding, absent speech
	MD/hearing loss/ovarian insufficiency syndrome	GGPS1	FTT, progressive

Abbreviations: ASD, autistic spectrum disorder; CMD, congenital muscular dystrophy; CMD‐CRB, CMD with cerebellar involvement; CNS, central nervous system; DGP, dystroglycanopathies; FCMD, Fukuyama CMD; FTT, failure to thrive; GDD, global developmental delay; ID, intellectual disability; MEB, muscle‐eye‐brain disease; MR, mental retardation; MRI, magnetic resonance imaging; WWS, Walker–Warburg syndrome.

WWS is the most severe CMD with global developmental delay (GDD), hypotonia, proximal muscle weakness, severely delayed or arrested motor milestones, seizures, elevated serum CK, myopathic changes in electromyography, and specific pathologic changes in muscle biopsy samples. WWS patients usually die within the first few months to years of life. Neuroimaging findings in WWS include agyria or cobblestone lissencephaly, hydrocephalus, corpus callosum agenesis, and cerebellar structural abnormalities such as cerebellar dysplasia/hypoplasia or cystic lesions. Eye abnormalities such as congenital cataracts, optic atrophy, myopia, microphthalmia, glaucoma, and buphthalmos are also observed (Figure 5). A recent publication showed a high prevalence of cochlear hypoplasia, particularly in the WWS phenotypes. ³ , ⁴⁷ , ⁴⁸ , ⁴⁹

Figure 5.

Total aphakia (L) and bupthalmos (R). From personal archive (H. T.).

MEB‐like/FCMD is less severe than WWS, with structural abnormalities in the brain and eye (especially anterior chamber abnormalities, glaucoma, and retinal dysplasia). These patients usually present with hypotonia, GDD, visual impairment, delayed motor milestones, and premature death in childhood. The most commonly mutated genes in MDDGA1 are POMT1, POMT2, and POMGNT1. ²⁶ , ⁴³ , ⁵⁰

MDDGB1 is another category of DGPs of moderate severity, including CMD with or without brain structural disorder and developmental delay. MDDGC1 or LGMD‐2I is an autosomal recessive disorder characterized by late‐onset muscle weakness, with or without ID, but without structural brain abnormalities. ⁵¹ MRI findings in DGPs are usually more severe than α2‐laminin‐deficient CMD, characterized by relatively diffuse white matter hyperintensities, pontine hypoplasia, and subcortical cerebellar cysts. In contrast, central white matter changes are a feature of merosin‐deficient CMD, and these changes show a consistent trend. This nonprogressive course of leukoencephalopathy in CMD may reflect a static neuronal and glial abnormality rather than an active degenerative process in the central myelin of these patients. ¹² , ¹⁸ , ⁴⁷ , ⁴⁸

ER protein

SELENON‐related myopathy

Selenoprotein N1 is an ER glycoprotein expressed in skeletal muscles and pulmonary parenchyma and encoded by the SEPN1 gene on chromosome 1p36. The role of this protein is in calcium homeostasis and cell protection against oxidative stress. ¹⁶ , ¹⁸ , ⁵² , ⁵³ The disorder is caused by homozygous or compound heterozygous mutation in the SEPN1 gene. Individuals have some distinctive features, including early‐onset spinal rigidity, generalized hypotonia with axial musculature dominancy weakness (strength under gravity in neck flexors and antigravity in neck extensors), palatal muscle weakness causing nasal speech, and failure to thrive. In most patients, its onset occurs before the age of 2 years. Nearly 100% of patients eventually reached independent ambulation (Figure 6). Despite ambulation, gradually progressive respiratory insufficiency occurs. Scoliosis and multiple joint contractures, with normal or mildly elevated CK and nonspecific muscle biopsy changes, are expected. The most characteristic features that become fully apparent during puberty are spinal stiffness, scoliosis, and disproportionate diaphragm involvement compared with limb weakness. More than 80% of patients eventually require assisted ventilation. ³ , ¹⁸ , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷

Figure 6.

Progression of rigid spine at age 3 (A), 6 (B), and 9 years (C), respectively. From the personal archive (H. T.).

Nuclear envelope proteins

LMNA‐related CMD

LMNA/C is an intermediate filament protein that provides nuclear scaffolding for protein complexes. Mutations in the LMNA gene can lead to laminopathies such as Emery–Dreifuss muscular dystrophy, LMGD type 1B, and LMNA‐associated CMD (L‐CMD) that affects multiple organs, including muscle, heart, peripheral nervous system, bone, and skin. ⁵⁸ , ⁵⁹ L‐CMD is an autosomal dominant disorder caused by a de novo mutation in the LMNA gene, which encodes LMNA/C. This is the most severe form of laminopathy and usually presents in the first two years of life with a “dropped head syndrome” due to weakness in the neck extensors and preservation of neck flexor muscles, early‐onset upper limb proximal weakness and lower limb distal weakness (foot drop), multiple contractures, delayed motor milestones, respiratory failure, variable CK elevation, and dystrophic pattern on muscle biopsy. ¹² , ¹⁸ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴

Proteins involved in ER to Golgi apparatus trafficking

CMD with fatty liver and infantile‐onset cataract

The responsible gene, TRAPCC11, is located on chromosome 4q35.1 and encodes transport protein particles (TRAPP), a multiprotein complex that transports vesicles from the ER to the Golgi apparatus. Its manifestations are cataracts from infancy, refractory seizures, cerebral atrophy, severe GDD, peripheral neuropathy, retinopathy, triple A syndrome, high CK (>1000 U/L), and liver and kidney involvement. ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸

Miscellaneous CMDs/CMD spectrum

Mitochondrial CMD (megaconial)

The enzyme choline kinase beta (CHKB), located at 22q13.33, maintains the normal level of phosphatidylcholine in skeletal muscle and plays an essential role in phospholipid biosynthesis. Mutations in this gene can cause megaconial CMD, which presents with very early‐onset hypotonia, GDD, premature muscular atrophy, ichthyosis, dilated cardiomyopathy, and autistic features, but without any brain abnormalities. Muscle biopsy shows a distinct pattern: absence of mitochondria in the center of the fibers, but giant mitochondria (megaconia) around (Figure 7). Observing the pattern of multisystem involvement, pathognomonic features in muscle biopsy, increased serum CK, and finding CHKB gene mutation confirms the diagnosis. ³ , ⁴¹ , ⁴² , ⁶⁹ , ⁷⁰ , ⁷¹

Figure 7.

Enlarged mitochondria at the periphery with central areas devoid of mitochondria on cytochrome c oxidase staining. Scale bar, 20 μm. Courtesy of Dr. Beril Talim.

Marinesco–Sjogren syndrome

Marinesco–Sjogren syndrome is a multisystem disorder with autosomal recessive inheritance caused by biallelic mutations in SIL1. The disease is characterized by severe mental retardation, early‐onset cataracts, findings of cerebellar involvement (cerebellar atrophy, ataxia, wide gait, nystagmus, dysarthria), and myopathy. Clinical findings, mildly elevated serum CK (usually two to four times the upper limit of normal), marginal vacuole formation in muscle biopsy specimens, and myopathic/dystrophic changes can suggest the diagnosis. ⁴² , ⁷² , ⁷³ , ⁷⁴

Other rare CMDs/CMD‐plus

MD with cerebellar involvement

This rare disorder can be caused by MSTO1 mutation. It manifests as ataxia, pigmentary retinitis, and atrophy of the cerebellum. ⁴²

MD with extrapyramidal signs

Mutation in the MICU1 gene causes muscle weakness, extrapyramidal involvement, increased CK levels, and episodic lethargy. ⁴²

CMD with cataracts and intellectual disability

An INPP5K gene mutation can cause short stature, cataract, and myopathy. ⁴²

Mucolipidosis type IV

Corneal opacity, absence of speech, pyramidal tract signs, and achlorhydria are signs of mucolipidosis type IV with a mutation in the MCOLN1 gene. ⁴²

MD/hearing loss/ovarian insufficiency syndrome

MD/hearing loss/ovarian insufficiency syndrome results in failure to thrive, progressive respiratory failure, scoliosis, and long‐term wheelchair use due to GGPS1 gene involvement. ⁴²

Diagnosis

The initial diagnosis of CMD rests on the physical examination and analysis of the family history, sometimes supported by muscle biopsy findings and CNS imaging.   In individuals with suspected CMD, the serum CK is often the first test performed. Muscle MRI and ultrasound are useful noninvasive tools to guide the differential diagnosis and muscle selection for biopsy. Brain MRIs may help to diagnose patients with suspected merosin‐deficient CMD or DGP. MRI of the lower extremity may also be ordered in suspected cases of collagen‐related CMD. Electromyography can identify the myopathic changes of CMD. ⁷⁵

Genetic testing has become the most important and now first‐line diagnostic method for patients suspected of CMD because it hastens the diagnosis and avoids expensive and invasive tests such as electrodiagnostic studies, imaging, and muscle biopsy. Most muscular dystrophies are single‐gene disorders. Molecular genetic tests, including multiplex ligation‐dependent probe amplification, Sanger sequencing, and next‐generation sequencing, specifically whole‐exom sequencing, are used for diagnosis. However, the clinical diagnostic yield varies from 40% to 60%, possibly due to unknown causative genes. ¹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁸ , ²⁶ , ²⁷ , ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸²

Differential diagnosis

The common differential diagnosis of CMD includes several general categories:

• (1)Myopathies: Congenital myopathies, metabolic myopathies, congenital myotonic dystrophy, and other muscular dystrophies.
• (2)Neuromuscular junction disorders: Congenital myasthenic syndromes, infantile botulism
• (3)Neuropathies: Hereditary neuropathies, spinal muscular atrophy (SMA), and congenital ataxia
• (4)Genetic syndromes: Prader–Willi syndrome
• (5)Acquired conditions: Acute hypoxic–ischemic encephalopathy and neonatal sepsis

To confirm or rule out this differential diagnosis, after a careful family history and physical examination, CK assays, electrodiagnostic studies with repetitive stimulation, brain MRI, muscle biopsy, and specific genetic or metabolic testing are recommended. ¹ , ⁶ , ³⁰ , ⁸⁰

Complications

Muscle weakness from CMD can lead to; frequent aspiration pneumonia and respiratory failure. Cardiomyopathy can be a manifestation of the disease itself or can be secondary and requires drug treatment. Immobility promotes osteoporosis and increases the risk of fractures. Scoliosis occurs with some subtypes, further reducing the patient's breathing capacity. ³ Pressure sores may develop in individuals with reduced mobility due to joint contractions and muscle weakness. Adrenal insufficiency, thyroid dysfunction, and vitamin D disorders have been documented, as have  convulsions, depression, and anxiety caused by the underlying disease. ¹ , ² , ³ , ⁸ , ¹⁴ , ⁸³ , ⁸⁴ , ⁸⁵

Treatment

There is currently no disease‐specific treatment for CMD, so treatment is mainly symptomatic and supportive. However, several potential therapies with multiple mechanisms are in clinical development, including genetically based therapies such as cell membrane stabilizers, gene regulators, and gene expression.  The use of antifibrotic, antiapoptotic, anti‐inflammatory agents and nonpharmacological therapies such as low‐protein diet are investigational. ⁸⁶ Selective estrogen receptor modulators can be effective against muscular dystrophy by different mechanisms such as anti‐inflammatory, antifibrosis, and increased muscle mass. Due to the activation of the mTOR pathway in the muscle of fucotin‐deficient mice, inhibition of the mTOR pathway with rapamycin suppresses fibrosis. They act as disease‐modifying drugs for DGpathy. ⁸⁷

Considering the reduced mitochondrial respiration and compensatory regulation of glycolysis in muscles of individuals with MDC1A, targeting the metabolism of the skeletal system, for example, with the use of metformin, might be a promising approach to improve muscle function. Also, considering the possible role of oxidative stress in patients with CMDs, drugs with an antioxidant function, such as N‐acetyl‐l‐cysteine and vitamin E, might improve muscle strength; reduce apoptosis, inflammation, and fibrosis; and improve morphological characteristics. ⁸⁸

Murakami et al., demonstrated that prednisolone at a dose of 0.5–1.0 mg/kg/day improved the gross motor function measurement scores in patients with FCMD. ⁸⁹ As genetics are now used to diagnose and classify neuromuscular disorders, particularly CMDs, they also appear promising in therapeutic strategies. Disease‐modifying gene therapies are the ideal way to target single‐gene, recessive disorders with a clear genetic cause. Adeno‐associated virus (AAV) is another promising treatment method, especially for MDC1A, which uses the virus for somatic gene transfer for high expression in the target tissue. Since the LAMA‐2 gene is large, the whole gene cannot fit into the viral package; miniaturizing the gene is one way to overcome this problem. As seen in Figure 2, in patients with LAMA‐2 mutations who lack laminin‐211, AAV transduction of microlaminin can establish a link between the extracellular matrix and the cell basement membrane. The limitation of this method is the low carrying capacity of the capsid. McKee and Yurchenco in 2022 compared two promoters, AAV9‐SPc5‐12‐αLNNd and AAV9‐CBh‐αLNNdΔG2, in which mice treated with AAV9‐CBh‐αLNNdΔG2 had higher gene expression, fewer seizures, and lower peripheral nerve involvement. ³ , ³⁷ , ⁷³ , ⁹⁰

Despite the current lack of proven drug therapy, physical therapy for prevention of joint deformity, muscle contracture, and scoliosis; noninvasive respiratory support to prevent respiratory distress; correction of gastric reflux; treatment of heart failure and respiratory infections; and nutritional therapy with new methods should be performed regularly to improve the quality of life and increase survival of these patients. ²

Prognosis

The prognosis of CMD depends on the type of protein involved, the severity of the disease manifestations, and the presence of abnormalities of the brain, heart, lungs, or other organs, and the occurrence of orthopedic complications such as kyphoscoliosis and joint contractures. ¹²

Conclusions

Over the last several decades, research into CMD has led to exciting discoveries about the disease and new causative genes. An increased understanding of the genetic basis of these disorders as well as innovative molecular approaches are expected to bring newer therapies for this group of conditions in the years to come.

Author Contributions

Haluk Topaloğlu: Validation; visualization; writing—original draft; writing—review and editing. Bita Poorshiri: Conceptualization; investigation; supervision; validation; visualization; writing—original draft; writing—review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Ethics Statement

The authors received signed consents of patient photography used.