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Neonatal Neuromuscular Disorders
Key Points
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Evaluation of neonatal hypotonia includes neuromuscular conditions, and the diagnostic work-up should be approached in a stepwise manner.
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A normal creatine phosphokinase does not completely rule out muscle disease.
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Electromyography is useful in the diagnostic evaluation of hypotonia and weakness.
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Spinal muscular atrophy (SMA) can present in the neonatal period and has time-sensitive treatments. Genetic testing for the commonly found gene deletion in SMA is increasingly available as newborn screen testing in the United States.
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The search for a genetic diagnosis is crucial in patients with neuromuscular disease.
Neonatal Neuromuscular Disorders
Neuromuscular disorders comprise diseases of the muscle (congenital myopathies and muscular dystrophies), neuromuscular junction (myasthenia gravis and congenital myasthenic syndromes), nerves (neuropathies), and anterior horn motor neurons (spinal muscular atrophies). They present in the neonatal period as floppy infant syndrome with or without contractures. Respiratory insufficiency and swallowing difficulties can be in the forefront of the clinical picture and are frequently associated with significant hypotonia and weakness.
This chapter reviews our current knowledge of neuromuscular disorders with neonatal onset and their clinical details alongside pathologic, genetic, and radiologic aspects as applicable. Finally, an approach to the diagnostic evaluation of neonates when a neuromuscular disorder is suspected is discussed.
Primary Muscle Disorders
Historically, neonatal muscle disorders were divided based on histopathologic criteria into (1) congenital muscular dystrophies (CMDs), (2) congenital myopathies (CMs), (3) congenital myotonic dystrophy, and (4) metabolic myopathies. CMDs demonstrate dystrophic changes on muscle biopsy, with disruption of the muscle fiber and its architecture. Congenital myopathies have more subtle changes with preservation of the muscle fiber architecture. While histopathologically and genetically distinct, their phenotypes are often indistinguishable and characterized by congenital onset of muscle weakness and hypotonia. Some distinguishing features of various disorders are apparent at birth, while others become apparent later. Muscle weakness tends to be progressive with CMDs and relatively static in CMs. Improvement in strength has been reported with some congenital myopathies. Involvement of the central nervous system is seen more often with CMDs and congenital myotonic dystrophy and less so with CMs. Creatine phosphokinase (CPK) tends to be elevated with CMDs and normal or mildly elevated with CMs. Many entities are sporadic or inherited in autosomal recessive fashion with few notable exceptions. Congenital myotonic dystrophy type 1 is inherited in autosomal dominant pattern and shows anticipation. Collagen VI- and RYR1 -related disorders can have both autosomal-dominant and autosomal-recessive inheritance. The genetic advancements of the last decade promised a better understanding of this heterogeneous group of disorders. Instead, it became clear that a pure genetic classification remains impractical for the practicing physician. There are numerous situations where one gene leads to multiple phenotypes and the same phenotype is caused by numerous genes. Recent attempts to classification are based on genetic but also pathologic and clinical data. In the end, a classification that follows a mechanistic approach will likely prove to be most helpful.
Congenital Muscular Dystrophies
CMDs comprise a heterogeneous group of disorders characterized by a dystrophic process on muscle biopsy. Classification schemas alongside diagnostic approaches have been proposed that take into account the recent expansion of knowledge. Given the numerous genes discovered, CMDs have most recently been separated into seven subtypes of disorders: merosin-deficient congenital muscular dystrophy, α-dystroglycanopathies, collagen VI-related disorders, LMNA -related congenital muscular dystrophy, SEPN1 -related myopathy, RYR1 -related myopathies, and CMD without a genetic diagnosis. SEPN1 and RYR1 , which are typically considered myopathies, are in this classification scheme secondary to the varying phenotype at presentation.
LAMA2-Related Congenital Muscular Dystrophy (Merosin-Deficient Congenital Muscular Dystrophies; MDC1A)
LAMA2 -related CMD is due to autosomal recessive mutations of LAMA2 gene known to encode the α 2 subunit of merosin. Merosin is an essential component of the extracellular matrix. In the UK, MDC1A was the most common form of congenital muscular dystrophy, followed, as a group, by dystroglycanopathies and collagen VI myopathies. Clinically, MDC1A often presents at birth or early infancy with severe hypotonia and diffuse weakness. A weak cry, poor suck and swallow, and respiratory failure are common. Contractures may be present at birth in the more severe cases or develop in time. As opposed to dystroglycanopathies, neonates with MDC1A typically have no encephalopathy, and cognitive as well as speech development is normal. On brain MRI, white matter T2 and FLAIR signal abnormalities become apparent in the second half of the first year and approximately 20% of patients develop seizures. A mild demyelinating neuropathy is often present, generally not at the forefront of clinical picture. CPK levels in neonatal period and infancy are elevated four to five times above normal limits. Muscle biopsy demonstrates decreased or absent laminin α 2 immunostaining aside from dystrophic features. Care for patients with LAMA2 mutations is supportive in nature.
Dystroglycanopathies
Dystroglycan complex includes α- and β-dystroglycan and represents one of the transmembrane complexes that link cytoskeleton with extracellular matrix as part of the larger dystrophin-glycoprotein complex. α-Dystroglycan, the extracellular component of the complex, through its heavily glycosylated segment, interacts with several extracellular matrix proteins such as laminin α 2 and agrin. As a receptor for several extracellular matrix proteins, dystroglycan plays a major role in the maintenance of muscle cell structural integrity and synaptogenesis. In the central nervous system, dystroglycan plays an important role in forebrain development, specifically neuronal migration as well as synaptic plasticity and blood-brain barrier integrity. Dystroglycan plays important roles in other tissues such as eye and secreting tissues.
Dystroglycanopathies are a phenotypically heterogenous group of disorders that share a common pathophysiologic theme: abnormal interaction of dystroglycan complex with extracellular matrix proteins because of defective α-dystroglycan O-glycosylation. Their phenotype ranges from severe neonatal muscle weakness with early lethality as well as abnormal brain and eye development to asymptomatic hyperCKemia discovered in adult years.
The modern classification of these disorders is based on their genotype and pathophysiology instead of severity. In this classification, dystroglycanopathies are subdivided into primary (due to mutations in DAG1 gene which encodes the two dystroglycans), secondary (due to mutations in genes known to encode enzymes involved in O-glycosylation of the α-dystroglycan), and tertiary (due to mutations in genes known to encode enzymes and other factors implicated in production of the oligosaccharide building blocks). Primary dystroglycanopathies are the most recent addition to the group and includes a handful of cases, all found in consanguineous families. Their phenotype parallels the more common secondary dystroglycanopathies and includes severe as well as mild forms. Secondary dystroglycanopathies are due to malfunction of various enzymes involved in α-dystroglycan O-glycosylation at the endoplasmic reticulum and Golgi apparatus levels. The number of enzymes involved and their encoding genes have seen significant expansion over the last two decades.
Severe forms, classically labeled as Walker Warburg syndrome” or “Muscle Eye Brain disease”, present at birth with severe muscle weakness and hypotonia, as well as often severe brain and eye malformations. Although hypotonia and muscle weakness are severe, the clinical picture is dominated by encephalopathy, brain and eye malformation, and sometimes seizures. CPK is generally elevated. Brain involvement includes one or a combination of the following findings: agyria, lissencephaly (type 2, “cobblestone”), focal pachygyria or polymicrogyria, heterotopia, complete or partial agenesis of corpus callosum, cerebellum abnormalities, brainstem abnormalities including a “kinked” appearance, posterior fossa cyst, occipital encephalocele microcephaly, hydrocephalus, and white matter changes. Eye abnormalities are quite variable as well and can include cataracts, abnormalities of the anterior chamber, abnormalities of the posterior chamber, microphthalmia, microcornea, small lens, retinal abnormalities, optic nerve hypoplasia, coloboma, and glaucoma. Many of these patients have significantly shortened life span and show little psychomotor developmental progress. Milder phenotypes present at birth or soon after with hypotonia and muscle weakness. MRI might show white matter abnormalities starting in the second half of the first year and cognitive disability which first becomes obvious as various degrees of global developmental delay. Yet, milder forms exist with onset as late as adult years. Tertiary dystroglycanopathies is another emerging group which phenotypically is indistinguishable from other dystroglycanopathies.
Collagen VI-Related Disorders
Collagen VI-related disorders are caused by mutations in the genes that encode one of the three subunits of collagen VI ( COL6A1 , COL6A2 , COL6A3 ) and are classically divided into Ullrich CMD and Bethlem myopathy. Overlaps between the two phenotypes are common though, and the reader is encouraged to think about this group of disorders as a continuum between the two entities. In collagen VI-related disorders there is often a combination of joint laxity and joint contractures in addition to hypotonia and weakness. While Ullrich CMD has a more severe phenotype and onset in utero, often with congenital contractures, Bethlem myopathy tends to be milder and has more variable onset starting in utero and extending into adult life. Ullrich CMD presents at birth with severe muscle weakness, hypotonia, and a combination of marked joint laxity (involving the distal joints) and joint contractures (involving the proximal joints, kyphoscoliosis, and torticollis). Weakness is slowly progressive and respiratory insufficiency is either present at birth or develops later. When it presents in utero or at birth, Bethlem myopathy tends to have a milder phenotype and behaves more like a congenital myopathy. Other useful distinguishing features for collagen VI-related disorders include a prominent calcaneus, hyperkeratosis pilaris on the extensor surfaces, keloid formation, and sometimes congenital hip dislocation. CPK is normal or moderately elevated and muscle biopsy can show both myopathic and dystrophic features. Diagnosis is generally suspected based on clinical grounds and confirmed by targeted genetic testing.
LMNA-Related Congenital Muscular Dystrophy
The LMNA gene, which is associated with autosomal dominant form of Emery–Dreifuss syndrome in older children or adults, has been found mutated in neonates and children with CMD. LMNA encodes for lamin A/C, which is a nuclear envelope protein. The syndrome is classically described as reduced fetal movements, severe hypotonia, and weakness with a “dropped head” appearance because of involvement of the neck muscles.
SEPN1-Related Myopathies
SEPN1 -related myopathies straddle the demarcation line between CMDs and CMs, and encodes for selenoprotein N. SEPN1 is an endoplasmic reticulum glycoprotein preferentially expressed early in the development, and with roles in redox signaling and Ca homeostasis. Most patients with SEPN1 -related myopathies present at birth or within the first 2 years of life with predominantly axial hypotonia, poor head control, and feeding difficulties. The distinguishing features of SEPN1 -related myopathies, including spine rigidity, amyotrophy, and respiratory impairment, became apparent in childhood. Despite a relatively well-defined phenotype, the pathologic findings are variable and include dystrophic features, multi-minicore lesions, fiber size disproportion, and desmin inclusions.
Congenital Myopathies
The term congenital myopathies (CMs) refers to muscle disorders that present in neonatal period or early infancy and lack dystrophic changes on muscle biopsy. CMs tend to have a slowly progressive or nonprogressive course. The severity spectrum is wide, starting with severe illnesses often fatal in the first years of life ( MTM1 and severe ACTA1 disorders), to mild muscle weakness leading to mild gross motor developmental delay. Muscle biopsy shows structural changes at the myofiber level in absence of dystrophic features. The type of structural abnormalities defines the various types of congenital myopathies. Electron microscopy is often very helpful and should always be included when CM is suspected. As with CMDs, genetic advances expanded our understanding of congenital myopathies. We now know that certain genotype might lead to several different histopathologic and clinical phenotypes. The best recognized congenital myopathies are core myopathy, nemaline myopathy, centronuclear myopathy, fiber-type disproportion myopathy, and myosin storage myopathy. In a population study, core myopathies were the most common, representing approximately half of all CMs cases, followed by nemaline and centronuclear myopathies each representing approximately 15% of all CMs cases. Typical neonates present with hypotonia, and weakness. More severe cases have respiratory insufficiency and swallowing difficulties. Elongated and weak face, high-arched palate, and mild ptosis are seen in some of the CMs (nemaline and centronuclear myopathies). Skeletal abnormalities such as hip dislocation, club feet, and pectus excavatum are common. As opposed to congenital muscular dystrophies, CPK may be normal or mildly elevated. Typically, electromyography (EMG) shows myopathic change. EMG can also be normal and even show neurogenic features. Aside from nonspecific myopathic features, muscle biopsy often reveals specific structural abnormalities that define each group of disorders. Genetic testing is often employed first nowadays.
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