Keywords
Historical perspectives on pediatric neuromuscular disease, DNA diagnostics, EMG, muscle biopsy, diagnostic tests, clinical classification of pediatric neuromuscular disease, clinical approach, presenting complaints
Introduction
The role of the clinician in the diagnosis and treatment of a weak child is as important today as it was in the 19th century, when pediatric neuromuscular diseases were first being recognized by such luminaries as Meryon (1852), Duchenne (1861), Werdnig (1891), and Hoffmann (1893), and later by Batten (1903). The clinician needs to react to the concerns of the patient and their parents at the first encounter. A detailed medical history and carefully performed physical examination remain the fundamental tools and starting point for assessing various symptoms and signs. This initial clinical assessment has three possible immediate outcomes: (1) the concerns of the patient and family appear to be unfounded, and the clinician can be reassuring. A follow-up visit is advised to substantiate this outcome and to give the parents peace of mind that all, indeed, is well; (2) the clinician shares the concerns of the patient and family but decides to use time as the first test to determine the natural history of the process; or (3) the clinician recognizes the importance of the clinical symptoms and realizes the need to perform diagnostic procedures as soon as possible.
This clinical approach places great demands on the physician at the first and subsequent encounters. Here, the difference between the 19th-century clinician and the 21st-century clinician is enormous. This difference is a measure of the scholarly advances of the past century, particularly over the past three decades, since the advent of molecular neurogenetics. Examples of such advances include major discoveries in the genetic analysis of the muscular dystrophies, congenital myasthenic syndromes, spinal muscular atrophies, and hereditary neuropathies. These advances in molecular neurogenetics have led to new diagnostic tests, which may confirm the clinical diagnosis accurately and noninvasively. Traditional diagnostic tests such as nerve conduction studies, electromyography (EMG), and open muscle biopsy are less often required in the evaluation of neuromuscular disorders in infancy, childhood, and adolescence. Nevertheless, these traditional tests remain useful in certain situations: to evaluate patients in whom molecular genetic analyses fail to confirm the initial clinical impression, to facilitate the rapid electrophysiologic diagnosis of a neuropathy or spinal muscular atrophy, or to focus more precisely on molecular mechanisms before ordering relatively expensive molecular genetic tests. The dramatic advances in DNA diagnostics have added to the complexity of a challenging clinical field and have left physicians occasionally uncertain about the relative indications for traditional tests such as EMG and muscle biopsy. Clearly, all these diagnostic tests remain useful, and it is up to the modern clinician to make informed decisions, after the initial clinical evaluation, to facilitate an accurate biomolecular diagnosis as quickly and as economically as possible.
Traditional Diagnostic Tests
The technique of muscle biopsy was first introduced by Duchenne in 1868, using a harpoon-like device to sample the affected tissue during life. This crude device was the harbinger of the biopsy needle. Earlier and later investigators used muscle tissues obtained after the patient’s death. These techniques have continued to be refined, and analysis of involved tissue has become increasingly elegant and precise, as demonstrated by advances in electron microscopy, enzyme histochemistry, immunocytochemistry, and single myofiber analysis. Today, a biopsied specimen can be processed for several studies, including light microscopy, electron microscopy, enzyme histochemistry, immunohistochemistry, biochemistry, tissue culture, and molecular studies, and protein expression patterns can be assessed in single 8-micron sections taken from muscle biopsies. Advances in electrophysiology have been equally dramatic. The first application of these physiologic principles to neuromuscular diseases dates to the latter part of the 19th century. However, the practical use of nerve conduction studies and needle EMG did not emerge until the mid-20th century. At that time, observations by Lambert at the Mayo Clinic in Rochester, Minnesota, Gilliatt at Queens Square in London, and Buchthal at the Institute of Neurophysiology in Copenhagen defined the electrical parameters of the normal peripheral motor and sensory unit as well as the potential for widespread application of these findings to the evaluation of neuromuscular disorders. These three clinical neurophysiologists, among others, also recognized the importance of carefully defined normal neurophysiologic values, which are still used today. These studies defined the significant maturational changes during early development that remain important to the performance and interpretation of pediatric EMG, as detailed in Chapter 3 . The more universal application of EMG to pediatric motor unit disorders had attracted increasing interest during the two decades that preceded the mapping and discovery of the SMN gene mutated in classic spinal muscular atrophy. Byers’ and Banker’s classification of the spinal muscular atrophies at Boston Children’s Hospital was an important early contribution later expanded by Dubowitz.
Other seminal reports continued to appear. Dyck and Lambert separated Charcot-Marie-Tooth disease into demyelinating and axonal forms, presaging a similar DNA classification that followed a quarter century later. Gutrecht and Dyck performed important anatomic studies defining the maturation of peripheral nerve myelination. These findings mirrored the normal increase in the speed of peripheral nerve conduction from infancy to age 5 years. Appreciation of these normal ranges for motor nerve conduction velocities also led to the definition of a subacute acquired polyneuropathy: chronic inflammatory demyelinating polyneuropathy (CIDP). These observations were important both because of CIDP’s predominant proximal presentation, often mimicking a myopathy, but particularly because CIDP is a treatable condition. These maturational distinctions also emphasize the importance of traditional testing modalities such as nerve conduction studies to enable diagnosis in complex cases with dual pathologies, such as the rare instances of CIDP superimposed upon genetic neuropathies.
Engel and Lambert applied microelectrode methodology in vitro , extending our understanding of the various uncommon congenital neuromuscular transmission defects (NMTDs). These observations helped define the normal physiology of neuromuscular transmission, as well as enhancing our ability to differentiate congenital, inherited NMTDs from acquired, immunologically mediated NMTDs. However, it remains difficult to make a precise clinical neurophysiologic diagnosis of some of these congenital NMTDs. For example, some electrophysiologic parameters are not well defined for the immature neuromuscular junction. Additionally, precise microelectrode analysis of a biopsied neuromuscular junction is still necessary for diagnosis of some conditions.
Infant motor unit potentials (MUPs) are typically quite small, mimicking the size of abnormal adult “myopathic” motor units. This maturational distinction sometimes challenges the clinical neurophysiologist who is attempting to differentiate a myopathy in a newborn from a normal response. The rapid acquisition of a full recruitment pattern encompassing very small MUPs may provide the initial clue to the presence of a myopathy. On some occasions, it is equally important for the clinical neurophysiologist to advise the referring physician that even though the MUPs may appear to be normal in a floppy infant, such a finding does not exclude a myopathy.
Similarly, the finding of fibrillation potentials may not define a neuromuscular disorder as either neurogenic or myopathic. Generally, these potentials signify a denervating process, but similar abnormalities are sometimes seen in myopathies. In reality, the fibrillation potential results from the disconnection of all or part of a myofiber from the nerve, so the principle remains intact; that is, fibrillation potentials signify denervation of the myofibers. It is important to emphasize that the MUP is the key to making the neurophysiologic distinction between a primary anterior horn cell process and one that relates to a dysfunction of the muscle fiber. Differentiating a normal immature MUP from a congenital myopathy or early dystrophy is a bigger challenge for the clinical neurophysiologist.
DNA analysis now frequently resolves the confusion in these clinical settings. The benefit of DNA analysis is apparent in the evaluation of Duchenne muscular dystrophy (DMD), where EMG and muscle biopsy were state-of-the-art diagnostic studies three decades ago. Today, the clinical diagnosis of children with suspected DMD or spinal muscular atrophy can be quickly confirmed by specific DNA testing. Similar changes are occurring in a number of the other hereditary neuromuscular disorders, as reviewed elsewhere in this book.
Clinical chemistry methods emerging after World War II provided another important means of distinguishing between neuropathies and myopathies. The serum transaminases and aldolase measures were introduced first, but measurement of serum creatine kinase (CK) activity has proved to be more tissue specific, CK expression being limited to muscle and brain. Elevated values—in excess of 1000 IU—favor a primary myopathic process. Other serum enzyme values usually parallel the serum CK values, but add little to our understanding of the precise disease process. As is true of every diagnostic procedure, the exceptions continue to accumulate. Thus, many “myopathies” often have normal serum enzyme values—witness congenital myopathies, metabolic myopathies, the periodic paralyses, and the various NMTDs. But the generalization is still helpful diagnostically, and a serum CK value is useful when first evaluating a patient with weakness, hypotonia, fatigue, or pain. A high serum CK value suggests a myopathy and mandates further investigation, but a normal value does not exclude primary pathology of the myofiber (e.g. congenital myopathies).
Other blood and urine tests have become available and provide valuable information as screening procedures. The serum and CSF lactate and pyruvate may be elevated in mitochondrial diseases, and carnitine and its acylated profile may be altered in defects of fatty acid oxidation. Immunologic tests may be informative, such as acetylcholine receptor and anti-MuSK antibodies in myasthenia gravis. As with all tests, abnormal results may be informative, but normal results may be consistent with the initial clinical diagnosis.
Modern Diagnostic Testing
The clinical landscape of modern medicine will continue to change as a result of the breathtaking advances in molecular genetics. These advances can be traced back to several seminal contributions over the past decades since the elucidation of the structure of DNA. Newborn screening was introduced in the 1960s by Robert Guthrie ; and now, with the increasing application of molecular diagnostics, expanded newborn screening has the potential of eliminating the often expensive “diagnostic odyssey” that begins with the onset of clinical symptoms postnatally. Even more exciting is the possibility of treating the genotype, rather than the clinical phenotype, as clearly witnessed by the phenylketonuria (PKU) model. This proactive approach obviates the need to “rescue” the phenotype since the treatment intervention will precede the onset of symptoms. Undoubtedly, there must exist a window of therapeutic opportunity for genetically determined neuromuscular diseases, and this window probably continues to close as the postnatal timeline is extended. For example, we know that the disease process is progressing for a period of time before clinical symptoms become manifest. Children with Duchenne muscular dystrophy have very high serum CK values in infancy, long before they develop symptoms in early childhood. Again, the PKU experience reinforces these basic principles. The longer the patient is symptomatic, the more difficult it will be to react to the symptoms, rescue the clinical phenotype and restore the patient to good health.
In 1969, Tay-Sachs disease was shown to be caused by hexosaminidase deficiency ; and the next year, the concept of preconception testing and counseling emerged. As a long-term result, Tay-Sachs disease has largely been eliminated in the at-risk Ashkenazi Jewish population. Now, over 100 recessive diseases, most untreatable and some affecting the neuromuscular system, can be prevented using this same model. Applying next-generation sequencing to preconception screening has the potential of eliminating many recessively transmitted neuromuscular diseases that are discussed throughout the several chapters of this book, analogous to the elimination of smallpox, poliomyelitis, and other infectious diseases by effective vaccine programs.
Next-generation molecular testing also will allow for a more complete interrogation of the human genome in puzzling clinical conditions like myoadenylate deaminase deficiency. This condition is present in 1% to 2% of the population, but most of the carriers are clinically asymptomatic, allowing us to speculate as to whether the condition is truly disease-causing, or whether it is a genetic susceptibility factor that remains silent in the absence of another genetic modifier. In some clinical settings, patients with myoadenylate deaminase deficiency are clearly symptomatic with aches, pain, fatigue, and weakness, and the forearm ischemic exercise test is abnormal with unchanging venous ammonia values. It is possible that these patients have another genetic factor that, when present (or absent), produces a clinical phenotype. The complex molecular mechanisms recently uncovered to explain “reversible cytochrome oxidase deficiency” are another example of multiple molecular factors acting in concert to produce clinical symptomatology.
When a specific genetic condition currently is being considered, DNA studies are increasingly the first laboratory test performed after the clinical evaluation and measurement of serum CK activity. The DNA studies may be targeted to the sequencing of the suspected gene when the clinical phenotype is essentially diagnostic, or broadened to include whole exome or next generation sequencing when the clinical phenotype is less specific. The traditional diagnostic tests mentioned earlier are increasingly reserved for the evaluation of acquired disorders (e.g. toxic, immune-mediated, and/or inflammatory) or genetic disorders that have failed initial DNA screening. Rarely, however, when DNA analysis in a boy with a DMD phenotype fails to reveal a dystrophin gene mutation and the family history is negative, one proceeds to a muscle biopsy. Immunostaining determines whether dystrophin is present or absent, and Western blot analysis allows the size and abundance of the protein to be determined.
Molecular diagnostics are increasingly valuable in the reclassification of clinical disease groups. One excellent example is limb-girdle muscular dystrophies (LGMDs). This category includes autosomal recessive (LGMD2) and autosomal dominant (LGMD1) forms. The autosomal recessive forms usually have an earlier onset, more progression, and higher serum CK activity, with a phenotype that overlaps with the dystrophinopathies. Cognitive involvement, when present, favors a dystrophinopathy, and a serum CK value in excess of 1000 IU/L usually favors a myopathic process rather than a neuropathic process such as spinal muscular atrophy type III.
DNA testing for LGMD1 and LGMD2 subtypes emerged from several research laboratories over the past decade and is now clinically available. Immunohistochemistry of biopsied skeletal muscle tissue remains useful in demonstrating abnormalities of the α-, β-, γ-, and δ-sarcoglycans; dystroglycans; dysferlin; and other proteins. The gene localization, mutated protein, and pattern of inheritance of the various LGMDs are discussed in Chapter 34 .
Patients with the autosomal dominant forms of LGMD (type 1) are usually older, with a slower clinical progression and less elevated serum CK values, with the possible exceptions of LGMDs types 1B and 1C.
These few examples emphasize the clinician’s ability to use modern molecular and traditional diagnostics to confirm a clinical diagnosis rapidly and economically. The neurologist has always been an expert in recognizing the clinical phenotypes, but the advances in molecular diagnosis now demand a sophisticated diagnostic approach to the causative genotypes. Although the phenotype-genotype correlation has sometimes remained elusive, probably because the biological rules still remain incompletely understood, the genotypic approach to diagnosis complements the phenotypic approach. While reliable phenotyping of patients will remain the gold standard in the field of neuromuscular medicine, DNA studies will continue to pave the way for a molecular classification of neuromuscular diseases.
Clinical Classification
The classic phenotypes represent the cornerstone of clinical diagnosis. Adherence to the classic phenotype is mandatory if one needs a clinically pure sample to identify a candidate gene. Misdiagnosis will affect the resulting logarithm of the odds (LOD) score in linkage analysis studies (discussed in Chapter 2 ). An experienced clinician can diagnose a child with DMD by inspection shortly after he enters the room, but modern neurogenetics has taught us that the phenotypic range of the dystrophinopathies is very broad, ranging from the classic Duchenne and Becker phenotypes to patients with myalgias, cramps, hyperCKemia, and possibly even isolated cognitive deficits. The expanded clinical spectrum of genetic conditions can challenge even the experienced clinician, and demand an appreciation of phenotypic and genotypic homogeneity and heterogeneity. Several different gene mutations may cause the same phenotype (e.g. emerin and lamin A/C gene mutations causing Emery-Dreifuss muscular dystrophy), and several different phenotypes may result from the same genotype (e.g. LGMD2B, Miyoshi distal myopathy, and distal myopathy with anterior tibial onset caused by dysferlin gene mutations; and autosomal dominant Emery-Dreifuss muscular dystrophy, LGMD1B, cardiomyopathy with conduction system disease, and partial lipodystrophy caused by mutations within the lamin A/C gene). As a result, phenotype-genotype correlations often remain a puzzle. The lack of correlation between gene defect or residual tissue enzyme activity and clinical condition implies that there are other genetic and environmental factors modifying the expression of the primary mutation.
Neuromuscular disorders are conveniently classified according to the anatomic structure of the motor unit. Diseases of the anterior horn cell are referred to as neuronopathies; of the peripheral nerve as neuropathies; of the neuromuscular junction as myasthenic syndromes or, more commonly today, neuromuscular transmission disorders; and of the myofiber as myopathies. Classically, each of these subgroups presents with distinctive clinical features that orient the clinician during the initial patient evaluation.
Neuronopathies and neuropathies represent a continuum of denervating diseases. Neuronopathies classically involve the cell body, and neuropathies classically affect their extensions and the investing myelin sheath. The dominant neuronopathies in the pediatric age group are the genetically determined spinal muscular atrophies. Their clinical picture varies to some degree, depending on the age at presentation. Infants with spinal muscular atrophy are typically weak and areflexic. The alert infant lying quietly on the examining table with a wide-eyed expression and tongue fasciculations, and predominantly distal movements of the limbs is easily recognized. The older child with the juvenile presentation has more obvious proximal weakness of the shoulder and pelvic girdle muscles and hyporeflexia, simulating the clinical presentation of a dystrophinopathy. However, joint contractures are less common in children with juvenile spinal muscular atrophy, and serum CK values tend to be normal or only slightly elevated. These distinctions allow one to quickly arrive at an initial clinical impression of a neuronopathy versus an active, progressive myopathy. Classically, the extensor digitorum brevis muscle is atrophied in juvenile spinal muscular atrophy and hypertrophied in DMD, another subtle finding that quickly leads the experienced clinician to a presumptive diagnosis. Neurogenic disease causes more wasting than myopathic disease does, and the loss of muscle bulk is more distal. However, these generalizations can be misleading in certain clinical entities. As mentioned previously, in the juvenile phenotype of spinal muscular atrophy, there may be more proximal weakness.
In contrast, certain myopathies are associated with predominantly distal weakness, as is seen, for example, with myotonic muscular dystrophy, desmin myopathy, Miyoshi myopathy, and the myopathy associated with nephropathic cystinosis. Fasciculations of the tongue are prominent in anterior horn cell diseases and may be seen occasionally in neuropathies. Certain metabolic diseases such as Pompe disease also involve the anterior horn cell and may produce fasciculations, but the EMG is distinctive, revealing myotonic discharges that are not seen with infantile spinal muscular atrophy or congenital neuropathies. Combined upper and lower motor neuron signs, the hallmark of amyotrophic lateral sclerosis, are seen infrequently in pediatric patients, but rare examples of juvenile motor neuron disease and neuronal intranuclear hyaline inclusion disease may be encountered, with upper and lower motor neuron signs, bulbar weakness, and fasciculations.
Associated sensory loss implicates the peripheral nerves and argues against motor neuron diseases, NMTDs, and myopathies. Loss of muscle stretch reflexes is also the hallmark of a peripheral neuropathy. Areflexia is the rule when sensory involvement is present. However, muscle stretch reflexes are often reduced or absent in patients with congenital nonprogressive myopathies such as central core disease and nemaline myopathy.
Cramps are the hallmark of denervating diseases and need to be distinguished from muscle contractures. Typically, cramps are associated with intense muscle pain and may cause a palpable mass in the muscle. These symptoms typically occur with the muscle at rest and are brief in duration and sudden in onset. Passive muscle stretching often leads to relief. EMG of a cramping muscle reveals high-frequency motor unit discharges similar to those seen during maximal muscle contraction. Cramps may occur in the absence of definable disease and are generally described as benign, often occurring at night. Otherwise, cramps usually indicate disease of the anterior horn cell, nerve roots, or peripheral nerve elements. Alternatively, cramping may signify the presence of a metabolic derangement altering the neuronal microenvironment, as is seen with renal failure, hypothyroidism, hepatic failure, adrenal insufficiency, or disturbances of electrolyte balance. Cramps and pain, however, are not limited to neurogenic diseases; myalgias and cramps may be seen as the minimal clinical expression of a dystrophinopathy, and painful cramps may accompany caveolinopathy (LGMD1C) or glycogen storage disease, as discussed in Chapter 30 , Chapter 34 , Chapter 39 . Pain and cramping have also been described in mitochondrial diseases and in inflammatory diseases such as dermatomyositis, polymyositis, and Guillain-Barré syndrome. Inflammation of the nerve roots may produce intense pain with the slightest movement, making examination of the child impossible. This discomfort may be so pronounced at times that the child becomes irritable and uncooperative, leading to an initial clinical impression of an acute encephalopathy rather than Guillain-Barré syndrome.
Contractures differ from cramps clinically and electrically. The contracture is electrically silent and may cause muscle pain and localized swelling of the muscle that persists for hours. Unlike cramps, contractures generally occur with exercise and suggest an underlying metabolic myopathy such as phosphorylase deficiency or other glycolytic enzyme defects. Contractures also may occur in patients with hypothyroidism, rippling muscle syndrome, Brody’s disease, and paramyotonia congenita.
Disorders of the neuromuscular junction characteristically present with intermittent symptoms, including weakness and fatigue. In contrast, disorders of the anterior horn cell, peripheral nerve, and muscle generally present with fixed symptoms that are often progressive over time. Fatigue has been underappreciated as a symptom of denervating diseases, particularly spinal muscular atrophy. Recent research has highlighted the early targeting of the synaptic region in both conditions, which may underpin their common symptomatology.
Inflammatory diseases of nerve and muscle may evolve, plateau, and then regress, whereas genetically determined diseases of the motor unit emerge and steadily progress over time. In the pediatric population, disorders of the neuromuscular junction include genetically determined NMTDs, acquired disorders such as infant botulism, and immunologically mediated disorders such as transient neonatal myasthenia gravis, fetal acetylcholine receptor inactivation syndrome, and immune-mediated juvenile myasthenia gravis. Each of these disorders is distinctive and often recognizable clinically by age at presentation and symptoms. EMG studies of the motor unit, particularly neuromuscular junction testing, as mentioned earlier, may be useful as an initial diagnostic study in these disorders.
Congenital disorders of neurotransmission are described in detail in Chapter 26 . These disorders produce varying degrees of weakness and fatigability, often beginning during infancy. Typical symptoms include hypotonia, ptosis, ocular motility disturbances and intermittent apnea. To some extent, these disorders overlap symptomatically with disorders of central neurotransmission, such as aromatic l -amino acid decarboxylase deficiency and tyrosine hydroxylase deficiency (see Chapter 6 ). Transient neonatal myasthenia gravis and infant botulism are acquired disorders of peripheral neurotransmission. The first follows the transplacental transfer of maternal antibodies in the setting of maternal myasthenia gravis; the second results from the ingestion of Clostridium botulinum spores that germinate in the intestinal tract and elaborate the botulinum toxin. Again, the clinical picture is distinctive in each situation. The diagnosis of transient neonatal myasthenia gravis is determined primarily by a family history and examination of the mother. Infant botulism is diagnosed by the clinical symptoms, which include dilated, poorly reactive pupils; constipation; decreased bowel sounds; limpness; apnea, often while feeding at the breast; and weakness, with diminished muscle stretch reflexes. Both conditions improve with time, and no specific treatment may be necessary beyond supportive care.
Acquired, immunologically mediated myasthenia gravis is more frequently encountered in later childhood or adolescence, although we have seen patients as young as 15 months with antibody-positive myasthenia gravis. The intermittent nature of the symptoms is informative, and repetitive motor nerve stimulation is essentially diagnostic, with a characteristic decrement in evoked compound muscle action potential responses. In the morning and at rest, patients are often less symptomatic or asymptomatic. Fatigue associated with repetitive stimulation or with the passage of time during the day is an important clinical characteristic suggesting a defect of neuromuscular transmission.
Intermittent symptoms also raise the diagnostic possibility of a periodic paralysis. The channelopathies are often associated with episodic weakness and myotonia. The myotonias, as a group of diseases, are subdivided into dystrophic and nondystrophic disorders. The dystrophic disorders include myotonic dystrophy and proximal myotonic myopathy. The nondystrophic myotonias and the periodic paralyses, now commonly referred to as channelopathies, result from genetic mutations of various ion channels in muscle. The channelopathies are subdivided according to the ion channel involved in the molecular defect. Sodium channelopathies include the hyperkalemic periodic paralyses and paramyotonia congenita, both transmitted as autosomal dominant conditions. The potassium-aggravated myotonias (myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia) are also transmitted as autosomal dominant conditions and are associated with sodium channel mutations.
Chloride channelopathies include myotonia congenita. This disorder is further subdivided into the autosomal dominant form, known as Thomsen’s disease, and the autosomal recessive form, known as Becker’s disease. Hypokalemic periodic paralysis is the best-known calcium channelopathy. Other channelopathies include Schwartz-Jampel syndrome, rippling muscle disease, Andersen Tawil syndrome, Brody’s disease, and malignant hyperthermia. Andersen Tawil syndrome is associated with periodic paralysis, cardiac arrhythmias, and dysmorphic facial features; Brody’s disease is associated with delayed relaxation and no myotonia; and malignant hyperthermia is an anesthetic-induced delayed relaxation of muscle, one form of which is transmitted as an autosomal dominant trait resulting from a mutation of the ryanodine receptor on chromosome 19.
Evaluation of patients with periodic paralysis is facilitated by an awareness of the phenotype. For example, patients with Andersen Tawil syndrome have characteristic dysmorphic features, including hypertelorism, short stature, low-set ears, and clinodactyly. These dysmorphic features, in the setting of prolonged Q-T interval and life-threatening ventricular arrhythmias, permit an accurate diagnosis in the office. Similarly, patients with Schwartz-Jampel syndrome are phenotypically distinctive, with short stature, bone and joint deformities, chondrodystrophy, hypertrichosis, blepharophimosis, and muscle stiffness. EMG shows nonvariable, continuous high-frequency electrical discharges with delayed muscle relaxation.
Myopathies also are characterized by loss of strength, but the degree of weakness is disproportionate to the degree of muscular atrophy, particularly early in the clinical course. As mentioned previously, the extent of muscular atrophy appears disproportionate in neurogenic diseases. Patients with myopathies appear to be unduly weak, without significant loss of muscle bulk. DMD stands out as a striking example. The muscular-appearing child with DMD appears remarkably weak, struggling to rise from the floor or walk up and down stairs. The large proximal muscles are differentially affected, with relative preservation of the distal muscles. Children with myotonia congenita often appear quite muscular, but struggle to keep up with their peers in sporting activities. Again, there are numerous exceptions to these generalizations, such as the many myopathies that affect distal muscles, including Welander’s and Miyoshi distal myopathies and telethonin deficiency (LGMD2G). Myotonic dystrophy also differentially affects the distal muscles. Gowers’ sign is a manifestation of pelvic girdle muscle weakness, most commonly seen in the setting of DMD ( Figure 1.1 ), but it can also be seen in other neuromuscular disorders, such as juvenile spinal muscular atrophy (type III), CIDP, and mitochondrial diseases.
