Chapter 1
Introduction: Historical Perspectives
Darryl C. De Vivo, Basil T. Darras, Monique M. Ryan, and H. Royden Jones, Jr.
INTRODUCTION infancy, childhood, and adolescence. Nevertheless, these traditional tests remain useful in certain situations: to The role of the clinician in the diagnosis and treatment of evaluate patients in whom molecular genetic analyses fail a weak child is as important today as it was in the 19th to confirm the initial clinical impression, to facilitate the century, when pediatric neuromuscular diseases were first 1 rapid electrophysiologic diagnosis of a neuropathy or being recognized by such luminaries as Meryon (1852), spinal muscular atrophy, or to focus more precisely on Duchenne (1861),2 Werdnig (1891),3 and Hoffmann 4 5 molecular mechanisms before ordering relatively expen- (1893), and later by Batten (1903). The clinician needs sive molecular genetic tests. The dramatic advances in to react to the concerns of the patient and their parents at DNA diagnostics have added to the complexity of a chal- the first encounter. A detailed medical history and care- lenging clinical field and have left physicians occasion- fully performed physical examination remain the funda- ally uncertain about the relative indications for traditional mental tools and starting point for assessing various tests such as EMG and muscle biopsy. Clearly, all these symptoms and signs. This initial clinical assessment has diagnostic tests remain useful, and it is up to the modern three possible immediate outcomes: (1) the concerns of clinician to make informed decisions, after the initial clin- the patient and family appear to be unfounded, and the ical evaluation, to facilitate an accurate biomolecular clinician can be reassuring. A follow-up visit is advised to diagnosis as quickly and as economically as possible. 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 pro- TRADITIONAL DIAGNOSTIC TESTS cess; or (3) the clinician recognizes the importance of the The technique of muscle biopsy was first introduced by clinical symptoms and realizes the need to perform diag- Duchenne in 1868, using a harpoon-like device to sample nostic procedures as soon as possible. the affected tissue during life.12 This crude device was This clinical approach places great demands on the the harbinger of the biopsy needle. Earlier and later inves- physician at the first and subsequent encounters. Here, the tigators used muscle tissues obtained after the patient’s difference between the 19th-century clinician and the death. These techniques have continued to be refined, and 21st-century clinician is enormous. This difference is a analysis of involved tissue has become increasingly ele- measure of the scholarly advances of the past century, gant and precise, as demonstrated by advances in electron particularly over the past three decades, since the advent microscopy, enzyme histochemistry, immunocytochemis- of molecular neurogenetics.6 11 Examples of such try, and single myofiber analysis. Today, a biopsied speci- advances include major discoveries in the genetic analysis men can be processed for several studies, including light of the muscular dystrophies, congenital myasthenic syn- microscopy, electron microscopy, enzyme histochemistry, dromes, spinal muscular atrophies, and hereditary neurop- immunohistochemistry, biochemistry, tissue culture, and athies. These advances in molecular neurogenetics have molecular studies,13 and protein expression patterns can led to new diagnostic tests, which may confirm the clini- be assessed in single 8-micron sections taken from muscle cal diagnosis accurately and noninvasively. Traditional biopsies.14 Advances in electrophysiology have been diagnostic tests such as nerve conduction studies, electro- equally dramatic. The first application of these physio- myography (EMG), and open muscle biopsy are less often logic principles to neuromuscular diseases dates to the required in the evaluation of neuromuscular disorders in latter part of the 19th century.2 However, the practical use
B.T. Darras, H. Royden Jones, Jr., M.M. Ryan & D.C. De Vivo (Eds): Neuromuscular Disorders of Infancy, Childhood and Adolescence, Second edition. DOI: http://dx.doi.org/10.1016/B978-0-12-417044-5.00001-9 © 2015 Elsevier Inc. All rights reserved. 3 4 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
of nerve conduction studies and needle EMG did not neuromuscular junction. Additionally, precise microelec- emerge until the mid-20th century. At that time, observa- trode analysis of a biopsied neuromuscular junction is still tions by Lambert at the Mayo Clinic in Rochester, necessary for diagnosis of some conditions. Minnesota, Gilliatt at Queens Square in London, and Infant motor unit potentials (MUPs) are typically quite Buchthal at the Institute of Neurophysiology in small, mimicking the size of abnormal adult “myopathic” Copenhagen defined the electrical parameters of the nor- motor units. This maturational distinction sometimes chal- mal peripheral motor and sensory unit as well as the lenges the clinical neurophysiologist who is attempting to potential for widespread application of these findings to differentiate a myopathy in a newborn from a normal the evaluation of neuromuscular disorders. These three response. The rapid acquisition of a full recruitment clinical neurophysiologists, among others, also recognized pattern encompassing very small MUPs may provide the the importance of carefully defined normal neurophysio- initial clue to the presence of a myopathy. On some logic values, which are still used today.15 20 These stud- occasions, it is equally important for the clinical neuro- ies defined the significant maturational changes during physiologist to advise the referring physician that even early development that remain important to the perfor- though the MUPs may appear to be normal in a floppy mance and interpretation of pediatric EMG, as detailed infant, such a finding does not exclude a myopathy. in Chapter 3. The more universal application of EMG Similarly, the finding of fibrillation potentials may not to pediatric motor unit disorders had attracted increasing define a neuromuscular disorder as either neurogenic or interest during the two decades that preceded the mapping myopathic. Generally, these potentials signify a denervat- and discovery of the SMN gene mutated in classic spinal ing process, but similar abnormalities are sometimes seen muscular atrophy.20,21 Byers’ and Banker’s classification in myopathies.29 In reality, the fibrillation potential results of the spinal muscular atrophies at Boston Children’s from the disconnection of all or part of a myofiber from Hospital was an important early contribution22 later the nerve, so the principle remains intact; that is, fibrilla- expanded by Dubowitz.23 tion potentials signify denervation of the myofibers. It is Other seminal reports continued to appear. Dyck important to emphasize that the MUP is the key to making and Lambert separated Charcot-Marie-Tooth disease into the neurophysiologic distinction between a primary ante- demyelinating and axonal forms, presaging a similar rior horn cell process and one that relates to a dysfunction DNA classification that followed a quarter century later.24 of the muscle fiber.29 Differentiating a normal immature Gutrecht and Dyck performed important anatomic studies MUP from a congenital myopathy or early dystrophy is a defining the maturation of peripheral nerve myelination.25 bigger challenge for the clinical neurophysiologist. These findings mirrored the normal increase in the DNA analysis now frequently resolves the confusion speed of peripheral nerve conduction from infancy to age in these clinical settings. The benefit of DNA analysis is 5 years.16 Appreciation of these normal ranges for motor apparent in the evaluation of Duchenne muscular dystro- nerve conduction velocities also led to the definition of a phy (DMD), where EMG and muscle biopsy were state- subacute acquired polyneuropathy: chronic inflammatory of-the-art diagnostic studies three decades ago. Today, the demyelinating polyneuropathy (CIDP). These observa- clinical diagnosis of children with suspected DMD or tions were important both because of CIDP’s predominant spinal muscular atrophy can be quickly confirmed by spe- proximal presentation, often mimicking a myopathy, but cific DNA testing. Similar changes are occurring in a particularly because CIDP is a treatable condition. These number of the other hereditary neuromuscular disorders, maturational distinctions also emphasize the importance as reviewed elsewhere in this book. of traditional testing modalities such as nerve conduction Clinical chemistry methods emerging after World War studies to enable diagnosis in complex cases with dual II provided another important means of distinguishing pathologies, such as the rare instances of CIDP superim- between neuropathies and myopathies. The serum transa- posed upon genetic neuropathies.26,27 minases and aldolase measures were introduced first, but Engel and Lambert applied microelectrode methodol- measurement of serum creatine kinase (CK) activity has ogy in vitro, extending our understanding of the various proved to be more tissue specific, CK expression being uncommon congenital neuromuscular transmission defects limited to muscle and brain. Elevated values—in excess (NMTDs).28 These observations helped define the normal of 1000 IU—favor a primary myopathic process.30 Other physiology of neuromuscular transmission, as well as serum enzyme values usually parallel the serum CK enhancing our ability to differentiate congenital, inherited values, but add little to our understanding of the precise NMTDs from acquired, immunologically mediated disease process. As is true of every diagnostic procedure, NMTDs. However, it remains difficult to make a precise the exceptions continue to accumulate. Thus, many clinical neurophysiologic diagnosis of some of these con- “myopathies” often have normal serum enzyme values— genital NMTDs. For example, some electrophysiologic witness congenital myopathies, metabolic myopathies, parameters are not well defined for the immature the periodic paralyses, and the various NMTDs. But the Chapter | 1 Introduction: Historical Perspectives 5
generalization is still helpful diagnostically, and a serum prevented using this same model. Applying next- CK value is useful when first evaluating a patient with generation sequencing to preconception screening has the weakness, hypotonia, fatigue, or pain. A high serum CK potential of eliminating many recessively transmitted value suggests a myopathy and mandates further investi- neuromuscular diseases that are discussed throughout the gation, but a normal value does not exclude primary several chapters of this book, analogous to the elimination pathology of the myofiber (e.g. congenital myopathies). of smallpox, poliomyelitis, and other infectious diseases Other blood and urine tests have become available and by effective vaccine programs. provide valuable information as screening procedures. Next-generation molecular testing also will allow for a The serum and CSF lactate and pyruvate may be elevated more complete interrogation of the human genome in puz- in mitochondrial diseases, and carnitine and its acylated zling clinical conditions like myoadenylate deaminase profile may be altered in defects of fatty acid oxidation. deficiency. This condition is present in 1% to 2% of the Immunologic tests may be informative, such as acetylcho- population, but most of the carriers are clinically asymp- line receptor and anti-MuSK antibodies in myasthenia tomatic, allowing us to speculate as to whether the condi- gravis. As with all tests, abnormal results may be infor- tion is truly disease-causing, or whether it is a genetic mative, but normal results may be consistent with the ini- susceptibility factor that remains silent in the absence tial clinical diagnosis. of another genetic modifier. In some clinical settings, patients with myoadenylate deaminase deficiency are clearly symptomatic with aches, pain, fatigue, and weak- MODERN DIAGNOSTIC TESTING ness, and the forearm ischemic exercise test is abnormal The clinical landscape of modern medicine will continue with unchanging venous ammonia values. It is possible to change as a result of the breathtaking advances in that these patients have another genetic factor that, molecular genetics. These advances can be traced back to when present (or absent), produces a clinical phenotype. several seminal contributions over the past decades since The complex molecular mechanisms recently uncovered the elucidation of the structure of DNA. Newborn screen- to explain “reversible cytochrome oxidase deficiency” are ing was introduced in the 1960s by Robert Guthrie31; and another example of multiple molecular factors acting in now, with the increasing application of molecular diag- concert to produce clinical symptomatology.34 nostics, expanded newborn screening has the potential of When a specific genetic condition currently is being eliminating the often expensive “diagnostic odyssey” that considered, DNA studies are increasingly the first labora- begins with the onset of clinical symptoms postnatally. tory test performed after the clinical evaluation and mea- Even more exciting is the possibility of treating the surement of serum CK activity. The DNA studies may be genotype, rather than the clinical phenotype, as clearly targeted to the sequencing of the suspected gene when the witnessed by the phenylketonuria (PKU) model. This pro- clinical phenotype is essentially diagnostic, or broadened to active approach obviates the need to “rescue” the pheno- include whole exome or next generation sequencing when type since the treatment intervention will precede the the clinical phenotype is less specific. The traditional diag- onset of symptoms. Undoubtedly, there must exist a win- nostic tests mentioned earlier are increasingly reserved for dow of therapeutic opportunity for genetically determined the evaluation of acquired disorders (e.g. toxic, immune- neuromuscular diseases, and this window probably con- mediated, and/or inflammatory) or genetic disorders that tinues to close as the postnatal timeline is extended. For have failed initial DNA screening. Rarely, however, when example, we know that the disease process is progressing DNA analysis in a boy with a DMD phenotype fails to for a period of time before clinical symptoms become reveal a dystrophin gene mutation and the family history is manifest. Children with Duchenne muscular dystrophy negative, one proceeds to a muscle biopsy. Immunostaining have very high serum CK values in infancy, long before determines whether dystrophin is present or absent, and they develop symptoms in early childhood. Again, the Western blot analysis allows the size and abundance of the PKU experience reinforces these basic principles. The protein to be determined. longer the patient is symptomatic, the more difficult it Molecular diagnostics are increasingly valuable in the will be to react to the symptoms, rescue the clinical phe- reclassification of clinical disease groups. One excellent notype and restore the patient to good health. example is limb-girdle muscular dystrophies (LGMDs). In 1969, Tay-Sachs disease was shown to be caused This category includes autosomal recessive (LGMD2) and by hexosaminidase deficiency32; and the next year, the autosomal dominant (LGMD1) forms.35 The autosomal concept of preconception testing and counseling emerged. recessive forms usually have an earlier onset, more pro- As a long-term result, Tay-Sachs disease has largely been gression, and higher serum CK activity, with a phenotype eliminated in the at-risk Ashkenazi Jewish population.33 that overlaps with the dystrophinopathies. Cognitive Now, over 100 recessive diseases, most untreatable and involvement, when present, favors a dystrophinopathy, some affecting the neuromuscular system, can be and a serum CK value in excess of 1000 IU/L usually 6 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
favors a myopathic process rather than a neuropathic pro- distal myopathy with anterior tibial onset caused by cess such as spinal muscular atrophy type III. dysferlin gene mutations; and autosomal dominant DNA testing for LGMD1 and LGMD2 subtypes Emery-Dreifuss muscular dystrophy, LGMD1B, cardio- emerged from several research laboratories over the myopathy with conduction system disease, and partial past decade and is now clinically available.36 38 lipodystrophy caused by mutations within the lamin A/C Immunohistochemistry of biopsied skeletal muscle tissue gene). As a result, phenotype-genotype correlations often remains useful in demonstrating abnormalities of the α-, remain a puzzle. The lack of correlation between gene β-, γ-, and δ-sarcoglycans; dystroglycans; dysferlin; and defect or residual tissue enzyme activity and clinical other proteins. The gene localization, mutated protein, condition implies that there are other genetic and envi- and pattern of inheritance of the various LGMDs are dis- ronmental factors modifying the expression of the cussed in Chapter 34.29 primary mutation. Patients with the autosomal dominant forms of LGMD Neuromuscular disorders are conveniently classified (type 1) are usually older, with a slower clinical progres- according to the anatomic structure of the motor unit. sion and less elevated serum CK values, with the possible Diseases of the anterior horn cell are referred to as neuro- exceptions of LGMDs types 1B and 1C. nopathies; of the peripheral nerve as neuropathies; of the These few examples emphasize the clinician’s ability neuromuscular junction as myasthenic syndromes or, to use modern molecular and traditional diagnostics to more commonly today, neuromuscular transmission disor- confirm a clinical diagnosis rapidly and economically. ders; and of the myofiber as myopathies. Classically, each Theneurologisthasalwaysbeenanexpertinrecognizing of these subgroups presents with distinctive clinical fea- the clinical phenotypes, but the advances in molecular diag- tures that orient the clinician during the initial patient nosis now demand a sophisticated diagnostic approach to evaluation. the causative genotypes. Although the phenotype-genotype Neuronopathies and neuropathies represent a contin- correlation has sometimes remained elusive, probably uum of denervating diseases. Neuronopathies classically because the biological rules still remain incompletely involve the cell body, and neuropathies classically understood, the genotypic approach to diagnosis comple- affect their extensions and the investing myelin sheath. ments the phenotypic approach. While reliable phenotyping The dominant neuronopathies in the pediatric age group of patients will remain the gold standard in the field of are the genetically determined spinal muscular atrophies. neuromuscular medicine, DNA studies will continue to Their clinical picture varies to some degree, depending on pave the way for a molecular classification of neuromus- the age at presentation. Infants with spinal muscular atro- cular diseases. phy are typically weak and areflexic. The alert infant lying quietly on the examining table with a wide-eyed expression and tongue fasciculations, and predominantly CLINICAL CLASSIFICATION distal movements of the limbs is easily recognized. The The classic phenotypes represent the cornerstone of clin- older child with the juvenile presentation has more obvi- ical diagnosis. Adherence to the classic phenotype is ous proximal weakness of the shoulder and pelvic girdle mandatory if one needs a clinically pure sample to iden- muscles and hyporeflexia, simulating the clinical presen- tify a candidate gene. Misdiagnosis will affect the result- tation of a dystrophinopathy.40 However, joint contrac- ing logarithm of the odds (LOD) score in linkage tures are less common in children with juvenile spinal analysis studies (discussed in Chapter 2). An experi- muscular atrophy, and serum CK values tend to be normal enced clinician can diagnose a child with DMD by or only slightly elevated. These distinctions allow one inspection shortly after he enters the room, but modern to quickly arrive at an initial clinical impression of a neurogenetics has taught us that the phenotypic range of neuronopathy versus an active, progressive myopathy. the dystrophinopathies is very broad, ranging from the Classically, the extensor digitorum brevis muscle is atro- classic Duchenne and Becker phenotypes to patients phied in juvenile spinal muscular atrophy and hypertro- with myalgias, cramps, hyperCKemia, and possibly even phied in DMD, another subtle finding that quickly leads isolated cognitive deficits.39 The expanded clinical spec- the experienced clinician to a presumptive diagnosis. trum of genetic conditions can challenge even the expe- Neurogenic disease causes more wasting than myopathic rienced clinician, and demand an appreciation of disease does, and the loss of muscle bulk is more distal. phenotypic and genotypic homogeneity and heterogene- However, these generalizations can be misleading in cer- ity. Several different gene mutations may cause the same tain clinical entities. As mentioned previously, in the phenotype (e.g. emerin and lamin A/C gene mutations juvenile phenotype of spinal muscular atrophy, there may causing Emery-Dreifuss muscular dystrophy), and sev- be more proximal weakness. eral different phenotypes may result from the same In contrast, certain myopathies are associated with genotype (e.g. LGMD2B, Miyoshi distal myopathy, and predominantly distal weakness, as is seen, for example, Chapter | 1 Introduction: Historical Perspectives 7
with myotonic muscular dystrophy, desmin myopathy, an initial clinical impression of an acute encephalopathy Miyoshi myopathy, and the myopathy associated with rather than Guillain-Barre´ syndrome.43 nephropathic cystinosis. Fasciculations of the tongue are Contractures differ from cramps clinically and electri- prominent in anterior horn cell diseases and may be seen cally. The contracture is electrically silent and may cause occasionally in neuropathies. Certain metabolic diseases muscle pain and localized swelling of the muscle that such as Pompe disease also involve the anterior horn cell persists for hours. Unlike cramps, contractures generally and may produce fasciculations, but the EMG is distinc- occur with exercise and suggest an underlying metabolic tive, revealing myotonic discharges that are not seen with myopathy such as phosphorylase deficiency or other gly- infantile spinal muscular atrophy or congenital neuropa- colytic enzyme defects. Contractures also may occur in thies. Combined upper and lower motor neuron signs, patients with hypothyroidism, rippling muscle syndrome, the hallmark of amyotrophic lateral sclerosis, are seen Brody’s disease, and paramyotonia congenita. infrequently in pediatric patients, but rare examples of Disorders of the neuromuscular junction characteristi- juvenile motor neuron disease and neuronal intranuclear cally present with intermittent symptoms, including weak- hyaline inclusion disease may be encountered, with upper ness and fatigue. In contrast, disorders of the anterior and lower motor neuron signs, bulbar weakness, and horn cell, peripheral nerve, and muscle generally present fasciculations.41,42 with fixed symptoms that are often progressive over Associated sensory loss implicates the peripheral time. Fatigue has been underappreciated as a symptom of nerves and argues against motor neuron diseases, denervating diseases, particularly spinal muscular atro- NMTDs, and myopathies. Loss of muscle stretch reflexes phy.44 Recent research has highlighted the early targeting is also the hallmark of a peripheral neuropathy. Areflexia of the synaptic region in both conditions, which may is the rule when sensory involvement is present. underpin their common symptomatology.45 However, muscle stretch reflexes are often reduced or Inflammatory diseases of nerve and muscle may absent in patients with congenital nonprogressive myopa- evolve, plateau, and then regress, whereas genetically thies such as central core disease and nemaline myopathy. determined diseases of the motor unit emerge and Cramps are the hallmark of denervating diseases and steadily progress over time. In the pediatric population, need to be distinguished from muscle contractures. disorders of the neuromuscular junction include geneti- Typically, cramps are associated with intense muscle pain cally determined NMTDs, acquired disorders such as and may cause a palpable mass in the muscle. These infant botulism, and immunologically mediated disorders symptoms typically occur with the muscle at rest and are such as transient neonatal myasthenia gravis, fetal acetyl- brief in duration and sudden in onset. Passive muscle choline receptor inactivation syndrome,46 and immune- stretching often leads to relief. EMG of a cramping mus- mediated juvenile myasthenia gravis. Each of these cle reveals high-frequency motor unit discharges similar disorders is distinctive and often recognizable clinically to those seen during maximal muscle contraction. Cramps by age at presentation and symptoms. EMG studies of the may occur in the absence of definable disease and are motor unit, particularly neuromuscular junction testing, generally described as benign, often occurring at night. as mentioned earlier, may be useful as an initial diagnos- Otherwise, cramps usually indicate disease of the anterior tic study in these disorders. horn cell, nerve roots, or peripheral nerve elements. Congenital disorders of neurotransmission are Alternatively, cramping may signify the presence of a described in detail in Chapter 26. These disorders produce metabolic derangement altering the neuronal microenvi- varying degrees of weakness and fatigability, often begin- ronment, as is seen with renal failure, hypothyroidism, ning during infancy. Typical symptoms include hypoto- hepatic failure, adrenal insufficiency, or disturbances of nia, ptosis, ocular motility disturbances and intermittent electrolyte balance. Cramps and pain, however, are not apnea. To some extent, these disorders overlap symptom- limited to neurogenic diseases; myalgias and cramps may atically with disorders of central neurotransmission, be seen as the minimal clinical expression of a dystrophi- such as aromatic L-amino acid decarboxylase deficiency nopathy,39 and painful cramps may accompany caveoli- and tyrosine hydroxylase deficiency (see Chapter 6). nopathy (LGMD1C) or glycogen storage disease, as Transient neonatal myasthenia gravis and infant botulism discussed in Chapters 30, 34, and 39. Pain and cramping are acquired disorders of peripheral neurotransmission. have also been described in mitochondrial diseases and in The first follows the transplacental transfer of maternal inflammatory diseases such as dermatomyositis, polymyo- antibodies in the setting of maternal myasthenia gravis; sitis, and Guillain-Barre´ syndrome. Inflammation of the the second results from the ingestion of Clostridium botu- nerve roots may produce intense pain with the slightest linum spores that germinate in the intestinal tract and movement, making examination of the child impossible. elaborate the botulinum toxin. Again, the clinical picture This discomfort may be so pronounced at times that is distinctive in each situation. The diagnosis of transient the child becomes irritable and uncooperative, leading to neonatal myasthenia gravis is determined primarily by 8 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
a family history and examination of the mother. Infant Evaluation of patients with periodic paralysis is facili- botulism is diagnosed by the clinical symptoms, which tated by an awareness of the phenotype. For example, include dilated, poorly reactive pupils; constipation; patients with Andersen Tawil syndrome have characteristic decreased bowel sounds; limpness; apnea, often while dysmorphic features, including hypertelorism, short stature, feeding at the breast; and weakness, with diminished mus- low-set ears, and clinodactyly.47 These dysmorphic cle stretch reflexes. Both conditions improve with time, features, in the setting of prolonged Q-T interval and life- and no specific treatment may be necessary beyond threatening ventricular arrhythmias, permit an accurate supportive care. diagnosis in the office. Similarly, patients with Schwartz- Acquired, immunologically mediated myasthenia Jampel syndrome are phenotypically distinctive, with short gravis is more frequently encountered in later childhood stature, bone and joint deformities, chondrodystrophy, or adolescence, although we have seen patients as young hypertrichosis, blepharophimosis, and muscle stiffness.48 as 15 months with antibody-positive myasthenia gravis. EMG shows nonvariable, continuous high-frequency elec- The intermittent nature of the symptoms is informative, trical discharges with delayed muscle relaxation. and repetitive motor nerve stimulation is essentially diag- Myopathies also are characterized by loss of strength, nostic, with a characteristic decrement in evoked com- but the degree of weakness is disproportionate to the pound muscle action potential responses. In the morning degree of muscular atrophy, particularly early in the and at rest, patients are often less symptomatic or asymp- clinical course. As mentioned previously, the extent of tomatic. Fatigue associated with repetitive stimulation or muscular atrophy appears disproportionate in neurogenic with the passage of time during the day is an important diseases. Patients with myopathies appear to be unduly clinical characteristic suggesting a defect of neuromuscu- weak, without significant loss of muscle bulk. DMD lar transmission. stands out as a striking example. The muscular-appearing Intermittent symptoms also raise the diagnostic possibil- child with DMD appears remarkably weak, struggling to ity of a periodic paralysis. The channelopathies are often rise from the floor or walk up and down stairs. The large associated with episodic weakness and myotonia. The myo- proximal muscles are differentially affected, with relative tonias, as a group of diseases, are subdivided into dystro- preservation of the distal muscles. Children with myoto- phic and nondystrophic disorders. The dystrophic disorders nia congenita often appear quite muscular, but struggle to include myotonic dystrophy and proximal myotonic keep up with their peers in sporting activities. Again, myopathy. The nondystrophic myotonias and the periodic there are numerous exceptions to these generalizations, paralyses, now commonly referred to as channelopathies, such as the many myopathies that affect distal muscles, result from genetic mutations of various ion channels in including Welander’s and Miyoshi distal myopathies and muscle. The channelopathies are subdivided according to telethonin deficiency (LGMD2G). Myotonic dystrophy the ion channel involved in the molecular defect. Sodium also differentially affects the distal muscles. Gowers’ sign channelopathies include the hyperkalemic periodic paraly- is a manifestation of pelvic girdle muscle weakness, most ses and paramyotonia congenita, both transmitted as auto- commonly seen in the setting of DMD (Figure 1.1), but it somal dominant conditions. The potassium-aggravated can also be seen in other neuromuscular disorders, such myotonias (myotonia fluctuans, myotonia permanens, and as juvenile spinal muscular atrophy (type III), CIDP, and acetazolamide-responsive myotonia) are also transmitted as mitochondrial diseases. autosomal dominant conditions and are associated with Gowers’ description of this maneuver occurred in his sodium channel mutations. writings on DMD, and little can be added to the original Chloride channelopathies include myotonia congenita. description.49 Patients “first put the hands on the ground, This disorder is further subdivided into the autosomal then stretch out the legs behind them far apart, with the dominant form, known as Thomsen’s disease, and the chief weight of the trunk resting on the hands, by keeping autosomal recessive form, known as Becker’s disease. the toes on the ground and pushing backwards, they manage Hypokalemic periodic paralysis is the best-known calcium to get the knees extended so that the trunk is supported by channelopathy. Other channelopathies include Schwartz- the hands and feet, all placed as widely apart as possible. Jampel syndrome, rippling muscle disease, Andersen Next the hands are moved alternately along the ground Tawil syndrome, Brody’s disease, and malignant hyper- backwards so as to bring a larger portion of the weight of thermia. Andersen Tawil syndrome is associated with the trunk over the legs. Then, one hand is placed on the periodic paralysis, cardiac arrhythmias, and dysmorphic knee, and a push with this and with the other hand on the facial features; Brody’s disease is associated with delayed ground is sufficient to enable the extensors of the hip to relaxation and no myotonia; and malignant hyperthermia bring the trunk into the upright position.” Gowers thought is an anesthetic-induced delayed relaxation of muscle, one that this maneuver was pathognomonic for pseudohyper- form of which is transmitted as an autosomal dominant trophic muscular paralysis.50 Since the original description, trait resulting from a mutation of the ryanodine receptor however, clinicians have come to understand that this sign on chromosome 19. is present whenever there is significant weakness of the hip Chapter | 1 Introduction: Historical Perspectives 9
(A) (D)
(B)
(E)
(C)
FIGURE 1.1 Duchenne muscular dystrophy and Gowers’ sign. This series of photographs shows the components of a “one-handed” Gowers’ maneuver. The patient uses hand support on the floor, initially bilateral then unilateral (A), and hand support on the thighs, either unilateral (B, C) or bilateral, to attain the standing position (D, E). and knee extensors, regardless of whether the underlying exceptions and overlapping features of the symptoms, disease process affects primarily nerve or muscle. as discussed previously. Nothing is more important than Muscle stretch reflexes tend to be relatively preserved a careful history and physical examination. Asking with myopathic diseases and are roughly proportionate to patients or their parents to describe the chronology of the degree of atrophy. When lost, the proximal reflexes are the clinical syndrome is of inestimable value. The tem- more affected than the distal reflexes. However, patients poral profile (the onset, duration, and evolution of the with congenital myopathies often have diminished reflexes symptoms and signs) usually suggests one or more diag- or areflexia. Clinically, if the patient is notably weak with nostic possibilities. For example, knowing that patients preserved muscle bulk and loss of muscle stretch reflexes, with DMD typically present with weakness at age 3 years the condition is most likely a myopathy. is important. Other conditions presenting in early child- hood include Becker’s dystrophy; Emery-Dreifuss dystrophy; facioscapulohumeral dystrophy; limb-girdle CLINICAL APPROACH dystrophy; myotonic dystrophy; inflammatory myopa- The clinical approach to the evaluation of a weak child thies; various metabolic diseases, including lipid storage demands a thorough understanding of the many rules myopathies; mitochondrial diseases; and various endo- that describe diseases of the motor unit and the several crine and metabolic disorders. 10 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
The presentation and the pattern of disease over time pain, weakness, or myoglobinuria provoked by exercise allow one to categorize the possible clinical conditions. quickly leads to the consideration of a metabolic disease, As a rule, the genetically determined neuronopathies and including the several glycolytic enzyme defects and mito- the muscular dystrophies are inexorably progressive from chondrial and lipid storage myopathies. Weakness associ- the time of onset. However, in infants and young children, ated with fever or fasting leads to suspicion of a defect of disease progression is often mitigated by normal child- fatty acid oxidation. Dietary factors, such as the ingestion hood development. As a result, at certain points in early of a high-carbohydrate meal, lead to the consideration of development, the parents may report that the child has periodic paralysis. Patients with paramyotonia congenita stabilized or actually improved functionally. Similarly, may report that cold exposure precipitates their symptoms some patients may have seasonal improvement owing to of muscle stiffness. increased outdoor activities, such as swimming. This sea- Involvement of other organs may lead to diagnostic sonal effect is particularly evident in patients with juve- possibilities. Cardiac disease often accompanies DMD, nile spinal muscular atrophy. Water activity and outdoor Becker’s muscular dystrophy, myotonic dystrophy, Emery- play generally have a beneficial effect on all patients with Dreifuss dystrophy, LGMD1B, LGMD1D, Andersen Tawil neuromuscular disorders. In contrast, other children have syndrome, and various metabolic disorders, including mito- episodic or saltatory patterns to their clinical symptoms, chondrial diseases, acid maltase deficiency, and carnitine which generally suggest an underlying ion channel distur- deficiency. Inflammatory diseases of muscle also may bance or metabolic disease. In addition, inflammatory dis- affect cardiac muscle. In contrast, diseases affecting ante- eases of the neuromuscular system may wax or wane rior horn cell, peripheral nerve, and neuromuscular junction symptomatically. Children with dermatomyositis fre- spare the heart. Multisystemic involvement is common in quently present with this type of history. When the serum mitochondrial diseases; strokes or stroke-like episodes, CK is markedly elevated, saltatory progression of the ill- migraine headaches, short stature, pigmentary retinopathy, ness favors an inflammatory disease of muscle rather than sensorineural hearing loss, proximal limb weakness, and a muscular dystrophy. lactic acidosis are common findings in children with the Weakness evident during the newborn period raises MELAS (mitochondrial encephalopathy and lactic acidosis other possibilities, such as spinal muscular atrophy, congen- with stroke-like episodes) phenotype. Muscle biopsy is ital muscular dystrophy, myotonic dystrophy, the several distinctive in MELAS, classically showing ragged red congenital myopathies defined by distinctive histochemical fibers (Figure 1.2). abnormalities, and certain metabolic diseases such as acid Similarly, respiratory failure leads to the consideration maltase deficiency, phosphorylase deficiency, and carnitine of various diseases that affect the muscle fiber, including palmitoyltransferase type II deficiency. These disorders the spinal muscular atrophies, muscular dystrophies, met- need to be considered, along with the congenital myas- abolic myopathies such as acid maltase deficiency and thenic syndromes and genetic peripheral neuropathies. carnitine deficiency, mitochondrial diseases, congenital CIDP may mimic many of these disorders. Where an myopathies such as nemaline and centronuclear myo- older child has weakness coupled with prominent pain pathy, and inflammatory myopathies such as polymyositis and misery, dermatomyositis is likely, particularly if there and dermatomyositis. are cutaneous abnormalities, including a violaceous dis- Liver involvement may be seen with mitochondrial coloration of the upper eyelids and punctate ulcerations DNA depletion syndrome, acid maltase deficiency, deb- of the extensor surfaces of the limbs. Electrical studies ranching enzyme deficiency, and carnitine deficiency. of the motor unit, EMG, muscle biopsy, and occasion- Ocular involvement may be expected with myotonic dys- ally nerve biopsy may be valuable in diagnosing these trophy, congenital muscular dystrophies, and mitochon- treatable conditions. drial diseases. Dysmorphic features may be seen with the Family history may provide valuable insight into the congenital myopathies, Andersen Tawil syndrome, and patient’s condition. Most disorders of the motor unit are Schwartz-Jampel syndrome. Fixed musculoskeletal con- genetically determined autosomal dominant, autosomal tractures are characteristic of certain long-standing myo- recessive, or X-linked disorders. Others are transmitted as pathies, such as DMD, Emery-Dreifuss dystrophy, and maternal, non-Mendelian traits, pathognomonic for mito- Bethlem myopathy. chondrial DNA mutations. Nothing may be more informa- Scoliosis is uncommon in ambulatory patients but is tive than examining the mother of a weak newborn infant characteristic of Friedreich’s ataxia. Spinal curvature may to determine whether she has evidence of myotonic dys- develop and progress alarmingly fast once the child becomes trophy, myasthenia gravis, inflammatory bowel disease, wheelchair-dependent. A multidisciplinary approach to these or another immune-mediated condition.51 patients is ideal, and complications can be presented or man- Similarly, identifying precipitating factors that may aged early in the clinical course (see Chapters 52 and 53). trigger the onset of symptoms is informative. A history of Children with neuromuscular disorders benefit from input Chapter | 1 Introduction: Historical Perspectives 11
(A) (B)
(C) (D)
FIGURE 1.2 (A) Muscle biopsy specimen from a child with myopathy and the A3243G mtDNA mutation commonly associated with the MELAS phenotype shows a ragged red myofiber (arrow). The reddish granular material in the subsarcolemmal zone reflects proliferation of mitochondria (modified Gomori trichrome). (B) A similar ragged red fiber exhibits intense histochemical staining of succinate dehydrogenase (complex II of the electron transport chain) (arrow). Complex II is entirely encoded by nuclear DNA. (C) The histochemical reaction for cytochrome-c oxidase (COX, or complex IV) of another fiber is unstained (arrow). Three subunits of complex IV are encoded by mitochondrial DNA and are adversely affected by the point mutation (3243) in MELAS to produce this COX-deficient fiber. (D) The smooth muscle cells of a small blood vessel (arrow) show promi- nent punctate staining of succinate dehydrogenase. This finding indicates that abnormal blood vessels are part of the pathology of MELAS syndrome. (Histopathology courtesy of Dr. Arthur P. Hays.) from several subspecialties, including general pediatrics, specific complications such as gastroesophageal reflux, neurology, psychiatry, orthopedics, physical medicine, reha- with resulting erosive esophagitis, and functional consti- bilitation, cardiology, pulmonary medicine, and genetics. pation are common to many neuromuscular disorders, Social services, physical therapy, occupational therapy, and particularly when symptoms occur in infancy. speech therapy are important interventions, assisting in the management of daily living activities. A multidisciplinary clinic is an ideal treatment setting for these patients. PRESENTING COMPLAINTS Unfortunately, some of these rehabilitative services are eco- Most children with neuromuscular disorders present with nomically challenging in today’s health care climate. hypotonia, weakness, fatigue, pain, or an elevated serum Gastrointestinal disturbances may be life-threatening CK value. Fatigue and pain are symptoms, and the others in mitochondrial diseases. Oromotor dysfunction, consti- are signs. The age of the patient influences the presenta- pation, diarrhea, malabsorption, and intestinal pseudo- tion. Infants and young children usually present with obstruction are well-recognized complications. Less signs, whereas older children and adolescents may have 12 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
symptoms that dominate the clinical picture. If symptoms These “motor milestones” vary from infant to infant, but are disproportionate or exist in the absence of signs, psy- weakness is easier to detect with advancing age. chogenic issues must be considered, particularly One cannot ascertain with certainty the presence of depression. sensory deficits at this young age. As a result, a sensori- The floppy infant is hypotonic and also may be weak. motor neuropathy may be difficult to distinguish from a The skill of the examiner is often tested in this setting. neuronopathy because the sensory loss may be difficult to Sorting out weakness from hypotonia can be challenging, define. The behavioral response is most valuable. A nox- and occasionally hypotonia and weakness exist without ious stimulus elicits a prompt withdrawal of the limbs. If any primary pathology of the peripheral motor unit. Many this reflex response is not accompanied by a grimace or genetic syndromes are dominated by congenital hypoto- cry, one should suspect a sensory disturbance. Deep sen- nia, so-called cerebral or central hypotonia. Examples sory disturbances affecting proprioception may disturb the include Prader-Willi syndrome, Down syndrome, Smith- early motor milestones. These infants progress normally Lemli-Opitz syndrome, Zellweger syndrome, and Coffin- to the crawling and cruising stages (9 12 months) but Siris syndrome, to name just a few. These conditions need then fail to walk independently and continually seek to be considered as alternatives to primary neuromuscular external support to maintain an erect posture. A young disorders such as spinal muscular atrophy, congenital girl with a congenital sensory neuropathy is shown in myasthenic syndromes, and congenital muscular dystro- Figure 1.3 as she constantly places her hand on the wall phies. Increased muscle stretch reflexes immediately to achieve better balance. direct attention to the more common central nervous Eliciting tendon reflexes in such young patients also system mechanisms for hypotonia. However, the relation- requires experience. Tapping on one’s own fingers held ship between tendon reflex activity and limb tone is over the appropriate tendon is useful and limits discomfort. generally not fixed. Dysmorphic features may help distin- Ankle jerks are particularly useful to elicit, as these guish a newborn with Prader-Willi syndrome from one responses are often absent in infantile-onset neuromuscular with Werdnig-Hoffmann syndrome and allow immediate disorders. However, tendon reflexes are difficult to elicit in molecular confirmation. Electrophysiologic and mor- other disorders as well, such as Prader-Willi syndrome—a phologic studies of muscle are no longer necessary in relatively common cause of neonatal cerebral hypotonia. most cases. Signs and symptoms of neuromuscular disease are Determining whether hypotonia is present can be chal- more obvious in older infants and children, and symptoms lenging. Several signs aid the clinician, such as the classic can be elicited more readily after age 2 years, when most scarf sign, in which the hand is drawn across the chest to children are beginning to speak. Again, the examiner the opposite ear. Other maneuvers and measures can be should take advantage of observation before intruding on used, but tone is qualitative and subjective. Tone itself is the child. Observing the child’s behavior and motor activ- nebulous; it is the subliminal muscle contraction that ities while taking a history from the parents often pro- opposes gravity and permits a person to maintain posture. vides significant information that leads to a clinical Thus, careful observation of an infant’s posture provides diagnosis. An appreciation of the expected motor mile- information about resting tone. Obviously, weakness and stones during late infancy and early childhood is of para- fatigue contribute to hypotonia, and time of day and rela- mount importance. For example, one expects most tionship to sleep also influence the degree of tone. children to be walking around 1 year of age. By age We have all experienced relative hypotonia at the conclu- 18 months, children are walking independently, and some sion of a long and fatiguing day. are starting to run and climb stairs without assistance. Tone is developmentally determined. A 28-week ges- By age 2 years, the child is able to run quite well, kick a tation premature infant is normally hypotonic, with mini- ball, and travel up and down stairs without hesitation. mal resistance to passive manipulation in all limbs. Flexor Standing on one leg and attempting to jump off a step is tone emerges during the remaining period of gestation, often accomplished by age 3 years, and hopping on one and at birth, a full-term infant has strong flexor tone that foot is attempted by age 4 years. By age 5 years, the child is evident on passive manipulation of the limbs. is able to hop well on either leg. Infantile postures and spontaneous limb movements Many important observations regarding movement in are best observed before intruding on the patient. A full- the supine, sitting, and standing positions can be made term infant demonstrates a flexed limb posture at rest and, while the child is fully clothed. The stance and gait can with advancing postnatal age, shows more spontaneous be observed, and one can determine whether the child is movements of the limbs and trunk. By 6 months, a normal rising up onto his or her toes or walking on flat feet. infant should be strong enough to sit and maintain an Engaging a young child in play with a ball or other object appropriate posture. By 12 months, most healthy infants of interest can allow additional observations, such as the are crawling, pulling to stand, and taking early steps. child arising from the floor, reaching over the head, or Chapter | 1 Introduction: Historical Perspectives 13
(A) (B) (C)
(D) (E) (F)
FIGURE 1.3 Congenital hypomyelination neuropathy and sensory ataxia. (A C) Clinical features in this child include poor balance and pes planus and valgus deformities of the feet. She has areflexia and slowed nerve conduction velocities. (D) A transverse section of the nerve biopsy shows no discernible myelinated fibers by routine histology (trichrome). (E) A transverse thin section (1 μm thick) of epoxy resin-embedded tissue has greater resolution than the paraffin section (6 μm thick) and demonstrates a barely visible thin, dark myelin sheath around each large, pale axon (toluidine blue). (F) A teased myelinated nerve fiber (arrow) shows a very thin myelin sheath as a double-contoured structure resembling a railroad track. Myelin sheaths of other fibers are too thin to identify clearly (osmium tetroxide). (Panels D, E, and F, courtesy of Dr. Arthur P. Hays.) pulling an object from the examiner’s hand. One can also certain muscle groups to evaluate routinely, knowing that note eye movements, the position of the upper eyelids, most diseases of the neuromuscular system are relatively and the facial expression under these conditions, particu- symmetrical and involve limb and axial muscle groups to larly if the child can be encouraged to smile or laugh, or a greater or lesser degree. Clearly, there are exceptions if the child becomes distressed and demonstrates facial to this statement. Some diseases are distinguished by the grimacing. In fact, most of the important observations fact that they are quite asymmetrical, such as facioscapu- regarding the neuromuscular system can be made under lohumeral muscular dystrophy, in which one might find these circumstances, and little may be added by the for- prominent involvement of one side of the body or the mal examination. congenital absence of a pectoral muscle. Nevertheless, Muscle testing can be accomplished in increasing a quick survey of major muscles is often informative detail with advancing age, although the functional mea- and sufficient. Testing of the neck flexors is particularly sures of strength are often the most informative at any useful, because these muscle groups are preferentially age. Determining the child’s strength is central to the affected in many myopathies. Weakness of muscle neuromuscular evaluation. We never analyze all of the groups in the shoulder and pelvic girdles is a useful 434 muscles in the human body. Rather, we select finding, as is weakness in the biceps, triceps, iliopsoas, 14 PART | I Clinical and Laboratory Approach to the Infant and Child with a Neuromuscular Problem
quadriceps, hamstrings, and distal muscles of the hands of superficial or deep sensory loss. Limb tone and tendon and feet. Strength in these muscles can be surveyed reflex activity should be assessed, but again, one need rather quickly. More formal assessment of all accessible not determine a precise grade. The patient has hypotonia, muscle groups is done using the grading system origi- hypertonia, or normal tone; the tendon reflexes are nally developed by the Medical Research Council in absent, diminished, normal, or hyperactive, with or with- 1943.52 This system has withstood the test of time and out clonus. The presence of Babinski’s signs clearly is still valuable in recording degree of weakness at indicates an upper motor neuron disease. A small number presentation and over time. of patients with DMD have initial extension of the Physicians have a tendency to be unnecessarily precise great toe after stimulation of the plantar surface of the regarding clinical observations. The Medical Research foot. Whether this represents evidence of upper motor Council system has five grades: 0 for no movement of the neuron disease, or differential weakness within the foot muscle, 1 for a flicker or trace of movement, 2 for active that limits the response of the great toe to one of exten- movement with gravity eliminated, 3 for active movement sion, can be debated. Assessing the response to plantar against gravity, 4 for active movement against gravity and stimulation in an infant can be challenging and is some applied resistance, and 5 for normal power. Strictly not critical in the overall assessment. Applying the speaking, only the 0 grade is unequivocal. Even a grade stimulus laterally on the foot (Chaddock’s reflex) avoids of 5 can be debated, because each examiner has his or her some of the other competing reflexes seen in this area own idea of normal power. However, to further subdivide during infancy. these categories by adding a plus or minus sign accom- The clinician needs to consider all the diagnostic clues plishes little. provided by the medical history and clinical examination Disrobing the child after initial observations have and then decide whether additional testing is necessary. been made frequently provides important clues. Children Often blood studies, including a serum CK measurement, are innately modest, and a compassionate clinician takes are sufficient. Occasionally, electrophysiologic studies of the time to reassure the patient while performing a care- the motor unit are indicated, particularly if the clinical ful physical examination. Appreciating the presence of evaluation points toward a neuronopathy, neuropathy, or dysmorphic features may be essentially diagnostic, for neuromuscular transmission disorder. These studies can the reasons mentioned earlier. Patterns of weakness and be performed quickly and relatively noninvasively by wasting, and the presence of fasciculations or other spon- nerve conduction studies and EMG. DNA testing may taneous movements of muscle are important. Eye move- quickly confirm the clinical impression of most muscular ments, eyelid posture, facial expression, wasting of the dystrophies, including the dystrophinopathies; channel- temporalis muscle, failure to close the eyes completely, opathies, including many of the periodic paralyses and inability to purse the lips or whistle during expiration, myotonias; and spinal muscular atrophies. Other testing nasality of voice, wasting of the sternocleidomastoid and may be valuable in selected instances. For example, brain trapezius muscles, wasting of the tongue, presence of a magnetic resonance imaging scans may be informative in deep crease running from the axilla obliquely toward the evaluating congenital muscular dystrophies such as neck, a step-like appearance where the base of the neck Fukuyama muscular dystrophy, merosin-deficient congen- and the clavicles meet, winging of the scapulae at rest ital muscular dystrophy, muscle-eye-brain syndrome, and or when the patient attempts to raise the arms in front of Walker-Warburg syndrome. Magnetic resonance imaging the body, atrophy of the intrinsic muscles of the hand or and magnetic resonance spectroscopy may be informative a semiflexed posture of the weakened fingers with some in mitochondrial diseases, in which selective involvement extension at the metacarpal phalangeal joints, exagger- of the basal ganglia is classic, and signal elevations of ated lumbar lordosis or curvature of the spine, protuber- brain and ventricular lactate may be seen. ance of the abdomen, wasting of the quadriceps or the Finally, the modern-day clinician may be overwhelmed anterior compartment muscles of the legs, tapering of by the explosion of new information and can be assisted the legs distally, tightness of the heel cords, abnormali- by several valuable websites: Online Mendelian Inheritance ties of the foot such as pes cavus and pes planus defor- of Man (http://www.ncbi.nlm.nih.gov/Omim/searchomim. mities, and presence of foot-drop are informative and html), National Library of Medicine: PubMed (http://www. often quickly bring one or more diagnostic possibilities ncbi.nlm.nih.gov/PubMed/), Gene Clinics (http://www: to mind. geneclinics.org), Emery-Dreifuss Muscular Dystrophy The physical examination should end with a search Mutation Database (http://www.path.cam.ac.uk/emd/), for other diagnostic clues. Retinopathy, deafness, cardiac Leiden Muscular Dystrophy (http://www.dmd.nl/), the dysfunction, respiratory insufficiency with paradoxical Neuromuscular Disease Center at Washington University breathing pattern, visceral enlargement, or cutaneous School of Medicine, St. Louis (http://www.neuro.wustl. abnormalities should be noted. A careful evaluation of edu/neuromuscular), and Muscular Dystrophy Association, the sensory system is important, searching for evidence USA (http://www.mdausa.org). Chapter | 1 Introduction: Historical Perspectives 15
CONCLUSION 3. Werdnig G. Zwei fru¨hinfantile heredita¨re Fa¨lle von progressiver Muskelatrophie unter dem Bilde der Dystrophie aber auf neuro- The field of pediatric neuromuscular disorders has contin- tischer Grundlage. Arch Psych Nervenkrankh 1891;22:437 80. ued to expand scientifically since the era of molecular neu- 4. Hoffmann J. U¨ berchronische spinale Muskelatrophie im Kindesalter, rogenetics began in the mid-1980s. The rapid changes in auf familia¨rer Basis. Dtsch Zeitschr Nervenheilk 1893;3:427 70. the field may be overwhelming to busy, practicing clini- 5. Batten FE. Three cases of myopathy, infantile type. Brain cians. Older children and their families are increasingly 1903;27:147 8. aware of these extraordinary advances through their own 6. Botstein D, White RL, Skolnick M, Davis RW. Construction of a access to the Internet, and they challenge us to remain genetic linkage map in man using restriction fragment length poly- informed and updated. They wait impatiently for us to morphisms. Am J Hum Genet 1980;32:314 31. 7. Murray JM, Davies KE, Harper PS, Meredith L, Mueller CR, translate these scientific achievements into clinical research Williamson R. Linkage relationship of a cloned DNA sequence on that will lead to more meaningful treatments and ultimately the short arm of the X chromosome to Duchenne muscular dystro- to cures. The chapters that follow represent an effort to phy. Nature 1982;300:69 71. capture this dynamic process at one point in time. The frus- 8. Davies KE, Pearson PL, Harper PS, Murray JM, O’Brien T, tration of the editors and the authors is similar to that of Sarfarazi M, et al. Linkage analysis of two cloned DNA sequences clinicians and their patients. On the one hand, much is hap- flanking the Duchenne muscular dystrophy locus on the short arm pening, and the knowledge base is expanding at a breath- of the human X chromosome. Nucleic Acids Res 1983;11:2303 12. taking pace. On the other hand, our daily management of 9. Francke U, Ochs HD, de Martinville B, Giacalone J, Lindgren V, patients is closer to that of our professional predecessors Disteche C, et al. Minor Xp21 chromosome deletion in a male who initially described many of the disorders discussed in associated with expression of Duchenne muscular dystrophy, this text. Advances in molecular genetics have been breath- chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet 1985;37:250 67. taking, and these advances will likely transform the clinical 10. Monaco AP, Bertelson CJ, Middlesworth W, Colletti CA, Aldridge J, approach from reactive (to presenting symptoms) to proac- Fischbeck KH, et al. Detection of deletions spanning the Duchenne tive (to genotypic lesions) in the near future. Patients will muscular dystrophy locus using a tightly linked DNA segment. be identified before the onset of clinical complaints, and Nature 1985;316:842 5. treatment will be anticipatory and preventive, emulating 11. Ray PN, Belfall B, Duff C, Colletti CA, Aldridge J, Fischbeck KH, the successes of newborn screening since the 1960s. et al. Cloning of the breakpoint of an X;21 translocation associated We can, currently, cite several treatment successes, with Duchenne muscular dystrophy. Nature 1985;318:672 5. such as intravenous immunoglobulin in autoimmune myas- 12. Duchenne GBA. Recherches sur la paralysie musculaire pseudohy- thenia gravis, CIDP, Guillain-Barre´ syndrome, and inflam- pertrophique ou paralysie myo-sclerosique. Arch Gen Med 1868;11 matory myopathies; advances in intensive care; and the 5 25, 179 209, 305 21, 429 43, 552 88. triumph of immunizations. Infantile poliomyelitis is no lon- 13. Carpenter S, Karpati G. Pathology of Skeletal Muscle. 2nd ed. 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