18 Pediatric Neuromuscular Disorders

HYPOTONIC INFANT 169 NEONATAL TRANSIENT MYASTHENIA GRAVIS 176 SPINAL MUSCULAR ATROPHY TYPE 1 171 CHARCOT-MARIE-TOOTH DISEASE 176 SPINAL MUSCULAR ATROPHY TYPE 2 171 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 178 SPINAL MUSCULAR ATROPHY TYPE 3 171 MYOTONIC DYSTROPHY 179 MUSCULAR DYSTROPHIES 171 PERIODIC PARALYSIS 180 DUCHENNE’S MUSCULAR DYSTROPHY 171 FABRY’S DISEASE 181 OTHER MUSCULAR DYSTROPHIES 173 METABOLIC MYOPATHIES 182 DERMATOMYOSITIS 174 MCARDLE’S DISEASE 182 INFANTILE BOTULISM 175 ACID MALTASE DEFICIENCY 183

Hypotonic Infant In order to localize, we need to determine if the prob- lem is central (cerebral hypotonia), or if it involves the spinal cord or the motor unit (peripheral hypotonia). If indeed it is a neuromuscular problem, it is important to Vignette assess which part of the motor unit is affected—the an- A 6-month-old girl was brought to your attention terior horn cell, the peripheral nerves, the neuromuscular because of poor motor development. She was never junction, or the muscles. able to roll over and had a very poor head control In the vignette both hypotonia and weakness are de- in a sitting position. She was the full-term product scribed. It is also indicated that the problem was discov- of an uncomplicated pregnancy, labor, and delivery. ered shortly after birth (two weeks after birth she started Two weeks after birth, she started having breathing having breathing and feeding difficulties). difficulty as well as feeding and swallowing prob- Cerebral hypotonia can easily be excluded in this in- lems. On examination, she appeared bright and fant. Babies with cerebral hypotonia manifest signs of alert, with appropriate language and social devel- opment, and normal facial expression without dys- nervous system involvement other than those reflecting morphic features. Extraocular movements were in- muscle function, such as lethargy, altered level of con- tact. There was poor head control with hand sciousness, poor response to visual or auditory stimuli, traction, and poor trunk and limb control in ventral seizures, and so on (Dubowitz). Other factors suggestive suspension. In the legs, she had total immobility. of central hypotonia are the presence of dysmorphic fea- Small amount of movement was confined to the feet tures, particularly involving the face and scalp, and mal- and marked proximal muscle weakness was noted. formations of other organ systems such as heart and limb Deep tendon reflexes were absent, and the breath- defects (Miller et al.). ing was mainly diaphragmatic. Spinal cord injury as a cause of hypotonia is also easily clinically excluded in this infant who was the full-term Summary A 6-month-old infant presenting with hypo- product of uncomplicated pregnancy, labor and delivery. tonia, weakness, and respiratory problems, without ap- An injury to the spinal cord due to traction can occur dur- parent dysmorphic features and with normal extraocular ing vaginal delivery, particularly when the baby presents muscles, appearing bright and alert. in a breech position (according to Fenichel, 75 percent with breech presentation and 25 percent with cephalic presen- Key word: floppy infant. tation). Clinically, spinal cord lesions manifest with weak- ness and hypotonia in association with sensory-level and Localization sphincteric abnormalities. Altered level of consciousness The first issue is to determine whether the patient is weak can also occur. Again, the vignette indicated normal labor or hypotonic, or both, because if not all hypotonic infants and delivery without complications. are weak, all weak infants are hypotonic. The patient in In this case—a baby who is mentally bright and alert, the vignette has clear evidence of weakness and interacting well socially, without any dysmorphism, but hypotonia. severely weak and areflexic—a disorder of the motor unit

169 170 18. Pediatric Neuromuscular Disorders should rank high on the list (Fenichel). The degree and Infantile botulism usually manifests between 6 weeks distribution of weakness and associated features can also and 6 months of age with neurological and nonneuro- help to localize within the different parts of the motor logical symptoms, the most constant of the latter ones unit. Important points in the vignette are normal cogni- being constipation. Neurological signs include a descend- tion, normal extraocular muscles, marked proximal leg ing paralysis sometimes associated with hyporeflexia, weakness, areflexia, and diaphragmatic breathing. Dis- weak cry, hypotonia, ophthalmoplegia, facial paralysis, orders of different parts of the motor unit are considered pupillary dilatation, and so on. in the differential diagnosis. In summary, neuromuscular junction disorders with their clinical characteristics seem less likely as a possible diagnosis in the vignette presented. Differential Diagnosis Finally, consideration is given to disorders of the mus- Disorders of the anterior horn cells, particularly infantile cle. Myopathies that enter the differential diagnosis of a spinal muscular atrophy (SMA), ranks high in the differ- hypotonic infant are the congenital myopathies, the ential diagnosis of this infant. Infantile SMA1(infantile infantile form of myotonic dystrophy, congenital mus- onset spinal muscular atrophy, Werdnig-Hoffman dis- cular dystrophies, and acid maltase deficiency. Congeni- ease) manifests at birth or during the first few months of tal myopathies can present at birth with weakness and life with severe weakness, particularly involving the hypotonia. proximal muscles, hypotonia, and areflexia. Sensation is In particular, nemaline myopathy has a severe infantile normal and there is no sphincteric abnormality. Infants form manifesting at birth with marked hypotonia and gen- are bright, alert, and expressive, with a very floppy body. eralized weakness, including the respiratory muscles that A disorder of the peripheral nerves to be considered as often require ventilatory support. Dysmorphic features part of the differential diagnosis because it can present can be noted with long narrow face and deformity of the during the neonatal period is congenital dismyelinating palate. This form has a poor prognosis, with death caused neuropathy. Peripheral neuropathies, including acute in- by respiratory failure and pneumonia. Muscle biopsy flammatory demyelinating polyneuropathy (Guillain- demonstrates the accumulation of intranuclear rods. Barre´ syndrome), are very rare in newborn babies. Cases Congenital myotonic dystrophy, which affects infants of GBS occurring during the first few months of life have born to mothers who have myotonic dystrophy, is mani- been described in few cases with severe hypotonia, as- fested at birth with severe hypotonia, prominent weak- cending paralysis, areflexia, and feeding, respiratory, and ness of proximal muscles, facial diplegia, sucking and autonomic compromise. An exception is congenital hy- feeding difficuties, and respiratory failure that can be pomyelinating neuropathy, which can present in the neo- fatal. natal period with progressive weakness, hypotonia, at- Congenital muscular dystrophies also manifest at birth rophy, and areflexia, and can simulate the picture of acute with hypotonia in combination with generalized weak- infantile spinal muscular atrophy. Extraocular muscles ness, including the face, and sucking and respiratory dif- are intact and feeding and respiratory problems can be ficulties, with varying degrees of severity. Other anom- fatal. Sural nerve biopsy demonstrates almost total ab- alies, such as ocular and brain malformations, can also sence of myelin formation. CSF studies show elevated occur in some of the congenital muscular dystrophies, proteins. such as hypoplasia of the optic nerve, microophthalmia, Disorders of the neuromuscular junction to be consid- corneal opacity, pachygyria, polymicrogyria, vermis hy- ered in the differential diagnosis of a hypotonic infant poplasia, and so on. Muscle biopsy demonstrates dys- include congenital myasthenic syndromes, transient neo- trophic changes. natal myasthenia gravis, and infantile botulism. Congen- The infantile form of acid maltase deficiency, which ital myasthenic syndromes are rare disorders of the neu- represents a severe metabolic myopathy due to deficiency romuscular junction manifesting in the newborn period of alpha-glucosidase, manifests with progressive weak- with weakness, hypotonia, fatigue during sucking, fluc- ness and significant hypotonia, usually during the first tuating ptosis, and weak cry, in babies who are trimester of life. The involvement of multiple organs with seronegative. hepatomegaly, cardiomegaly, and macroglossia also Transient neonatal myasthenia gravis occurs in ap- occurs. proximately 10 percent of infants whose mothers have In conclusion, considering all the possible causes of myasthenia gravis (Dumitru et al.) and varies in severity hypotonia in infancy, the best diagnosis in the vignette is of manifestations, which can include generalized weak- infantile spinal muscular atrophy. ness, hypotonia, weak cry, feeding and respiratory diffi- culties, facial weakness, and ptosis. Acetylcholine recep- Clinical Features tor antibodies are discovered in babies who have a seropositive mother and the disorder is self-limited with The spinal muscular atrophies are hereditary autosomal most patients being symptom-free within six weeks. recessive disorders affecting the anterior horn cells and Muscular Dystrophies 171 cranial nuclei and characterized by progressive weakness, Serum measurements of creatine kinase may or may diffuse denervation, and atrophy. Three forms of SMA not show elevation, but are usually normal in SMA type have been decsribed, the most severe being the early in- 1 and 2. fantile or type 1 (Werdnig-Hoffman disease). The other Electrodiagnostic evaluation may demonstrate normal two are the late infantile form or type 2 (intermediate) conduction velocities, decreased amplitude of the com- and the juvenile or type 3 (Kugelberg-Welander disease). pound muscle action potential, and signs of denervation and reinnervation on needle EMG study. Spinal Muscular Atrophy Type 1 Muscle biopsy shows evidence of neurogenic atrophy with atrophic round fibers and fiber type grouping. SMA type 1, also called acute infantile paralysis or Werdnig-Hoffman disease, presents at birth or during the first few months of life with severe proximal weakness, Treatment preferentially affecting the lower extremities, and marked There is no available treatment and the management is hypotonia. Weakness can be so profound that only move- based on preventing and treating complications, in par- ments in the hands and feet can be observed. Sometimes ticular respiratory compromise, joint and spinal defor- a subtle tremor of the fingers called polyminimyoclonus is mities, and failure to thrive. noted. The baby tends to assume a frog-like position and breathing is mainly diaphragmatic due to intercostal mus- cle weakness, which can cause the bell-shaped deformity. Other characteristic features include fasciculations and at- Muscular Dystrophies rophy of the tongue, areflexia, normal sensation, and nor- mal sphincteric function. Extraocular and facial muscles The dystrophies are genetic, progressive myopathies are also spared. Affected infants are bright and alert. caused by defects in structural proteins. The prognosis is poor due to severe respiratory compro- mise and most succumb before reaching 2 years of age. Duchenne’s Muscular Dystrophy Spinal Muscular Atrophy Type 2 SMA type 2, or intermediate form, is characterized by a later occurrence of the symptoms, usually after 6 months Vignette of age, proximal lower extremity weakness, hypotonia, A 7-year-old boy was brought to your attention be- hypo-reflexia, areflexia, tongue fasciculations, and nor- cause of a gait disorder. He was a full-term product mal intellectual function. Many patients are able to sit of uncomplicated pregnancy and delivery with no without support but only a limited number reach the abil- evidence of fetal distress. He started crawling at 8 ity to stand and walk with assistance. months and walking at 15 months. At the age of 3 The prognosis is more favorable than with type 1 and his mother noticed that he was falling more fre- the survival longer, but joint contractures and kyphosco- quently than his playmates and seemed to have dif- liosis can occur and respiratory compromise represents ficulties climbing stairs. He could never jump over the most serious complication. his shoes or a toy on the floor. There was no double vision or speech difficulties. The mother had mild Spinal Muscular Atrophy Type 3 diabetes and a maternal uncle was wheelchair- SMA type 3, or Kugelberg-Welander disease, manifests bound since his teens and died of heart disease. On after the age of 18 months with proximal muscle weak- examination the boy appeared dull and distractible. ness, particularly in the lower limbs, that can be respon- Cranial nerve examination was unremarkable ex- sible for a waddling gait in ambulatory patients, often in cept for a large tongue. Lumbar lordosis and pro- association with lumbar lordosis and prominent abdomen. tuberance of the abdomen were noted as well as Deep tendon reflexes are decreased or absent and diffuse Achilles’ tendon contractures and mild hyperthro- fasciculations are observed, particularly of the tongue. phy of the gastrocnemius muscle. Strength in the Extraocular muscles are always intact. arms was decreased, especially serratus anterior The course is slowly progressive with a survival that and pectorals, and prominent scapular winging can reach the second decade of life. was noted. Deep tendon reflexes were absent and Babinski’s sign was negative. When walking, his Diagnosis heels did not strike the ground and his gait was waddling. Genetic studies are important because all these disorders are due to mutations in the spinal motor neuron gene lo- cated on chromosome 5q13. Summary A 7-year-old boy with progressive weakness. 172 18. Pediatric Neuromuscular Disorders

Localization and Differential Diagnosis • Inflammatory myopathies, such as dermatomyositis and polymyositis. The history and neurological examination help in local- • Infectious myopathies, such as viral myositis (HIV, izing the lesion to a specific component of the motor unit. coxsackievirus) or parasitic myositis (trichinosis, toxo- Progressive weakness can be due to disorders of the plasmosis, and so on). following: • Toxic myopathies due to alcohol or drugs, such as ste- • Anterior horn cells, such as spinal muscular atrophy or roids, vincristine, cloroquine, and so on. other motor neuron diseases. • Myopathies associated with endocrine or systemic dys- • Peripheral nerves, such as hereditary, or acquired: (id- function such as hypothyroidism or hyperthyroidism, iopathic, metabolic, infectious, and inflammatory Addison’s disease, Cushing’s syndrome, renal and neuropathies). electrolyte dysfunction, and so on. • Neuromuscular junction, such as myasthenia gravis. • Muscle, such as muscular dystrophies; congenital; met- Inflammatory myopathies, especially dermatomyositis, abolic; or inflammatory myopathies. with the typical features of fever, rash, muscle pain, and weakness are not featured in the vignette. Polymyositis The history and neurological examination help localize without evidence of other target organ involvement is un- to a disorder of the muscles. common before puberty (Fenichel). None of the acquired Gait abnormality can be caused by proximal or distal childhood myopathies secondary to endocrinopathy, toxic lower extremity weakness. In the vignette, there is clear exposure, or infection are supported by the clinical find- indication of proximal muscle weakness. With proximal ings in the vignette. weakness, the pelvis is not stabilized and waddles from Many factors suggest that the boy described in the vi- side to side as the child walks (Fenichel 1997). Lumbar gnette has a hereditary myopathic disorder. These factors lordosis and protuberance of the abdomen are due to include the insidious onset and relentless progression of weakness of the abdomen, back, and pelvic girdle mus- the symptoms and the positive family history significant cles. Progressive proximal weakness of insidious onset in for a maternal uncle wheelchair-bound since his teens and children is often an indication of an underlying myopathic deceased for cardiac problems. This may point to a pos- process, in particular a muscular dystrophy (preferred sible X-linked disorder of the muscles. diagnosis). We can easily exclude many inherited muscle disor- On the other hand, juvenile spinal muscular atrophy, ders. Congenital myopathies, for example, are muscle which is a neurogenic process involving the anterior horn disorders that present at birth with hypotonia, weakness, cells, also manifests with progressive proximal weakness and respiratory dysfunction. The distribution of weakness predominantly affecting the lower extremities, lumbar is diffuse and in some cases, such as nemaline myopathy, lordosis, and a waddling gait. Juvenile SMA has other predominantly distal. Skeletal deformities and dys- distinctive clinical features, including minipolymyo- morphic features also also present. The diagnosis is based clonus that can be prominent, fasciculations of the on muscle biopsy. tongue, signs of bulbar involvement, variable reflexes, Other hereditary disorders of the muscle such as myo- and extensor plantar responses in some cases. tonic dystrophy, myotonia congenita, and periodic paral- Neurogenic and myopathic processes can usually be ysis can be easily excluded. Patients with myotonic dys- differentiated by the clinical features and also by diag- trophy, which is an autosomic dominant disorder, have a nostic studies, particularly needle EMG and muscle typical facial appearance due to marked weakness of the biopsy. facial muscles. Myotonia is characteristic and the distri- Disorders of the neuromuscular junction, such as ju- bution of weakness is mainly distal with slow progression venile myasthenia gravis, are easily clinically excluded to the proximal muscles. Myotonia congenita manifests by the case presented in the vignette because of the lack with muscle stiffness and myotonia in patient with normal of typical characteristics of MG, such as fatigable weak- strength and reflexes. Periodic paralysis is characterized ness and ocular and bulbar involvement, and the descrip- by episodic and not chronic weakness precipitated by tion in the vignette of clinical findings not related to myo- heavy meals, emotional stress, or strenuous physical thenia (muscle hypertrophy, contractures, absent deep activity. tendon reflexes, and so on). Metabolic myopathies are hereditary disorders char- Therefore, the best initial diagnosis of the vignette re- acterized by exercise intolerance. Some cases, such as the mains a disorder of the muscle. Loss of tendon reflexes juvenile form of type II glycogenosis, can sometimes sim- in myopathic processes occurs if the degree of weakness ulate a dystrophynopathy due to the clinical features of is severe. proximal muscle weakness, delayed motor milestones, Childhood myopathies can be distinguished into ac- waddling gait, and lumbar lordosis, presenting during the quired and inherited disorders. Acquired disorders of first decade of life. Hypertrophy of the calf muscles has muscle include also been described. Respiratory compromise can be se- Muscular Dystrophies 173 vere and fatal. As opposed to the muscular dystrophies, rhythmia. Gastrointestinal dysfunction can manifest with cardiomegaly, hepatomegaly, and cranial nerve dysfunc- acute gastric dilatation, also called intestinal pseudo- tion, although uncommon, can manifest in some cases. obstruction. Finally, a very important category of inherited muscle Intellectual functions can also be affected, and the av- disorders needs to be considered: the muscular dystro- erage IQ of the child with DMD is one standard deviation phies. Duchenne’s muscular dystrophy appears to be the below the normal mean. most likely diagnosis of the child described in the vignette who has a history of progressive proximal weakness, hy- Diagnosis pertrophic muscles, areflexia, and a maternal relative who was wheelchair-bound since his early teens (which in this Creatine kinase is significantly increased from 50 to 100 case suggests a possible X-linked disorder). times the normal values. Abnormally high levels can be detected at birth before the clinical manifestations be- come apparent. Clinical Features Needle electromyography shows increased insertional Duchenne’s muscular dystrophy (DMD) is an X-linked activity with positive sharp waves and fibrillation poten- recessive disorder that affects only males and manifests tials, and short- and long-duration motor unit action po- with progressive muscular weakness that becomes appar- tentials that recruit early. ent when the boy starts walking. It affects 1 in 3500 live Muscle biopsy may demonstrate regenerating and male births (Berg). Approximately one third of cases ap- necrotic muscle fibers, large hypercontracted fibers, ex- pear to be due to new mutations (Amato and Dumitru). cessive variation of muscle fiber diameter, increased The abnormal gene product in both Duchenne’s and endomysial fibrosis, and muscle fiber loss with fat Becker’s muscular dystrophy is a reduced muscle content accumulation. of the structural protein dystrophin (Fenichel). In Du- Genetic tests may show detectable mutations on rou- chenne’s muscular dystrophy the dystrophin content is 0 tine DNA testing. The distrophin gene, located at Xp21, to 3 percent of normal, whereas in Becker’s muscular is the largest known gene and is very susceptible to mu- dystrophy the dystrophin content is 3 to 20 percent of tations and deletions. normal. The clinical manifestations become evident at the time Treatment of walking, and most children appear normal at birth and Some improvement in muscle strength and pulmonary are able to reach some motor milestones, such as sitting function has been obtained with the use of prednisone and standing. Gait is usually clumsy and waddling and and deflazacort (a synthetic derivative of prednisolone) the boys experience frequent falls, cannot run with their in randomized double-blind controlled trials. peers, and have great difficulty climbing stairs. Toe walk- Supportive care is the mainstay of treatment with or- ing caused by Achilles’ tendon contractures, calf hyper- thopedic and cardiorespiratory management. Gene ther- trophy, and difficulty arising from the floor are also noted. apy with myoblast transfer and vector-mediated gene The distribution of muscle weakness is mainly proximal, transfer are other new approaches. particularly involving the lower extremities, pelvic and Prenatal diagnosis determined in males is possible by paraspinal muscles, and also the shoulder girdle muscles. testing for the deletion in chorionic villus or amniocen- Prominent lumbar lordosis and abdominal protuberance tesis fluid. also occur. Gower’s sign, which is not specific for the muscular dystrophies but can also be observed in other neuromuscular disorders with significant proximal weak- Other Muscular Dystrophies ness such as spinal muscular atrophies, manifests with Following are capsule summaries of four other muscular certain maneuvers that allow the boy to arise from the dystrophies: floor, such as pushing himself upright after getting onto his hands and knees and then climbing up the legs. Becker’s muscular dystrophy This disorder shows a progressive, relentless course to • Later onset of symptoms than DMD, often after 8 years the point that ambulation becames an impossible task and of age the patients are relegated to a wheelchair around the age • X-linked recessive inheritance. of 12. Joint contractures and hyposcoliosis also develop, • Ability to walk maintained beyond age 16. and respiratory compromise may represent a serious com- • Pattern of muscle weakness similar to DMD but less plication. Cranial nerve musculature is not affected but frequent contractures. the tongue can be enlarged. • Longer survival: patients can reach middle age and The involvement of other organs is also a feature of beyond. DMD. Signs of cardiac dysfunction vary from asymptom- Emery-Dreyfuss muscular dysytrophy atic cases to congestive heart failure and cardiac ar- • X-linked recessive inheritance. 174 18. Pediatric Neuromuscular Disorders

• Early onset of prominent joint contractures, particu- nerves, neuromuscular junction, or muscle. Another dis- larly of the Achilles’ tendons, elbows, and posterior tinction is between hereditary and acquired disorders. cervical muscles. This child presents with progressive proximal muscle • Progressive muscular weakness and atrophy in a hu- weakness without any disturbance of sensory or auto- meroperoneal distribution. nomic function. The weakness is bilateral, mainly prox- • Frequent cardiomyopathy with conduction abnormalities. imal, and associated with pain. All these symptoms point • CK levels only moderately elevated. toward a muscle disorder. The different categories of Facioscapulohumeral muscular dystrophy (see also later muscle disorders include vignette) • Muscular dystrophies. • Autosomal dominant transmission with strong • Metabolic myopathies. penetrance. • Myopathies secondary to metabolic, endocrine, toxic, • Weakness of the shoulder girdle and scapular fixation and systemic disorders. muscles is characteristic. • Inflammatory myopathies. • Biceps and triceps are affected with deltoid muscles relatively spared. Considering the muscular dystrophies first, Du- • Facial weakness is also an important feature. chenne’s and Becker’s muscular dystrophies can be easily Limb-Girdle muscular dystrophy ruled out because they are X-linked hereditary disorders • Autosomal recessive transmission. that affect only boys. The characteristic symptoms of pro- • Slowly progressive, symmetrical, proximal weakness, gressive, insidious proximal weakness in these muscular with or without facial involvement. dystrophies become apparent when the child begins to • Onset in the second or third decade. walk, and always before five years of age. • Elevated serum CK, but less than DMD. Facioscapulohumeral muscular dystrophy is character- ized by marked facial and shoulder-girdle muscle weak- ness. In the lower extremities, the tibialis anterior muscle is the first and most significantly involved, resulting in a Dermatomyositis frequent foot drop. Limb-girdle dystrophy includes several groups of dis- orders characterized by mild and severe forms presenting with progressive muscular weakness of the upper and Vignette lower extremities, sometimes associated with calf pseu- A 5-year-old girl was noted to be having trouble dohypertrophy and usually an autosomal recessive climbing stairs during the last six months. She re- inheritance. fused to walk for more than two blocks or ride her The metabolic myopathies are a group of muscle dis- bicycle, complaining that her legs hurt. She has orders characterized by a specific metabolic abnormality. also been very irritable with low-grade fever and They include disorders of glycogen metabolism, disorder poor appetite. A pediatrician who examined the girl of nucleotide and lipid metabolism, and mitochondrial noticed some erythematous areas over the knees myopathies. These disorders have specific characteristics and elbows. Blood tests including a CK level were that can be easily ruled out in the vignette (see vignette normal. On examination she was alert and coop- in Chapter 19). erative. There was mild weakness of neck flexor and The inflammatory myopathies are disorders character- moderate weakness of the pelvic girdle muscles. ized by progressive proxymal weakness, inflammatory DTR were hypoactive. She had a tiptoe gait. changes of muscle on biopsy, increased levels of CK, and signs of muscle membrane instability and fiber loss on Summary A 5-year-old girl presenting with progressive electrodiagnostic studies. They include polymyositis, der- proximal muscle weakness and hyporeflexia associated matomyositis, and inclusion body myositis. Dermato- with myalgia, systemic symptoms, and a rash over the myositis in particular, with its characteristic features of knees and elbows. The CPK level is reported as normal. progressive symmetrical weakness preferentially affect- ing the proxymal muscles, myalgia, skin changes, and systemic manifestations, represent the best possible di- Localization and Differential Diagnosis agnosis of the child described in the vignette. The localization is clearly the peripheral nervous sys- Dermatomyositis tends to manifest between 5 and 10 tem. There are no signs of central nervous system years of age. The insidious onset of proximal weakness involvement. may be preceded by systemic manifestations that include Next, it is important to determine which part of the low-grade fever, fatigue, anorexia, muscle pain and dis- motor unit is involved: anterior horn cells, peripheral comfort, and artralgia. The onset of the disease can be Infantile Botulism 175 subacute over a few weeks or acute over a few days and Infantile Botulism is often preceded by an infection. Proximal muscles are preferentially involved and com- mon complaints are difficulty climbing up stairs, getting up from a low seat, and combing or blow drying the hair. Vignette Distal muscles may also be involved and, in particular, 1 A4⁄2-month-old baby boy was brought to the ER the involvement of the calf muscles may be responsible because of respiratory distress. The mother noticed for contractures and toe walking. Weakness of the flexor that for the last few days he had stopped rolling muscles of the neck is observed in approximately one half over and lifting his head and had experienced se- of children (Menkes). Bulbar dysfunction with dysphagia vere constipation. There was no fever or vomiting. and dysarthria can also occur in more severe cases. Deep On examination the child was hypotonic and are- tendon reflexes can be preserved or diminished. flexic. He had limited extraocular movements, and Cutaneous manifestations are an important feature of gag reflex was absent. Prenatal and perinatal his- the disorder and include a purplish erythematous rash in tories as well as past medical history were normal the periorbital area that can extend into the cheeks and with typical developmental milestones. forehead. Knuckles, elbows, and knees can also became affected. The periungual region in the hands also can 1 Summary A4⁄2-month-old baby, who had a normal show erythematous changes. medical history up until few days ago, when he stopped Subcutaneous calcifications are more common in chil- rolling over and lifting his head, experiencing constipa- dren than in adults, and according to Dumitru, can occur tion and respiratory problems. in 30 to 70 percent of children. They tend to appear over pressure points (buttocks, knees, elbows) and can be of Localization and Differential Diagnosis varying size, from barely palpable to very large and dis- figuring, particularly in children inadequately treated. The vignette describes a case of acute respiratory distress Systemic complications include cardiac involvement, due to a neuromuscular disorder (signs of hypotonia and gastroparesis, and gastrointestinal tract perforation. Other areflexia indicate a disorder of the motor unit). The next complications include residual weakness with contrac- step is to determine which level of the motor unit is af- tures, and subcutaneous calcifications. fected: anterior horn cells, peripheral nerve, neuromus- cular junction, or muscle. Among the disorders of the anterior horn cells, infantile Diagnosis spinal muscular atrophy can manifest with respiratory Laboratory studies demonstrate elevation of serum levels compromise in the neonatal period. Extraocular muscles of muscle enzymes: CK, LDH, SGOT, and SGPT. Serum are typically spared and severe constipation is not a fea- CK can be significantly elevated up to 50 times the upper ture. Acute anterior horn cell disease due to polyomyelitis limits of normal. However, serum levels can also be nor- is uncommon since the advent of polio immunization ex- mal, particularly in the early stages, and therefore a nor- cept in immunodepressed patients and is characterized by mal laboratory level does not exclude the diagnosis of fever, meningeal signs and an asymmetrical flaccid polymyositis or dermatomyositis. paralysis. Electrodiagnostic studies, particularly needle EMG, Acute disorders of the peripheral nerves, such as GBS, show signs of membrane instability represented by pro- is rare in children younger than 2 years of age (Evans). fuse fibrillations and positive sharp waves. Motor unit GBS usually presents with progressive ascending motor potentials are of short duration and polyphasic, and may weakness and sensory symptoms. Respiratory dysfunc- show early recruitment. tion can complicate the course of the disorder but is un- Muscle biopsy demonstrates the typical finding of peri- likely to be an initial manifestation. fascicular atrophy. Disorders of the neuromuscular junction, typically in- fantile botulism (preferred diagnosis) can present be- Treatment tween 3 and 18 weeks of age with weakness, hypotonia, and hyporeflexia or areflexia. The neurological manifes- Corticosteroids are considered the treatment of choice. tations can be preceded by several days or few weeks of The initial dose of prednisone is 2 mg/kg/day, not to ex- constipation and poor feeding. On examination the child ceed 100 mg/day, followed after clinical improvement by may appear lethargic and hypotonic with diminished an alternate-day regimen. If the patient does not respond spontaneous movements. Ptosis, extraocular and facial to this regimen, then immunosuppressive agents such as muscle weakness, reduced or absent gag reflex, and poor methothrexate, azathioprine, or cyclosporine can be used. suck can also be noted. Pupillary reaction to light may be Plasmapheresis is another option. impaired. Respiratory function can be compromised due 176 18. Pediatric Neuromuscular Disorders to weakness of the respiratory and pharyngeal muscles Summary A 2-day-old baby with severe hypotonia, gen- and infants may require assisted mechanical ventilation. eralized weakness, respiratory distress, apathy, and a Disorders of the muscle that can manifest with respi- weak cry. ratory compromise in the neonatal period include the con- genital myotonic dystrophy and the rare metabolic my- Localization and Differential Diagnosis opathies (acid maltase deficiency and myophosphorylase deficiency). These disorders can easily be clinically ruled Again, the distinction between cerebral versus motor-unit out from the vignette. Congenital myotonic dystrophy hypotonia should be made in this infant. There is no men- that may cause complications, such as polyhydramnios or tion in the vignette of any decreased level of conscious- decreased fetal movements, during the prenatal period is ness, seizures, dysmorphic features, or other organ mal- characterized by severe hypotonia and respiratory distress formation that may indicate a cerebral localization. If the that become manifest immediately after birth. Acid mal- symptoms are localized to the motor unit and the family tase deficiency manifests at birth or during the first weeks history (myasthenic mother) is considered, transitory neo- of life with severe hypotonia and respiratory failure but natal myasthenia ranks high on the list of the possibilities. severe organomegaly is also present. Myophosphorylase Transient neonatal autoimmune myasthenia gravis oc- deficiency can rarely present with a severe infantile form curs in 10 percent of children born to mothers with my- characterized by marked hypotonia and respiratory failure asthenia gravis (Dumitru et al.). The disorder is caused and usually manifests during the teenage years with ex- by the passive transfer through the placenta of circulating ercise intolerance, cramps, and myoglobinuria. antiacetylcholine receptors antibodies from the myas- In summary, infantile botulism represents the preferred thenic mother to the fetus. The onset of the symptoms is diagnosis of the child in the vignette. usually during the first three day of life with generalized weakness, hypotonia, respiratory distress, a weak cry, Diagnosis poor feeding due to suck problems, facial muscle weak- The diagnosis is confirmed when the toxin is identified ness, and ptosis. in the stool specimen. Both type A and type B spores of Clostridium botulinum have been implicated. Diagnosis Electrophysiological findings in botulism are indica- The disorder is self-limited with a mean duration of tive of a presynaptic defect of the neuromuscular junction symptoms of 18 to 20 days. Diagnostic approach includes and show a moderate increment of the compound muscle the demonstration of high serum concentration of Ach- action potential present in the affected muscles after rapid binding antibodies in the newborn and transient improve- repetitive stimulation. ment of weakness by the subcutaneous or intravenous Treatment injection of edrophonium chloride 0.15 mg/kg. Treatment of infantile botulism is based on supportive measures including respiratory support and nasogastric Treatment feeding. The treatment includes anticholinesterase medications, plasma exchange if the weakness is severe, and mechan- Neonatal Transient Myasthenia ical ventilation. Gravis

Charcot-Marie-Tooth Disease Vignette A 2-day-old baby boy was transferred to the ICU because of poor feeding, poor cry, generalized Vignette weakness, diminished activity, apathy, respiratory A 16-year-old boy started having difficulty running distress, and severe hypotonia. The infant was born at the age of 6, which steadily progressed. By the four weeks premature through an emergency C- age of 12, he had mild weakness and wasting of the section after spontaneous rupture of the mem- thenar and interossei muscles and a bilateral foot branes. The initial examination was normal. The drop. He was previously diagnosed as having a mother had a history of myasthenia gravis since the learning disability. There was no other medical his- age of 21 and has had several miscarriages. The tory. The boy was adopted and the family history father of this child was unknown. One sibling had was not available. On examination there was distal several bone deformities plus juvenile diabetes. limb atrophy. Hand grip, wrist and foot dorsiflexion Charcot-Marie-Tooth Disease 177

and eversion were weak. DTR were absent except more widespread central nervous system or other system for trace in the biceps and triceps. Vibration was involvement. Neuropathies associated with spinocerebel- decreased at the ankles. lar degeneration include Friedreich’s ataxia, which is an autosomal recessive disorder characterized by involve- Summary A 16-year-old boy with a history of chronic ment of the peripheral nerves with distal weakness, wast- progressive distal weakness atrophy and sensory ing, sensory loss, and areflexia, and other characteristic disturbances. symptoms, such as dysarthria, ataxia, titubation of the head, nystagmus, bilateral Babinski’s sign, and so on. Hereditary neuropathies associated with specific met- Localization and Differential Diagnosis abolic defects include disorders that can easily be ex- Considering the different parts of the motor unit, there is cluded from the vignette. Refsum disease, associated with no doubt that the vignette indicates involvement of the a defect of phytanic acid metabolism, has distinctive peripheral nerves. Next, it is important to determine if the clinical features in addition to peripheral nerve dysfunc- disorder is hereditary or acquired. tion, such as retinitis pigmentosa presenting with night After excluding a toxic or metabolic etiology, the most blindness, hypoacusis ataxia, and other cerebellar signs, likely categories of chronic neuropathies to be considered such as tremor, nystagmus, and elevated protein level in are the hereditary neuropathies and chronic inflammatory the CSF. demyelinating polyneuropathy (CIDP) (Ouvrier et al.). Fabry disease, which is due to deficiency of the lyso- Hereditary neuropathies are considered the most common somal enzyme alpha-galactosidase, is an X-linked disor- type of chronic neuropathies in children. Of the hereditary der manifesting with painful distal paresthesias due to group, 40 percent had peroneal muscular atrophy (Cov- small fiber neuropathy and angiokeratoma, particularly anis in Pantepiadis). When considering the hereditary over the trunk, buttocks, and scrotum. neuropathies, it is important to determine if the neurop- Metachromatic leukodystrophy, caused by deficiency athy occurs as a sole manifestation of a peripheral nerve of the lysosomal enzyme arylsulfatase A, presents with disorder or if it is associated with other symptoms sug- gait dysfunction, hyporeflexia, and hypotonia, often pre- gestive of a more widespread involvement of the nervous ceding the signs of CNS, involvement in the late infantile system or other organs. The patient in the vignette had form. In the juvenile form, the presentation is often with experienced a distal sensorimotor neuropathy without behavior dysfunction and cognitive impairment. other clinical manifestations. This type of picture can rep- Globoid cell leukodystrophy, due to deficiency of gal- resent Charcot-Marie-Tooth (CMT) disease, which is the actosylceramidase can have signs of peripheral nerve in- most common of the inherited polyneuropathies. volvement but the classic manifestations are represented Clinical manifestations of CMT are characterized by by severe mental and motor impairment, seizures, optic symmetrical weakness and atrophy, preferentially involv- atrophy, and so on. ing the lower extremities distally and to a lesser extent Tangier disease and abetalipoproteinemia are men- the upper extremities without any signs of a more wide- tioned here for completion. The former, due to deficiency spread involvement. Charcot-Marie-Tooth disease is a of high-density lipoproteins, has typical features of neu- heterogenous group of hereditary disorders. CMT type I ropathy and enlarged yellow-orange tonsil, a pseudo- is the most common variety and is characterized by an syringomyelic picture of dissociated sensory loss com- autosomal dominant inheritance and clinically by distal bined with weakness and atrophy of the upper extremities weakness, atrophy, sensory loss, and foot deformity, par- or multifocal mononeuropathies. Abetalipoproteinemia, ticularly pes cavus and hammer toe. Nerve biopsy shows due to absence of apolipoprotein B, is characterized by evidence of extensive demyelination with onion bulb for- progressive peripheral neuropathy associated with reti- mation. CMT type II usually manifests later than type I nitis pigmentosa, and severe fat malabsorption. with similar features but less prominent weakness and Chronic acquired neuropathies of children, particularly deformity and without enlargement of the peripheral CIDP, also need some consideration in the differential nerves. diagnosis of the child described in the vignette. CIDP is A third variety of inherited polyneuropathy, Dejerine- more common in adults than in children and is charac- Sottas disease, or hereditary motor and sensory neurop- terized by progressive or relapsing weakness that affects athy (HMSN) type III, is an autosomal recessive disorder the upper and lower extremities proximally and distally. characterized by presentation in infancy or early child- The proximal weakness can be pronounced but the atro- hood with generalized weakness, preferentially distal; hy- phy is rarely significant. potonia; deformities of hands, feet, and spine and en- Toxic and metabolic causes of neuropathies also need larged peripheral nerves. to be mentioned for completion. These can be drug in- Other hereditary and metabolic neuropathies can be duced (e.g., isonazid, nitrofurantoin, vincristine, etc.) or distinguished based on their clinical characteristics and secondary, for example, to diabetes or uremia. 178 18. Pediatric Neuromuscular Disorders

In general, during childhood and adolescence, chronic Electrophysiological studies demonstrate significantly peripheral neuropathies are usually caused by a hereditary decreased conduction velocity on nerve conduction stud- metabolic or a familial degenerative disorder. ies. The hereditary demyelinating neuropathies typically Finally, as part of the differential diagnosis, motor neu- show a uniform and symmetrical slowing without con- ron diseases, such as hereditary spinal muscular atrophy, duction block or temporal dispersion. Nerve biopsy particularly types 2 and 3, may simulate CMT types I and demonstrates extensive demyelination and onion bulb II in some aspects but the weakness mainly affects the formation. proximal muscles and sensation is completely normal. The hereditary distal myopathies and myotonic dystrophy CMT Type II have their typical characteristics that help the distinction. This type is the neuronal form of peroneal muscular at- rophy and is characterized by an autosomal dominant Clinical Features and Diagnosis transmission and by similar clinical features to type I ex- The most common cause of peroneal muscular atrophy cept for later onset, less severe weakness and deformities, in children is a hereditary motor and sensory neuropathy, and less common involvement of the upper extremities. usually CMT. There are two main entities within the Peripheral nerves are not enlarged and electrophysio- CMT phenotype: logical findings demonstrate normal or minimally abnor- mal conduction velocities and features of axonal loss on • CMT-I (HMSN I): The hypertrophied or demyelinating needle EMG. Nerve biopsy demonstrates axonal atrophy form characterized by severe reduction in nerve con- and wallerian degeneration. The only major difference duction velocities and nerve biopsy findings consistent between this disease and CMT-I is in the electrophysio- with demyelination and onion bulb formation. logical and pathological findings. • CMT-II (HMSN-II): The neuronal form with normal or near normal conduction velocity and nerve bi- opsy findings of axonal loss without significant de- Facioscapulohumeral Muscular myelination. Dystrophy CMT Type I CMT type I is the most frequent form and is characterized Vignette: Serratus Anterior by an autosomal dominant inheritance and onset during the first or second decade of life. Some cases can be sec- A 15-year-old girl started noticing difficulty run- ondary to spontaneous mutations. There are three genetic ning, climbing rope, and blow-drying her hair variants of this condition: about eight months ago. Her medical history was unremarkable except for feeling tired when raising • CMT-IA is due to segmental duplication of 1.5 mega- her arms for some time during the last year. When base of DNA at the region 17p 11.2–12, or to a mu- examined she stated that she has never been able tation of the peripheral myelin protein 22. to drink through a straw or whistle. She had a mild • CMT-IB is caused by mutations in the myelin protein facial weakness, scapular winging, and mild weak- PO, which is located on chromosome 1q22–23. ness and atrophy of latissimus dorsi, trapezius, • CMT-IC is not linked to any chromosome. rhomboids, serratus, and anterior biceps and tri- ceps muscles. Deltoids were of normal strength. She The clinical features manifest with gait impairment due had a bilateral foot drop. Reflexes and sensation to weakness and atrophy of the intrinsic foot and peroneal were normal. Family history was unremarkable ex- and anterior tibial muscles. Foot drop and steppage gait cept the father had scapular winging and could may result. Absent ankle jerk is a very common finding never whistle or do pull-ups. and the rest of the reflexes can be decreased or absent. Patients may also show the appearance of inverted cham- Summary A 15-year-old girl with history of progressive pagne bottle legs due to severe atrophy below the knees. weakness involving face, shoulder muscles, and distal Sensory complains are usually rare but the examination legs, and scapular winging. The father has scapular wing- may show decreased joint position sense and vibration in ing and could never whistle or do pull-ups (this indicates the distal extremities. Foot deformities are common, par- weakness of the face, shoulders, and proximal upper ex- ticularly pes cavum, equinovarus, and hammer toe. tremities in the father). Distal weakness and atrophy of the upper extremities can also gradually occur. Peripheral nerves are clinically Localization and Differential Diagnosis enlarged in 25 percent of children with CMT type I (Dumitru et al.). The disorder has a slow course of Weakness associated with normal reflexes and intact sen- progression. sation suggest a disorder of the muscles. Childhood my- Myotonic Dystrophy 179 opathies can be inherited or acquired. The child described and triceps muscles with almost normal forearm muscles in the vignette had a father who manifested some com- has suggested the definition of Popeye arms. Winging of mon clinical features, such as scapular winging and in- the scapula occurs and can be prominent. In the lower ability to whistle, suggesting an inherited dominant extremities, the anterior tibialis muscle is usually affected disorder. with the result of foot drop and frequent falling. The pattern of weakness involving the facial, scapular, Laboratory findings include a mild to moderate in- stabilizer, and proximal upper extremities muscles and crease of the CK level and electrophysiological findings anterior tibialis muscles with resultant foot drop, is typ- of short duration, small amplitude polyphasic potentials ical of facioscapulohumeral muscular dystrophy (FSH). with early recruitment. Muscle biopsy shows variation in Patients cannot purse their lips, use a straw, or whistle. fiber size with rounded or angulated atrophic fibers. Weakness and atrophy mainly involves the humeral mus- Mononuclear inflammatory cells may be demonstrated. cle groups sparing the forearm musculature and deltoid muscle but greatly affecting biceps and triceps. Scapular winging can be prominent and the anterior compartment muscles of the distal legs can also be affected. Myotonic Dystrophy Other muscular dystrophies can be easily distinguished by their clinical characteristics. Limb-girdle dystrophies are a heterogeneous group of autosomal recessive and Vignette autosomal dominant disorders that manifest with pro- gressive weakness of the pelvic girdle and shoulder mus- An 8-year-old boy was referred to the school coun- culature of varying severity. Calf hypertrophy and scap- selor because of inattentiveness, poor school per- ular winging can occur. Facial weakness, which is typical formance, and hyperactivity. On examination he of FSH, is not a feature. was mildly retarded and showed facial weakness Emery-Dreifuss muscular dystrophy is an X-linked re- with a tented upper lip. His mother was divorced cessive disorder affecting only males and characterized and could not keep a steady job because she was by progressive weakness and atrophy particularly of bi- always falling asleep at work during the day. She ceps, triceps, and peroneal muscles, early prominent con- had cataracts removed at the age of 25 and showed tractures of the elbows and Achilles’ tendon, and cardio- facial weakness and bilateral foot drop. myopathy. Facial weakness is not a feature. Duchenne’s and Becker’s muscular dystrophies can be Summary An 8-year-old boy with mental retardation easily excluded for obvious reasons (course of disease, and facial weakness. His mother has facial weakness and distribution of weakness, progression, severity, X-linked distal limb weakness and a history of cataracts removed inheritance affecting only males). at a young age. In addition she has daytime sleepiness Myotonic dystrophy with its characteristics of myoto- that interferes with her job performance. nia, facial appearance, and distal limb weakness, can be easily distinguished and ruled out by the vignette. Localization and Differential Diagnosis Congenital myopathies that can be associated with an FSH dystrophy-like phenotype, such as nemaline myopa- The history points to a hereditary disorder presenting with thy and centronuclear myopathy, are commonly accom- facial weakness and mental retardation. The mother had panied by dysmorphic features and skeletal abnormalities facial and distal leg weakness as well as a history of cat- such as narrow facies and high arched palate, micro- aracts and hypersomnolence. Several inherited disorders, gnathia, prognathism pectus escavatum; hyposcoliosis; particularly muscular dystrophies can manifest with sig- pescavus or club feet. Deep tendon reflexes are reduced nificant facial weakness. or absent. Facioscapulohumeral dystrophy can present during in- Acquired myopathies, such as inflammatory or sec- fancy with marked facial weakness but other features im- ondary to endocrine, toxic, or infectious processes, may portant for the diagnosis observed in the patients and fam- have an insidious onset and always need to be ruled out ily members are shoulder girdle weakness and atrophy, when considering weakness in children because they can and winging of the scapulae. Only rarely can mental re- be treated. tardation be observed. In this vignette, the clinical features shown by the mother and the child do not indicate a case of FSH. Clinical Features and Diagnosis Myotonic dystrophy, particularly congenital myotonic FSH is an autosomal dominant disorder linked to the telo- dystrophy, can clearly represent the case described in the meric region of chromosome 4q35 (Dumitru et al.). The vignette. Facial muscle weakness is an important clinical clinical features include weakness of the facial, shoulder manifestation. Children may show an expressionless face girdle, and proximal upper extremity muscles with spar- and triangular mouth with a tented upper lip or inverted ing of the deltoid muscles. The involvement of the biceps V-shape appearance. Mild or moderate mental retardation 180 18. Pediatric Neuromuscular Disorders is another significant feature. The vignette does not give Summary A 14-year-old boy with acute motor weakness information about the prenatal and perinatal history of and areflexia. Other details provided by the history are: this child. In congenital myotonic dystrophy, infants may normal cranial nerves and normal sensory examination. present at birth with hypotonia, and feeding and respira- tory difficulties. Decreased fetal movements can also be Localization and Differential Diagnosis observed by the mother before the baby is born. Clinical The symptoms are clearly associated with a disorder of myotonia cannot be present in infants but is usually dem- the motor unit. Next is to determine the component in- onstrated in older children after the age of 5 years. Con- volved: peripheral nerve, neuromuscular junction muscle, genital myotonic dystrophy is nearly always transmitted or anterior horn cell. by a mother affected with myotonic dystrophy, even Disorders of peripheral nerve causing acute weakness though in some cases she may not be aware of having the include Guillain-Barre´ syndrome (GBS) as well as neu- disorder. ropathies secondary to infectious, metabolic, and toxic Classic myotonic dystrophy manifests with facial and causes. In GBS there is progressive weakness over sev- distal limb weakness. Myotonia, a disturbance of muscle eral days and rarely is the evolution rapid, in less than 24 relaxation after contraction, can be demonstrated by ac- hours. Cranial nerve involvement, autonomic dysfunc- tion or percussion particularly in the hands but also in the tion, sensory deficits, and paresthesias are common, and eyelids or tongue. Other features include behavioral and respiratory compromise can occur. cognitive dysfunction with personality disorders and im- Infectious causes of neuropathies, such as diphtheria, pairment of memory and spatial orientation. Posterior have distinguishing characteristics, such as systemic subscapular cataracts can be present. Signs of cardiac in- symptoms and palatal paralysis. Metabolic disorders, volvement with arrhythmias and sleep disorders, such as such as acute intermittent porphyria, can present with an sleep apnea and daytime hypersomnolence, are other acute paralysis but abdominal symptoms such as pain, features. nausea, and vomiting, are often prominent, and auto- nomic and sensory symptoms are common. Seizures are Diagnosis another important finding. Toxic neuropathies due to The diagnosis is based on the clinical characteristics and drugs or toxins are associated with a recognizable of- family history. CK can be mildly elevated. The needle fending agent. Most of the toxic neuropathies have a sub- EMG study may demonstrate the typical myotonic dis- acute or chronic evolution. charges with characteristic waxing and waning of both Disorders of the neuromuscular junction to be consid- amplitude and frequency. DNA test for the expanded ered in the differential diagnosis of acute weakness are CTG (cytosine, thymine, guanine) repeat on chromosome myasthenia gravis and botulism. In myasthenia gravis, 19 may show an unstable expansion of a CTG trinucle- symptoms are often related to involvement of ocular, fa- otide repeat sequence. cial, and bulbar muscles and reflexes are usually normal. The fatigable weakness is an important clinical sign. Bot- ulism can be responsible for acute weakness, but cranial Treatment nerve involvement and large, poorly reactive pupils rep- No treatment is effective in improving muscle strength. resent some typical findings. Disorders of the anterior horn cell such as amyotrophic lateral sclerosis, spinal muscular atrophy, and polio, can Periodic Paralysis be easily excluded from the vignette for the lack of char- acteristic signs and symptoms. Considering muscle dysfunction as the origin of the acute weakness, the periodic paralysis needs great con- Vignette sideration because they can present with attacks of acute, A 14-year-old boy woke up in the middle of the severe limb weakness. Primary hyperkalemic periodic pa- night unable to move his limbs. He was able to talk ralysis, also called potassium-sensitive periodic paralysis, and did not complain of double vision. The day of is an autosomal dominant disorder with onset during this event he was at a friend’s birthday party, but childhood caused by mutations in the muscle membrane he denied using alcohol or illicit drugs. He was sodium channel. Clinically, it manifests with attacks of alert and oriented. Cranial nerves examination acute weakness usually lasting less than a few hours and triggered by rest following strenuous exercise. Serum po- showed normal extraocular movements, pupillary tassium level is normal between attacks but can be in- function, palatal movements, and gag reflex. There creased during the acute paralysis. was a flaccid limb paralysis with areflexia. Sensory Hypokalemic periodic paralysis, which represents the exam was intact to all modalities. most common type of periodic paralysis, is an autosomal Fabry’s Disease 181 dominant hereditary disorder due to mutations in calcium veal objective findings. The involvement of other systems channel of skeletal muscles. Symptoms appear during the helps in the diagnosis of this syndrome, which is caused first two decades, with episodes of acute paralysis that by a deficiency of the lysosomal enzyme alpha- tend to occur during the night or early in the morning and galactosidase. are precipitated by meals rich in carbohydrates and so- Other familial juvenile polyneuropathies have distinc- dium, stress, or sleep following heavy exercise. The tive clinical characteristics. Refsum disease is an auto- weakness tends to involve the upper and lower extremity somal recessive disorder of lipid metabolism character- muscles sparing the facial and extraocular muscles and ized by retinitis pigmentosa that presents as night only rarely causing respiratory compromise. Sensation is blindness, cerebellar dysfunction, deafness, and periph- normal and reflexes are diminished or absent. The paral- eral neuropathy. ysis lasts several hours with gradual return to normality Acute intermittent porphyria is characterized by a pre- over a few days. The episodes of weakness are associated dominantly motor neuropathy with weakness of the upper with low potassium levels with normal potassium be- and lower extremities and facial and bulbar muscles ac- tween attacks. The treatment is based on potassium ad- companied by abdominal symptoms, seizures and psy- ministration and prophylactic measures. chiatric disturbances. Tangier disease, which is caused by a deficiency of high-density lipoproteins, manifests with an asymmetri- Fabry’s Disease cal or symmetrical peripheral neuropathy or with a sy- ringomyelic presentation. A typical feature is the yellow- ish-orange colored tonsils. Methachromatic leukodystrophy is characterized by Vignette progressive cerebral dysfunction with ataxia, spasticity, speech and intellectual deterioration, and optic atrophy A 13-year-old boy started complaining of a burning and associated signs of peripheral nerve involvemnt. pain in his toes and fingers after playing soccer The hereditary motor and sensory neuropathies (CMT- with his friends during the summer. His medical I and -II) are autosomal dominant disorders manifesting history revealed some prior attacks of diarrhea and with distal weakness and atrophy and foot deformities. abdominal pain diagnosed as food intolerance. The The hereditary motor and sensory neuropathy type III clinical examination revealed a reddish purple rash (Dejerine-Sottas) manifests with progressive weakness, around the scrotum and umbilical area. Corneal atrophy, and sensory ataxia. opacity was noted on slit lamp examination. The neurological examination showed no objective signs of sensory impairment, reflex loss, or weak- Clinical Features ness. In the family history, a maternal uncle suf- Fabry’s disease (angiokeratoma corporis diffusum) is an fered multiple strokes and had heart disease and X-linked disorder due to deficiency of the lysosomal en- hypertension. zyme alpha-galactosidase. Clinical symptoms include characteristic episodic painful paresthesias, described as Summary A 13-year-old boy complaining of painful dis- burning and lancinating pain, involving the distal extrem- tal paresthesias precipitated by exercise. Neurological ex- ities and triggered by hyperthermia due to strenuous ex- amination is apparently normal. Other symptoms and ercise, infection, or other causes. The neurological exam- signs are: diarrhea, abdominal pain, skin lesions, and eye ination shows no objective signs of sensory abnormality, involvement with corneal opacity. reflex loss, or weakness. Motor and sensory nerve con- duction studies and EMG are normal because Fabry’s dis- Localization and Differential Diagnosis ease causes involvement of the small myelinated and un- myelinated nerve fibers. The vignette suggests a hereditary disorder with an X- Autonomic dysfunction manifests with episodic diar- linked transmission by mentioning in the family history rhea, nausea, vomiting, and hypohydrosis. Dermatologic that a maternal uncle had cardiac problems and hyperten- signs manifest with angiokeratoma, which is characterized sion and suffered multiple strokes. This is a metabolic by a dark red maculopapular rash involving the peri- hereditary multisystem disorder in which one of the clini- umbilical area and the scrotum, inguinal area, and peri- cal signs is intermittent painful paresthesias. neum. The ophthalmologic involvement is mainly char- The categories of disorders to be considered are the acterized by corneal opacity. juvenile metabolic polyneuropathies, in particular Fabry’s Serious complications are represented by signs of vas- disease, which is an X-linked disorder characterized by cular dysfunction with multiple strokes, hypertension, burning, lancinating pain in the extremities aggravated by myocardial ischemia, premature atherosclerosis, and so hyperthermia. The neurological examination may not re- on. Fatal complications are also due to renal failure. 182 18. Pediatric Neuromuscular Disorders

Diagnosis The examination is usually normal between attacks but one third of patients with McArdle’s disease may develop Laboratory investigations show a decreased level of fixed, mild proximal weakness due to the recurrent at- alpha-galactosidase A activity. The disorder is linked on tacks of rhabdomyolysis (Dumitru et al.). a mutation of the alpha-galactosidase gene located on Disorders of fatty acid metabolism that enter the dif- chromosome Xq21–22. ferential diagnosis mainly include carnitine palmitoyl- transferase deficiency (CPTD). This disorder usually Treatment manifests with muscular pain, cramps, and fatigue after Treatment is symptomatic. intense or prolonged exercise or hyperthermia. Recurrent myoglobinuria is precipitated by prolonged exercise or fasting and renal failure can occur. Patients do not ex- Metabolic Myopathies perience the second-wind phenomenon as with McArdle disease and the examination is normal between the epi- McArdle’s Disease sodes. In myophosphorylase deficiency some patients may develop fixed proximal weakness due to rhabdo- myolisis. In CPT deficiency, serum concentration of cre- Vignette atine kinase and EMG are normal between attacks. The A 13-year-old boy had experienced stiffness, muscle forearm ischemic exercise is normal. pain, and cramps while in the school gym lifting In the differential diagnosis of exercise intolerance, weights. This became a problem during a recent myoadenylate deaminase deficiency is another disorder school-sponsored walk when he was forced to stop to be considered. The onset of symptoms is late adoles- after two miles and at frequent intervals afterward. cence to middle age, with muscle pain of varying severity, A few days later, while lifting weights again, he fatigue, and myoglobinuria after exercise. The second- developed stiffness, cramps, and severe pain in his wind phenomenon does not occur. The forearm ischemic arms and shoulders. He was otherwise in good exercise test shows normal increase of serum lactate with- health and there was no history of weakness, numb- out a rise of ammonia level. ness, incoordination, or difficulty walking. In the Mitochondrial myopathies can be excluded by the vi- family, a paternal uncle had a history of muscle gnette, but they enter the differential diagnosis of exercise pain on exercise and renal disease. intolerance. Symptoms are heterogeneous and include hy- potonia in infancy, myalgia, exercise intolerance, myo- globinuria, proximal weakness, and so on. A variety of Summary A 13-year-old boy with history of stiffness, neurological syndromes with a multiplicity of symptoms pain, and cramps on exercise and normal neurological are also part of the mitochondrial disorders and include examination. A paternal uncle suffered from muscle pain psychomotor retardation, seizures, dementia, movement and renal disease. disorders, migraine-type headache, stroke-like episodes, Localization and Differential Diagnosis dysmorphic features, short stature, deafness, and multiple organ involvement. The vignette describes a case of exercise intolerance char- acterized by episodes of muscle pain, cramps, and stiff- Clinical Features ness triggered by exercise. This is a typical feature of McArdle’s disease (myophosphorylase deficiency) is an metabolic muscle disease. The metabolic myopathies in- autosomal recessive disorder affecting preferably males clude disorders of glycogen, lipid, or mitochondrial me- and characterized by exercise intolerance with symptoms tabolism. The only disorder of nucleotide metabolism in- of myalgia, fatigue, stiffness, cramps, and weakness, typ- volving muscle is myoadenilate deaminase deficiency. ically precipitated by brief strenuous activity, such as lift- Typical symptoms of metabolic myopathies are exercise ing weights, or prolonged low-impact exercise, such as intolerance, muscle pain, stiffness, cramps, fatigue, myo- long walks or swimming. globinuria, and, in some cases, weakness of proximal or The second-wind phenomenon is described as the abil- distal muscles. ity to slow down and rest as soon as patients experience In the patient described, the occurrence of symptoms muscle pain to avoid an attack and continue exercising following brief episodes of strenuous exercise (weight with better durability. Patients can reduce the intensity lifting) or prolonged low-intensity exercise (long walk) effort so that they can maintain the activity for a longer is typical of McArdle’s disease (myophosphorylase de- period of time. ficiency). This disorder, whose hallmark is exercise in- The physical examination between attacks can be nor- tolerance during childhood, can be clinically similar to mal or show some degree of proximal weakness. Myo- the other disorders of glycogen metabolism, and labora- globinuria and renal insufficiency may complicate the tory investigations need to point to the correct diagnosis. picture, usually in later stages. Metabolic Myopathies 183

Diagnosis disorders presenting with organomegaly. These include the infantile cytochrome C oxidase deficiency, debranch- The serum CK level is usually elevated. The needle EMG ing enzyme deficiency, and so on. is normal but myopathic features can also be found. The Cytochrome C oxidase deficiency, which can manifest exercise forearm test demonstrates a rise in ammonia with severe hypotonia, weakness, poor feeding, and res- level, but not in the level of lactic acid. Muscle biopsy piratory difficulty in the newborn, can also be associated demonstrates abnormal glycogen accumulation in the with cardiac dysfunction but rarely cardiomegaly. subsarcolemmic and intermyofibrillar areas. McArdle’s Debranching enzyme deficiency or type III glycoge- disease is due to a mutation in the gene encoding for nosis is not characterized by severe weakness and hypo- myophosphorylase on chromosome 11q13. tonia, as is AMD, and typically can manifest with seizures related to hypoglycemia. Treatment Infantile acid maltase deficiency needs to be differen- No therapy is available, although gene therapy is a pos- tiated from spinal muscular atrophy type I (Wernig- sible consideration. Hoffman disease) affecting the anterior horn cells, but the organomegaly, in particular cardiomegaly, is character- istic of AMD. Acid Maltase Deficiency Clinical Features Vignette Acid maltase deficiency, which has an autosomal reces- A 6-month-old boy had a history of severe hypo- sive inheritance is caused by a deficiency of the lysoso- tonia and feeding and respiratory difficulties, since mal enzyme alpha-glucosidase due to mutations on the the age of 3 months. On examination he was very gene encoding for acid maltase, which is located on chro- floppy and weak and rested limply, with his tongue mosome 17q 21–23. Three forms have been described: protruded. There was no evidence of atrophy or fas- the severe infantile form, the childhood-onset type, and ciculations. The pediatrician noted that he was the adult-onset variant. tachypneic and had an enlarged liver and heart. The infantile form is characterized by severe weakness Family history and perinatal history were and hypotonia, respiratory and feeding problems, in ad- unremarkable. dition to organomegaly that includes hepatomegaly, car- diomegaly, and macroglossia. Onset is usually during the Summary A 6-month-old boy with hypotonia, weak- first three months and the disease is rapidly progressive ness, feeding and respiratory problems, and organomeg- and carries a poor prognosis. aly with hepatomegaly and cardiomegaly. The juvenile type manifests during the first decade of life with proximal muscle weakness and respiratory com- promise. Organomegaly is rare. Localization and Differential Diagnosis The adult-onset form, which manifests in the third or The first goal is to categorize the hypotonia as of central fourth decade, is characterized by weakness, mainly in- or peripheral origin. volving the proximal muscles, simulating a limb-girdle Cerebral hypotonia is characterized by decreased level muscular dystrophy. of alertness and the presence of dysmorphic features. Pe- ripheral hypotonia is suggested when the infant is bright Diagnosis and alert but severely weak and areflexic. Another im- portant consideration is the localization of the motor unit Laboratory studies show significant deficiency of alpha- disorder at one of his different levels: the motor neuron, glucosidase activity in the infantile form. The CK level peripheral nerve, neuromuscular junction, or muscle. in the serum is usually moderately elevated. Sometimes there can be a combination of cerebral and Electrophysiological tests demonstrate normal sensory motor unit hypotonia. and motor nerve conduction studies (except in advanced The presence of organomegaly, hepatomegaly, and car- cases were the amplitude of the CMAP may drop). Nee- diomegaly suggests a metabolic disorder, particularly a dle EMG shows abnormal spontaneous activity, including metabolic myopathy. Pompe’s disease or glycogenosis myotonic discharges, fibrillation, positive waves, and type II (acid maltase deficiency, AMD), characterized by complex repetitive discharges, particularly in the para- severe weakness, hypotonia, and feeding and respiratory spinal muscles. compromise in association with organomegaly, can be Muscle biopsy may demonstrate abnormal glycogen clearly represented by the child described. The infantile accumulation between and within the myofibrils and be- form of AMD must be distinguished from other muscle neath the sarcolemma. 184 18. Pediatric Neuromuscular Disorders

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