Pathogenesis.

Guillain-Barré syndrome is thought to be an acute-onset immune-mediated demyelinating neuropathy. Approximately two thirds of cases are preceded by an acute, influenza-like illness from which the affected individual has recovered by the time the neuropathy becomes symptomatic. Infections with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae, or prior vaccination, have been shown to have a significant epidemiologic association with Guillain-Barré syndrome.⁶ There has been no consistent demonstration of an infectious agent in peripheral nerves in these patients, and an immunological reaction is generally favored as the underlying cause. A similar inflammatory disease of peripheral nerves can be induced in experimental animals by immunization with a peripheral nerve myelin protein. A T cell–mediated immune response ensues, accompanied by segmental demyelination induced by activated macrophages. Transfer of these T cells to a naive animal results in comparable lesions. Moreover, lymphocytes from individuals with Guillain-Barré syndrome have been shown to produce demyelination in tissue cultures of myelinated nerve fibers. Circulating antibodies may also play a part, and plasmapheresis can be an effective treatment.⁶

Clinical Course.

The clinical picture is dominated by the ascending paralysis. Deep tendon reflexes disappear early in the process; although sensory involvement can often be detected, it is less troublesome than the weakness. The nerve conduction velocity is slowed because of the multifocal destruction of myelin segments involving many axons within a nerve. There is elevation of the CSF protein due to inflammation and altered permeability of the microcirculation within the spinal roots as they traverse the subarachnoid space. Inflammatory cells are contained within the roots, however, and there is little to no CSF pleocytosis. Many patients spend weeks in hospital intensive-care units before recovering normal function. With improved respiratory care and support, the mortality rate has fallen from 25% in the past but is still considerable; some 2% to 5% die of respiratory paralysis, autonomic instability, cardiac arrest, or the complications of treatment. Up to 20% of hospitalized patients have long-term disability.^5,6

Pathogenesis and Molecular Genetics.

The disease is genetically heterogeneous. The most common subtype (known as HMSN IA or CMT1A) has a duplication of a large region of chromosome 17p11.2, resulting in “segmental trisomy” of this region. The duplicated segment includes the gene that encodes peripheral myelin protein 22 (PMP22), a transmembrane protein expressed in compacted myelin. PMP22 and a set of related proteins are involved in the compaction of myelin in the peripheral nervous system (Fig. 27-5). Mutations affecting these myelin-associated genes result in demyelinating neuropathies of the HMSN I phenotype.¹⁴ Mutations in another gene, on chromosome 1, which codes for myelin protein zero (MPZ), produce an identical clinical phenotype (HMSN IB). Additional pedigrees with hereditary demyelinating neuropathy show mutations in genes encoding structural proteins (connexin-32), protein degradation pathways (LITAF), and myelination induction genes (early growth response 2, EGR2).^12,14

FIGURE 27-5 Relationship between the proteins of compacted myelin and the lipid bilayers. Myelin basic protein (MBP) is an intracellular protein that has a role in myelin compaction. Mutant forms of myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), and periaxin (PRX) cause hereditary demyelinating neuropathies of the Charcot-Marie-Tooth, type 1 category.

Clinical Course.

The disorder is most often autosomal dominant, and although it is slowly progressive, the disability of sensorimotor deficits and associated orthopedic problems such as pes cavus are usually limited in severity, and a normal life span is typical.

Clinical Course.

The most common peripheral neuropathy in type 2 diabetes mellitus is the symmetric neuropathy that involves distal sensory and motor nerves. Individuals with the neuropathy develop decreased sensation in the distal extremities with less evident motor abnormalities. The loss of pain sensation can result in the development of ulcers, which heal poorly because of the diffuse vascular injury in diabetes and are a major cause of morbidity. Another manifestation of diabetic neuropathy is dysfunction of the autonomic nervous system; this affects 20% to 40% of individuals with diabetes mellitus, nearly always in association with a distal sensorimotor neuropathy.¹⁷ Diabetic autonomic neuropathy has protean manifestations, including postural hypotension, incomplete emptying of the bladder resulting in recurrent infections, and sexual dysfuction. Some affected individuals, especially elderly adults with a long history of diabetes, develop a peripheral neuropathy that manifests itself as a disorder of single individual peripheral or cranial (oculomotor nerve) nerves (mononeuropathy), or of several individual nerves in an asymmetric distribution (multiple mononeuropathy or mononeuropathy multiplex). The pathogenesis of mononeuropathies in adult-onset diabetes is thought to involve vascular insufficiency, and ischemia of the affected peripheral nerve.¹⁷

Genetics.

All forms of SMA are associated with mutations affecting survival motor neuron 1 (SMN1), a gene on chromosome 5 that is required for motor neuron survival. This region of chromosome 5 also contains variable numbers of copies of a second highly homologous gene, SMN2. Homozygous deletions of SMN1 (or less commonly, intragenic mutations) cause SMA.²⁶ The number of copies of the homologous SMN2 modifies the clinical phenotype, with more copies being associated with milder neurologic phenotype. SMN genes are expressed in all tissues, so why mutations or deletions of these genes cause only neuronal loss is not clear. It is postulated that the SMN protein is critical for normal axonal transport and integrity of neuromuscular junctions, and thus promotes survival of motor neurons.

Morphology. The typical histologic finding in muscle is large numbers of atrophic fibers, often only a few micrometers in diameter (Fig. 27-8). This is unlike the groups of angulated atrophic fibers seen in denervation atrophy of muscle in adults. In SMA the muscle fiber atrophy often involves an entire fascicle, a feature known as panfascicular atrophy. There are also scattered large fibers that are two to four times normal size.

FIGURE 27-8 Spinal muscular atrophy with groups of round atrophic muscle fibers, or panfascicular atrophy, resulting from denervation atrophy.

Clinical Course.

The most common form of SMA, Werdnig-Hoffmann disease (SMA type 1), has its onset at birth or within the first 4 months of life with severe hypotonia (lack of muscle tone and “floppiness”). It usually leads to death within the first 3 years of life. The other two forms (SMA 2 and SMA 3) present at later ages, either in early childhood (between 3 and 15 months of age in SMA 2) or in later childhood (after 2 years of age in SMA 3). Those with SMA 2 usually die in childhood after age 4, whereas those with SMA 3 often survive into adulthood.

Pathogenesis and Molecular Genetics.

DMD and BMD are caused by abnormalities in DMD, a gene that is located in the Xp21 region. DMD is one of the largest human genes, spanning 2.3 million base pairs, and 79 exons. It encodes a 427-kD protein named dystrophin. A large proportion of the genetic abnormalities are deletions, with frameshift and point mutations accounting for the rest.²⁷ Approximately two thirds of the cases are familial, and the remainder represent new mutations. In the affected families females are carriers; they are clinically asymptomatic but often have elevated serum creatine kinase and show minimal histologic abnormalities on muscle biopsy. Female carriers and affected males who survive into adulthood are also at risk for developing dilated cardiomyopathy.²⁷

Dystrophin is a cytoplasmic protein located adjacent to the sarcolemmal membrane in myocytes (Fig. 27-9). It is concentrated at the plasma membrane over Z-bands, where it forms a strong mechanical link to cytoplasmic actin. Thus, dystrophin and the dystrophin-associated protein complex form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix. The role of this complex of proteins in transferring the force of contraction to connective tissue has been proposed to be the basis for the myocyte degeneration that occurs in the absence of dystrophin²⁸ or various other proteins that interact with dystrophin (see later). Muscle biopsy specimens from individuals with DMD show little or no dystrophin by both staining and western blot analysis (Fig. 27-10). People with BMD, who also have mutations in the dystrophin gene, have diminished amounts of dystrophin, usually of an abnormal molecular weight, reflecting mutations that allow synthesis of an abnormal protein of smaller size (Fig. 27-10B).

FIGURE 27-9 Relationship between the cell membrane (sarcolemma) and the sarcolemmal associated proteins. Dystrophin, an intracellular protein, forms an interface between the cytoskeletal proteins and a group of transmembrane proteins, the dystroglycans and the sarcoglycans. These transmembrane proteins have interactions with the extracellular matrix, including the laminin proteins. Dystrophin also interacts with dystrobrevin and the syntrophins, which form a link with neuronal-type nitric oxide synthetase (nNOS) and caveolin. Mutations in dystrophin are associated with the X-linked muscular dystrophies; mutations in caveolin and the sarcoglycan proteins with the limb-girdle muscular dystrophies, which can be autosomal dominant or recessive disorders; and mutations in the α2-laminin (merosin) with autosomal recessive congenital muscular dystrophy.

FIGURE 27-10 A, Duchenne muscular dystrophy (DMD) showing variation in muscle fiber size, increased endomysial connective tissue, and regenerating fibers (blue hue). B, Western blot showing absence of dystrophin in DMD and altered dystrophin size in Becker muscular dystrophy (BMD) compared with control

(arrow) (Con). (Courtesy of Dr. L. Kunkel, Children’s Hospital, Boston, MA.)

Clinical Course.

Boys with DMD are normal at birth, and early motor milestones are met on time. Walking, however, is often delayed, and the first indications of muscle weakness are clumsiness and inability to keep up with peers. Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle. Enlargement of the muscles of the lower leg associated with weakness, a phenomenon termed pseudohypertrophy, is an important clinical finding. The increased muscle bulk is caused initially by an increase in the size of the muscle fibers and then, as the muscle atrophies, by an increase in fat and connective tissue. Pathologic changes are also found in the heart, and patients may develop heart failure or arrhythmias.²⁷ Although there are no well-established structural abnormalities of the central nervous system, cognitive impairment is a component of the disease and is sometimes severe enough to be considered a form of mental retardation. Serum creatine kinase is elevated during the first decade of life but returns to normal as muscle mass decreases. Death results from respiratory insufficiency, pulmonary infection, and cardiac decompensation. Gene therapy has received a great deal of attention but has been hampered by the size of the DMD gene. There has been success in experimental animals with two delivery systems: wild-type stem cell injections directly into muscle; and systemic injection of adenoassociated viruses carrying genes engineered to produce small, but functionally competent, portions of the dystrophin protein.²⁹ Induction of specific exon skipping using antisense RNA has been shown to restore the open reading in certain mutated DMD genes, and increase dystrophin expression in muscle biopsies.³⁰

Boys with BMD develop symptoms at a later age than those with DMD. The onset occurs in later childhood or in adolescence, and is followed by a slower and more variable rate of progression, although there is considerable variation between pedigrees. Many patients have a nearly normal life span. Cardiac disease is frequently seen in these patients.

Pathogenesis.

Inherited as an autosomal dominant trait, myotonic dystrophy is associated with a CTG trinucleotide repeat expansion on chromosome 19q13.2–q13.3. This expansion affects the mRNA for the dystrophia myotonia protein kinase (DMPK).³³ In normal subjects, fewer than 30 repeats are present; disease develops with expansion of this repeat, and several thousand repeats may be present in severely affected individuals. The mutation is not stable within a pedigree; with each generation more repeats accumulate, and the disease becomes more severe, a phenomenon called anticipation (Chapter 5). Expansion of the trinucleotide repeat influences the eventual concentration of protein product. However, it is not established if the disease is caused by abnormality of the protein affected by the trinucleotide repeat, or if this alters splicing of other RNAs.

Clinical Course.

The disease often presents in late childhood with abnormalities in gait secondary to weakness of foot dorsiflexors and subsequently progresses to weakness of the hand intrinsic muscles and wrist extensors. Atrophy of muscles of the face and ptosis ensue, leading to the typical facial appearance. Cataracts, which are present in virtually every patient, may be detected early in the course by slit-lamp examination. Other associated abnormalities include frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma IgG, and abnormal glucose tolerance. Dementia has been reported in some cases.

Pathogenesis.

As their name indicates, these diseases are caused by mutations in genes that encode ion channels.³⁴ Hyperkalemic periodic paralysis results from mutations in the gene that encodes a skeletal muscle sodium channel protein (SCN4A), which regulates the entry of sodium into muscle during contraction. The gene for hypokalemic periodic paralysis encodes a voltage-gated L-type calcium channel.

Malignant hyperpyrexia (malignant hyperthermia) is a rare clinical syndrome characterized by a marked hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later hyperpyrexia) triggered by anesthetics, most commonly halogenated inhalational agents and succinylcholine. The clinical syndrome may occur in predisposed individuals with hereditary muscle diseases, including congenital myopathies, dystrophinopathies, and metabolic myopathies. Mutations in several genes have been identified in families with susceptibility to malignant hyperthermia, including genes encoding L-type voltage-dependent calcium channel, notably the rynodine receptor (RyR1).³⁵ Upon exposure to anesthetic, the mutant receptor allows uncontrolled efflux of calcium from the sarcoplasm. This leads to tetany, increased muscle metabolism, and excessive heat production. Diagnosis can be made either by identifying the genetic mutation or by exposing biopsied muscle to the anesthetic agent and observing contraction.

Clinical Course and Genetics.

The relationship between clinical course and the genetic alterations in the mitochondrial disorders is not straightforward; however, three general types of mutations have been defined. One consists of point mutations in mtDNA. Disorders associated with these show a maternal pattern of inheritance; some examples include myoclonic epilepsy with ragged red fibers, Leber hereditary optic neuropathy, and mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes. As in other diseases caused by mutations in mtDNA, the expression of the disease is quite variable due to unequal distribution of mtDNA in affected cells (Chapter 5). A second set of mutations involves genes encoded by nuclear DNA and shows autosomal dominant or autosomal recessive inheritance. Some cases of subacute necrotizing encephalopathy (Leigh syndrome), exertional myoglobinuria, and infantile X-linked cardioskeletal myopathy (Barth syndrome) are due to mutations in nuclear DNA. The final subset of mitochondrial myopathies is caused by deletions or duplications of mtDNA. Examples include chronic progressive external ophthalmoplegia, characterized by a myopathy with prominent weakness of external ocular movements. Kearns-Sayre syndrome, another myopathy in this group, is also characterized by ophthalmoplegia but, in addition, includes pigmentary degeneration of the retina and complete heart block.

Dermatomyositis.

As the name implies, individuals with dermatomyositis have an inflammatory disorder of the skin as well as skeletal muscle. It is characterized by a distinctive skin rash that may accompany or precede the onset of muscle disease. The classic rash takes the form of a lilac or heliotrope discoloration of the upper eyelids associated with periorbital edema (Fig. 27-13A). It is often accompanied by a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Grotton lesions). Muscle weakness is slow in onset, bilaterally symmetric, and often accompanied by myalgias. It typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. Fine movements controlled by distal muscles are affected only late in the disease. Dysphagia resulting from involvement of oropharyngeal and esophageal muscles occurs in one third of the affected individuals. Extramuscular manifestations, including interstitial lung disease, vasculitis, and myocarditis, may be present in some cases. Compared with the control populations, adults with dermatomyositis have a higher risk of developing visceral cancers. According to several studies, 20% to 25% of adults with dermatomyositis have cancer.⁴⁴

FIGURE 27-13 A, Dermatomyositis. Note the heliotrope rash affecting the eyelids. B, Dermatomyositis. The histologic appearance of muscle shows perifascicular atrophy of muscle fibers and inflammation. C, Inclusion body myositis showing a vacuole within a myocyte.

(Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

Juvenile dermatomyositis⁴⁵ causes a similar onset of rash and muscle weakness but more often is accompanied by abdominal pain and involvement of the gastrointestinal tract. Mucosal ulceration, hemorrhage, and perforation may occur as the result of the dermatomyositis-associated vasculopathy. Calcinosis, which is uncommon in adult dermatomyositis, occurs in one third of youths with juvenile dermatomyositis.

Polymyositis.

This inflammatory myopathy is characterized by symmetric proximal muscle involvement, similar to that seen in dermatomyositis. It differs from dermatomyositis by the lack of cutaneous involvement and its occurrence mainly in adults. Similar to dermatomyositis, there may be inflammatory involvement of heart, lungs, and blood vessels.

Inclusion Body Myositis.

In contrast with the other two entities, inclusion body myositis begins with the involvement of distal muscles, especially extensors of the knee (quadriceps) and flexors of the wrists and fingers.⁴⁶ Furthermore, the weakness may be asymmetric. It is an insidiously developing disorder that typically affects individuals over the age of 50 years. Most cases are sporadic, but familial cases have been recognized as “inclusion body myopathy.”

Etiology and Pathogenesis.

The cause of inflammatory myopathies is unknown, but the tissue injury is most likely mediated by immunological mechanisms. Capillaries seem to be the principal targets in dermatomyositis. Deposits of antibodies and complement are present in small blood vessels, and are associated with foci of myocyte necrosis. B cells and CD4+ T cells are present within the muscle, but there is a paucity of lymphocytes within the areas of myofiber injury. The perifascicular distribution of myocyte injury also suggests a vascular pathogenesis.

In contrast, polymyositis seems to be caused by cellmediated injury of myocytes. CD8+ cytotoxic T cells and macrophages are seen near damaged muscle fibers, and the expression of HLA class I and class II molecules is increased on the sarcolemma of normal fibers. Similar to other immune-mediated diseases, antinuclear antibodies are present in a variable number of cases, regardless of the clinical category (Chapter 6). The specificities of autoantibodies are quite varied, but those directed against transfer RNA synthetases seem to be more or less specific for inflammatory myopathies.⁴⁷

The pathogenesis of inclusion body myositis is less clear. As in polymyositis, CD8+ cytotoxic T cells are found in the muscle, but in contrast to the other two forms of myositis, immunosuppressive therapy is not beneficial. Intracellular deposits of β-amyloid protein, amyloid β–pleated sheet fibrils, and hyperphosphorylated tau protein, features shared with Alzheimer disease, have drawn attention to a possible relationship to aging. The protein deposition may result from abnormal protein folding. The two hereditary forms of inclusion body myopathy have a similar morphology. The autosomal recessive form is caused by mutations in the GNE gene (encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), and the autosomal dominant form is caused by mutations in the gene encoding myosin heavy chain IIa.^46,48

The diagnosis of myositis is based on clinical symptoms, electromyography, elevated creatinine kinase in serum, and biopsy. Electromyography (EMG) is particularly informative; mixed neurogenic and myopathic changes on EMG are suggestive of inflammatory myopathy. As might be expected, muscle injury is associated with elevated serum levels of creatine kinase. Biopsy is required for definitive diagnosis. Immunosuppressive therapy is beneficial in adult and juvenile dermatomyositis and in polymyositis but not in inclusion-body myositis.

Pathogenesis.

In most instances the autoantibodies against the AChR lead to loss of functional AChRs at the neuromuscular junction by (1) fixing complement and causing direct injury to the postsynaptic membrane, (2) increasing the internalization and degradation of the receptors, and (3) inhibiting binding of acetylcholine. Electrophysiologic studies are notable for diminished motor responses after repeated stimulation; nerve conduction is normal. Sensory as well as autonomic functions are not affected. Despite the evidence that antibodies to AChR have a critical pathogenic role, there is not always a correlation between antibody titers and the neuromuscular deficit. Interestingly, in light of the immune-mediated etiology of the disease, thymic abnormalities are common in these patients, but the precise link between thymic function and autoimmunity is uncertain. Regardless of the type of thymic pathology, most affected individuals improve after thymectomy.

Clinical Course.

Typically, weakness begins with the extraocular muscles; drooping eyelids (ptosis) and double vision (diplopia) cause the affected individual to seek medical attention. However, the initial symptoms may take the form of generalized weakness. The weakness fluctuates over days, hours, or even minutes, and intercurrent medical conditions can lead to exacerbations. Patients show improvement in strength in response to administration of anticholinesterase agents, which remains a useful clinical test. Respiratory compromise was a major cause of mortality in the past; 95% of affected individuals now survive more than 5 years after diagnosis because of improved methods of treatment and better ventilatory support. Effective forms of treatment include anticholinesterase drugs, prednisone, plasmapheresis, and thymectomy when thymic lesions are present.⁵⁰