Neuromuscular disorders - JPED · main neuromuscular disorders in children, that include the diseases affecting the motor unity, i.e. spinal motor neurons, peripheral nerves, neuromuscular

Jornal de Pediatria - Vol. 78, Supl.1 , 2002 S89

REVIEW ARTICLE

S89

0021-7557/02/78-Supl.1/S89Jornal de PediatriaCopyright © 2002 by Sociedade Brasileira de Pediatria

Abstract

Objective: to discuss the most important aspects for performing a differential diagnosis among themain neuromuscular disorders in children, that include the diseases affecting the motor unity, i.e. spinalmotor neurons, peripheral nerves, neuromuscular junction and muscular fibers.

Sources: the revision of the clinical aspects that should be considered for a prompt differentialdiagnosis among several neuromuscular disorders as well as between those and the main causes ofsecondary muscular hypotonia due to central nervous system or systemic disturbances, is based on theclinical experience acquired along the last 12 years in following-up children with NeuromuscularDisorders attended at the outpatient Service of Neuromuscular Disorders at the Hospital das Clínicas daFaculdade de Medicina da Universidade de São Paulo. In addition, it is based on Medline revision and onthe revision of the most recent numbers of Neuromuscular Disorders, the official journal of the WorldMuscle Society.

Summary of the findings: in children most of neuromuscular disorders are genetic conditions and themost common of them are X-linked Progressive Muscular Dystrophy of Duchenne, Spinal MuscularAtrophy, Congenital Muscular Dystrophy, Myotonic Dystrophy and Congenital Myopathies.

Conclusions: over the last decade due to the phenomenal development in human molecular geneticsthe pathogenesis of several neuromuscular disorders in children has been clarified. Nowadays many newdiagnostic methods, including techniques of fetal diagnosis, and a more objective genotype-phenotypecorrelation as well as classification are available.

J Pediatr (Rio J) 2002; 78 (Supl.1): S89-S103: neuromuscular disorders of children, spinal muscularatrophy, congenital myastenic syndromes, muscular dystrophy, congenital myopathies, metabolicmyopathies.

Neuromuscular disorders

Umbertina C. Reed*

* Associate Professor, Department of Neurology, School of Medicine, Universidade de São Paulo.

Introduction

Under the generic designation of neuromusculardisorders, we find different disorders caused by the primaryinvolvement of the motor unit, which is composed of motorneuron, nerve root, peripheral nerve, myoneural junctionand muscles. In children, most of these disorders aregenetically determined. Acquired neuromuscular disordersare extremely rare in adults. Over the last decade, advancesin molecular genetics were useful for diagnosis and genetic

counseling, paving the way for fetal diagnosis. We expectthat such advances contribute to the development of genetherapy, which is apparently the only prospect for thetreatment of a considerable number of hereditaryneuromuscular disorders of childhood that are currentlybeing treated only with palliative methods, such as motorrehabilitation and corrective orthopedic surgeries of thefibrous tendon retractions and skeletal deformities.

S90 Jornal de Pediatria - Vol. 78, Supl.1, 2002

Although the classification of neuromuscular disordersaccording to the different topographies of the motor unit isnot frequently used in our practice, it is a didactic way ofdescribing such conditions (Tables 1 and 2).

Clinical status

Age and manifestation of clinical symptoms are importantfactors for the establishment of the differential diagnosis incases of neuromuscular disorders in children.

In newborns (NB) and infants, the hypotonic syndromeis usually observed. This syndrome comprises twosemiologic groups1: the paralytic group, affected by theprimary involvement of the motor unit (neuromusculardisorders), and the non-paralytic group, affected by a centralnervous system (CNS) disorder or by non-neurologicalsystemic causes. In the paralytic group, muscular hypotoniais associated with motor deficit and hyporeflexia or areflexiaof deep and archaic reflexes, usually with normal level ofalertness. In the non-paralytic group, a precarious level ofalertness is frequently observed, associated with a poorresponse to auditory and visual stimuli, incoordinate suctionand swallowing, metabolic disorders, epileptic seizures or,even, a pre- or perinatal history suggesting cerebral distress.

Hypotonia is particularly important in NBs with muscularhypotonia (neuromuscular disorder) in the paralytic group,since, in contrast with the physiological hypertonia insemiflexion seen in a healthy NB, it gives the impression of

a severely affected baby. However, in infants, due to thephysiological hypotonia observed in the second or thirdmonth of life, retardation or non-acquisition of some stagesof the motor development constitute the most valuableaspect. Lack of resistance to passive motion and to passiveswing of the limbs is the main semiologic characteristic ofhypotonia in this age group (Figure 1a). Depending on thetype of neuromuscular disorder, some severely affectedNBs and infants have difficulty in sucking or swallowing, aswell as respiratory insufficiency (Table 3, Figure 1b).

Older children with neuromuscular disorder usuallypresent the girdle syndrome, which consists of proximalmotor deficit and hypotrophy of the scapular and pelvicgirdle, (Figure 2a); more rarely, however, a distal or diffusedeficit can be observed (Figure 2b). Walking difficulties,associated with constant oscillation of the pelvis, is usuallypresent at the initial stages of dystrophic processes intoddlers, in addition to frequent falls and difficulty inrunning or climbing up stairs. The especially proximalinvolvement of the muscles of the thighs, hip, and spinalcolumn leads to an aggravation of lumbar lordosis and to thecharacteristic myopathic sign on rising (Gowers� sign),which consists of rising up from the floor by fixing eachsegment of the limbs in extension, as if the child was risingover himself/herself. In the scapular girdle, proximalmuscular involvement is expressed by the winged scapula,in which, when the arms are risen, the scapulae move awayfrom the posterior thoracic wall, becoming elevated and

Table 1 - Neuromuscular disorders

Involvement of peripheral motor neuronGenetic cause: infantile spinal amyotrophy (types I, II, III)Acquired cause: enterovirus infection, especially polyomyelitis

Involvement of roots and peripheral nervesGenetic cause: hereditary motor-sensitive polyneuropathies

(several), especially Charcot-Marie-Tooth type I and Déjerine-Sottas (type III)

Acquired cause: several, especially Guillain-Barré syndrome

Involvement of the myoneural junctionGenetic cause: congenital myasthenic syndromeGenetic cause: severe myasthenia and botulism

Involvement of muscular fiber: myopathiesGenetic cause: congenital muscular dystrophy (several subtypes),

progressive muscular dystrophy (several subtypes, especiallysex-linked Duchenne or Becker muscular dystrophy), myotonicdystrophy (Steinert�s disease), congenital myopathies (severalsubtypes), metabolic myopathies (several subtypes)

Acquired cause: several types of myositis, especiallypolydermatomyositis

Table 2 - Neuromuscular diseases - genetically determinedmyopathies

Congenital muscular dystrophy (CMD)

Progressive muscular dystrophy (PMD)Sex-linked PMD, Duchenne, Becker and Emery-Dreyfuss formsGirdle-like PMD, LGMD 1 form (dominant autosomal) andLGMD 2 (recessive autosomal)Fascio-scapulo-humeral PMD (infantile and classic forms)

Myotonic dystrophy (congenital and infantile forms)

Congenital myopathiesCentral coreNemalineMyotubularCongenital fiber disproportionMyopathy with minimal changesOther

Metabolic myopathiesMitochondriopathiesBeta-oxidation disordersGlycogenosisChannelopathies

Neuromuscular disorders - Reed UC


projected (Figure 2a, b). Depending on the time at whichsymptoms appear and on the progression of the disease,motor deficit and muscular atrophy are associated withfibrous tendon retractions and skeletal deformities (Figure3a). Muscular atrophy involving especially distal limbsegments and accompanied by foot deformities (equinusand varus) evokes a diagnosis of motor-sensitive hereditarypolyneuropathy. There are other manifestations that arehighly suggestive of neuromuscular disorders at any age,and that constitute important semiologic data for differentialdiagnosis, among which we have (Table 4): facialdysmorphism (Figure 4) and high-arched palate, involvementof facial and ocular muscles, especially palpebral ptosis,and rarely, congenital multiple arthrogryposis, which isdetected at birth. The latter, although it also occurs incerebral and non-neurological disorders, is more common,or say, less rare in neuromuscular disorders, indicatingreduction of intrauterine mobility, which is occasionallyreported by the mother as a reduction of fetal movement.

Another aspect that indicates a reduction in intrauterinemobility and that can be found especially in congenitalmyopathies, is luxation of the coxofemoral joint, since thecavity of the acetabulum is shaped by intrauterine muscularcontraction. In more severe cases, polyhydramnios is alsoobserved, depending on the difficulty of the fetus to swallowthe amniotic fluid.

Figure 1 - Semiologic aspects of neuromuscular disorders in infants and young children:a) CMD, 12-month-old children with hypotonia and muscular weakness: lackof resistance to passive motion and severe delay in motor development,inability to hold their head steady; b) ISA type I (Werdnig Hoffmann disease):extremely severe phenotype, children are not able to sit down, facial involvement(fish mouth) and thoracic deformity

Table 3 - Clinical aspects of neuromuscular disorders: severitydegree in hypotonic NBs and infants

Severe involvement with frequent difficulty to suck andrespiratory insufficiency

ISA-I (Werdnig-Hoffmann)MSHP III (severe congenital)Severe neonatal myasthenia and congenital myasthenic syndromeCMD (brain-ocular and merosin-negative forms)Fascio-scapulo-humeral dystrophy (infantile form)Congenital myotonic dystrophySex-linked myotubular myopathyNeonatal nemaline myopathyMitochondriopathies, glycogenosis type II (Pompe)

Moderate involvement with delayed motor development andvariable degrees of weakness and muscular atrophy

MSHP III (infantile)Merosin-positive CMDCongenital myopathies: myotubular, nemaline, congenital fiberdisproportionMitochondriopathies

Mild involvement, compatible with practically normal activity

ISA-IIICongenital myasthenic syndromeCongenital myopathies in general: central core, myotubular,congenital fiber disproportion and othersMitochondriopathies, beta-oxidation disorders, glycogenosis



The onset and development of the disease also suggestsome specific neuromuscular disorders (Table 4). Acomplaint of increased weakness by the end of the day or

Figure 2 - Semiologic aspects of neuromuscular disorders in older children: a) patientwith Duchenne PMD: typical myopathic pattern with atrophy of proximalprevalence, aggravation of lumbar lordosis, calf hypertrophy and retraction ofAchilles tendon; b) congenital myopathy: pattern of severe diffuse hypotrophyand winged scapula

Figure 3 - Semiologic aspects of neuromuscular disorders in older children: a)ISA type II, intermediate form (severe phenotype, child is able to sitdown, but is not able to walk): progressive muscular atrophy anddiffuse fibrous tendon retraction; b) ISA type III (variable phenotype,usually mild or moderate, child is able to walk): mild muscular atrophy,few restraints in the daily life


after a period of greater physical activity suggests amyasthenic phenomenon, which characterizes disorders ofthe myoneural junction. Disorders that evolve into bouts,


Table 4 - Clinical and evolutive aspects of neuromusculardisorders

Facial involvement and/or dysmorphismISA-ISevere myasthenia and congenital myasthenic syndromeMerosin-negative CMDCongenital myotonic dystrophyFascio-scapulo-humeral dystrophy (infantile form)Congenital myopathies: nemaline, myotubular, congenital fiberdisproportion

Changes in ocular movement , especially palpebral ptosisSevere myasthenia and congenital myasthenic syndromeMyotubular congenital myopathyCongenital fiber disproportionCongenital myotonic dystrophyMitochondriopathies

Arthrogryposis or early fibrous tendon retractionCMDCongenital myotonic dystrophyISA-IMSHP III (severe congenital and infantile)Fiber congenital disproportion

Involvement associated with the central nervous system (mentaldeficiency, epilepsy, neuroimaging changes)

Sex-linked PMDCMDCongenital myotonic dystrophyMitochondriopathies and ß-oxidation disordersGlycogenosis type II (Pompe)Congenital myopathies (myotubular)

Systemic involvement (cardiac, visceral, endocrin and others)Metabolic myopathies: glycogenosis, mitochondriopathies,ß-oxidation disordersMyotonic dystrophyOnly cardiac: PMD in general, especially sex-linked forms

Fluctuating course or outbreaks triggered by infections, physicalactivity, type of food intake, stress, medication

Severe myasthenia and congenital myasthenic syndromeMetabolic myopathies in general: mitochondriopathies,ß-oxidation disorders, glycogenosis, periodic paralysis/channelopathies

Variable phenotype that allows multiple degrees of muscularweakness, atrophy and fibrous tendon retractions, usuallycompatible with independent walking

ISA-IIIMSHP-I (Charcot-Marie-Tooth)Severe myastheniaMerosin-positive CMDCongenital myopathies (nemaline, myotubular, congenital fiberdisproportion), Metabolic myopathies (mitochondriopathies,ß-oxidation disorders, glycogenosis, periodic paralysis/channelopathies)

Figure 4 - Semiologic aspects ofneuromuscular disorders inchildren - merosin-negativeCMD: facial debility anddeformity


triggered by infections, physical activities, type of nutrition,stress and medications, suggest different types ofmetabolic myopathies, such as mitochondriopathies, beta-oxidation disorders, glycogenosis, periodic paralysis

(channelopathies). Still with regard to metabolicmyopathies, complaints of easy fatigue, muscle pain, and,occasionally, cramps are relatively common. In particularcases, the bouts can culminate in severe myoglobinuria.

On the other hand, an acute or subacute manifestationwith an ascending pattern or one that preferably affects thecervical and bulbar musculature - possibly associated witha previous history of infection or with erythematous skindisorders - is an indicative sign of the two major acquiredneuromuscular disorders: acute demyelinating polyradiculo-neuritis (Guillain-Barré) and polydermatomyositis,respectively. Still with regard to acute or subacutemanifestation, relevant environmental factors (exposure totoxic agents, insect bite, food poisoning, among others) aresuggestive of acquired polyneuropathy and, particularly inour country, of botulism.

Finally, some specific semiologic signs, such asfasciculation in patients with infantile spinal amyotrophy,and the myotonic phenomenon in some channelopathies(typically, in myotonic dystrophy, also known as Steinert�sdisease), are practically restrained to the above mentioneddisorders. Fasciculation is the involuntary contraction ofmuscle fibers of denerved motor units; they can bespontaneous or provoked by muscular percussion, especiallyin the muscles of the tongue and chest. They are oftenaccompanied by polymyoclonia of the distal parts of limbs,and can be observed in the hyperextension of the fingers.The myotonic phenomenon is characterized by the absenceof relaxation following a voluntary muscle contraction; itcan be verified in a shake of hands, with percussion of thetongue or thenar or when the patient, while sneezing, can notreopen his/her eyes.


Table 5 - Neuromuscular disorders. Diagnostic techniques

Muscular enzyme è CPK increasePMD in general, especially sex-linked formsCMD, especially merosin-negativeMyotonic dystrophyCongenital myopathy - congenital fiber disproportionInflammatory myopathies (polydermatomyositis)

Electromyography with specific findings:ISAPolyneuropathies in generalSevere myasthenia and congenital myasthenic syndromeMyopathies in general, especially myotonic syndromes

Muscular biopsy with specific findings:

Optical microscopy:Structural congenital myopathies (central core, nemaline,myotubular)GlycogenosisInflammatory myopathies (polydermatomyositis)

Occasionally: ß-oxidation disorders (lypid accumulation);mitochondriopathies (ragged red fibers)

Immunohistochemistry:Sex-linked PMD, Duchenne and Becker forms (dystrophy)CMD (merosin)Girdle-like PMD in general (sarcoglycanopathies and others)

Electronic microscopy:Structural congenital myopathiesMitochondriopathies


Still with regard to the evaluation of children withneuromuscular disorder, we must be aware of a possibleassociation with systemic (especially hepatic and cardiac)and metabolic (especially lactic acidosis) changes, inaddition to clinical or neuroradiological manifestations ofchanges in the CNS (Table 4). Such associations stronglysuggest different types of metabolic myopathies (beta-oxidation disorders, glycogenosis, mitochondriopathies).CNS involvement may also be observed in some subtypesof congenital muscular dystrophy and in myotonic dystrophy(Steinert�s disease), which can also be associated with awide spectrum of systemic changes. Among the entitiesassociated with progressive muscular dystrophy (PMD),clinical status is generally strictly muscular, occasionallyaccompanied by cardiac involvement, except in the mostcommon and severe PMD of childhood -sex-linked -Duchenne or Becker syndrome-, which can frequentlyevolve into mental retardation and cardiac disorders.

When trying to establish the differential diagnosis ofneuromuscular disorders in children, we must rememberthat the majority of these entities can present a clinicaldevelopment that is highly variable in terms of severity;however, generally, in the same family, but not only, thesame phenotype is maintained (Table 4). Examples ofneuromuscular disorders with highly variable phenotypesare infantile spinal amyotrophy type III, and Charcot-Marie-Tooth disease type I, congenital myasthenicsyndrome, merosin-positive congenital muscular dystrophy,fascio-scapulo-humeral PMD, some congenital myopathies(nemaline, myotubular, congenital fiber type disproportion)and, also, most mitochondrial pathologies and beta-oxidationdisorders.

Diagnosis

Neuromuscular causes of hypotonia are usually assessedby determining muscle enzymes - especially creatinephosphokinase (CPK) -, electromyography (EMG), andmuscle biopsy, or by using molecular markers (Table 5).

In the investigation of neuromuscular disorders, CPKlevels may help to differentiate primary (myopathic) andsecondary (neurogenic) muscular involvement, caused by adisorder of the peripheral motor neuron (Table 5). Asignificant increase in CPK serum level in a NB is highlysuggestive of congenital muscular dystrophy, in its differentforms, purely muscular or associated with CNS and ocularinvolvement, and, particularly, of the merosin-negativeform. More rarely, congenital myotonic dystrophy can beobserved; in infants and children, in addition to congenitalmuscular dystrophy and, typically, to inflammatorymyopathies and to preclinical stages of PMD, enzymaticincreases can be associated with congenital myopathies,congenital fiber type disproportion, and infantile myotonicdystrophy. In boys with Duchenne PMD, who are commonlytaken to medical appointments from the age of three, due tofrequent falls, difficulty in running or climbing up stairs, as

well as a particular difficulty in rising up, extremely elevatedCPK levels, approximately 10,000U/L or over, constitutesome highly suggestive evidence for establishing thediagnosis and a formal indication for the genetic study of theDNA, thus requiring neither an EMG nor a muscle biopsyat this point.

EMG, which presents an electrographic tracing thatallows us to establish if either the motor neuron, roots orperipheral nerves, myoneural junction or the muscle fiber isinvolved, is indispensable for an immediate diagnosis ofinfantile spinal amyotrophy, since the identification ofoccasional DNA deletion in 5q is time-consuming or can beinaccessible in certain centers. Also, the rare cases ofhereditary motor-sensitive polyneuropathies and themyasthenic syndromes are easily diagnosed with EMG. Incases of muscle disorder, EMG is particularly useful inpatients with extremely mild involvement, cases in whichthe indication of biopsy or a longer follow-up is a difficultdecision. EMG is also recommended for toddlers withgirdle syndrome, and in whom we cannot precisely establishthe onset of symptoms; differential diagnosis betweenmyopathy and infantile spinal amyotrophy type III shouldbe established in these cases.


Table 6 - Neuromuscular disorders. Diagnostic techniques:molecular genetics

Infantile spinal amyotrophy: deletions of exons 7 and 8 (SMNgene) in locus 5q11-q13 (mechanism of gene dosage)

Congenital myotonic dystrophy: expansion of repetitive sequenceof CTG trinucleotides in locus 19q13.3

Fascio-scapulo-humeral dystrophy: deletion of the repetitivesequence of 3.3 kb in locus 4q35

Mitochondrial encephalomyopathies: analysis of specificmutation points

Motor-sensitive hereditary polyneuropathies: different types ofmutations in locus 17p11.2-12 , peripheral myelin protein-22and 1q22-23, myelin protein zero (mechanism of gene dosage)


Muscle biopsy (Table 5) using optic microscopy,complemented by electronic microscopy, is particularlyimportant for the differential diagnosis of congenitalmyopathies with structural abnormalities, as well as ofglycogenosis. A considerable number of mito-chondriopathies do not present specific findings at musclebiopsy; however, some conditions, especially thosedepending on mutations of the mitochondrial DNA, showpeculiar ragged red fibers, which are rare in cases of nuclearDNA defects, at optic microscopy (modified Gomoritrichrome). In addition, some mitochondriopathies canpresent, at electronic microscopy, abnormal proliferationand morphological changes in the mitochondria. In somemitochondriopathies, because of defects in the delivery(carnitine cycle) and use (ß-oxidation of fatty acids) of thesubstrate, accumulation of lipids can be observed. In somemitochondriopathies with deficiency of respiratory chaincomplexes, the enzymatic biochemical defect can beanalyzed through histochemistry.

In children with congenital muscular dystrophy, PMD,and congenital myotonic dystrophy, muscle biopsy showsonly dystrophic aspects which, albeit nonspecific anddenoting only primary muscular involvement, suggest thediagnosis; immunohistochemistry allows assessing merosin(laminin alpha 2) qualitatively in the different types ofcongenital muscular dystrophy, as well as dystrophin, whenthere is as suspicion of a sex linked PMD, and severalproteins specific to the girdle syndromes, especiallysarcoglycans. These proteins can be quantitatively analyzedusing the Western Blot techniques.

In myopathies with different associated involvement ofthe CNS, particularly in some mitochondriopathies, insome forms of congenital muscular dystrophy, and incongenital myoclonic dystrophy, a cranial nuclear magneticresonance can show some suggestive changes of thesepathologies, respectively, changes in the nuclei at the baseof the brain and brainstem, in some mitochondriopathies;changes in the white matter; cortical malformations andcerebellar atrophy, in some subtypes of congenital musculardystrophy and nonspecific areas of hypersignal in T2,probably corresponding to gliosis, in myotonic dystrophy.

When data indicating metabolic myopathy are found,particularly mitochondriopathy with defects in pyruvatemetabolism, Krebs cycle or respiratory chain, lab examsshould be required in order to determine the concentrationof lactate, pyruvate, alanine and ketonic bodies in the blood,CSF and urine; electrolytes, gasometry and ß-oxidationprofile of fatty acids should also be requested to help theestablishment of the differential diagnosis.

Differential diagnosis of muscular disorders also includescardiac evaluation, since, in addition to sex-linked PMD,Duchenne and Becker syndromes, some mito-chondriopathies, glycogenosis, congenital myopathies withstructural abnormalities and myotonic dystrophy may presentcardiomyopathy.

Finally, studies in molecular genetics, performed atspecialized centers, are essential to confirm diagnosis inmost cases of infantile spinal amyotrophy, in sex-linkedPMD, fascio-scapulo-humeral PMD, and myotonicdystrophy (Steinert�s disease) (Table 6). Molecular genetictests, although they are not applicable to a wide range ofconditions, can be carried out in order to help to classify thedifferent forms of congenital muscular dystrophy, girdle-like PMD, nemaline myopathy, mitochondrial myopathies,and hereditary motor-sensitive polyneuropathies. However,in the different forms of congenital muscular dystrophy,although possible, identification of deletions in a specificlocus (6q for merosin-negative form, 9q for Fukuyamaform, 1q for Finnish type, and others) cannot be performedbased on clinical, neuroradiological and immuno-histochemical specific findings.

Although we cannot present a detailed description ofeach neuromuscular disorder in the current review article,we will briefly present some essential data required forrecognizing the disorders most frequently seen in ourpractice.

Infantile spinal amyotrophy (ISA)

ISA is a degenerative disorder of motor neurons of theanterior cornu of the medulla spinalis and motor nuclei ofsome cranial nerves, presenting an almost exclusivelyautosomal recessive inheritance. After sex-linked DuchennePMD, ISA is the second most frequent neuromusculardisorder of childhood, with an incidence of 1:25,000 to1:20,000 births.1-5 The classification of ISA dependsmainly on the age of onset and level of motor involvement.In children, there are three basic clinical forms (Figures 1b;3a, b).

S96 Jornal de Pediatria - Vol. 78, Supl.1, 2002 Neuromuscular disorders - Reed UC

� ISA Type I (severe): onset until 6 months of life. Patientsare not able to sit down without assistance and generallydye before the age of two due to respiratory intercurrentdiseases;

� ISA Type II (intermediate): onset before 18 months oflife. Patients can sit down without assistance, but do notacquire orthostatic position and do not walk, presentinga severe amyotrophic status and skeletal deformities;

� ISA Type III (benign): onset after 18 months of life.Patients acquire orthostatic position and walk withvariable motor restraint.

Since 1990, studies in molecular genetics have mappedthe locus of the disease in 5q11.2-13.3,6 associating theSurvival Motor Neuron (SMN) gene with the mechanismthat causes the degeneration of motor neurons. Althoughthe corresponding protein has not been completely identified,it has been suggested that its level depends on the numberof copies of the SMN2 gene, and that its severity is inverselyproportional to the quantity of protein.7-10 Since the level ofdeletions in the SMN gene is high, molecular studiespromote not only diagnosis (anteriorly based on EMG), butalso fetal diagnosis.

In type I ISA, Werdnig-Hoffman disease, all musclesare affected by the neurogenic or secondary atrophy, exceptfor the diaphragm, limb muscles and ocular muscles. In30% of the cases, fasciculation can be observed. Muscularweakness is predominantly proximal, and fast thoracicdeformity and muscle contractures are observed. Generally,death occurs in the first 24 months of life, due to respiratoryinfections associated with paralysis of the intercostal orbulbar muscles, unless intensive therapy resources areavailable at home.

In type II, with hypotonia and muscular debility in lowerlimbs appearing between six and twelve months of life, thechild preserves the ability to sit down, but cannot walk. Theinitially moderate involvement of upper limbs and intercostalmuscle slowly aggravates over the years; muscle contracturesand skeletal deformities appear later on, around adolescence.Tongue atrophy and fasciculation may occur. In this type, aswell as in type III, irregular trembling (minipolymyoclonus)is frequently observed, more easily evidenced in thehyperextension of hands and fingers. During the seconddecade of life, the progression of the disease is accelerated,as the clinical status becomes highly restrictive, presentingdeath risk.

Clinical form type III, which is more benign, presents aclearly proximal character, showing a slow involvement ofthe pelvic girdle and, later, of the scapular girdle. Type IIIISA may be mistaken for some forms of PMD, albeit not sosevere, particularly in the occasional presence ofpseudomuscular hypertrophy and slightly increased CPK.Other patients do not present this pseudomyopathic aspectand evolve into generalized atrophy. The condition canprogress fast during adolescence, leading to invalidation in

the second decade; in other cases, the condition is limited toa mild involvement of the proximal limb muscles, compatiblewith a practically normal life (Figure 3b).

In addition to these established main clinical variables,non-classifiable forms exist, presenting different severitylevels; supposedly, the later the onset, the smaller the extentof the paralysis. In addition to early onset, respiratory andbulbar musculature involvement are indicative signs of anegative prognosis.

Motor-sensitive hereditary polyneuropathies (MSHP)

Among the several forms of MSHP, few are characteristicof childhood.

MSHP I, the demyelinating form of Charcot-Marie-Tooth disease, can be observed in children after the age ofthree, through a slowly progressive anterior tibialinvolvement, leading to a peculiar �dropped foot� and�equine march�. Gradually, a predominantly distal atrophyappears, as well as a significant bilateral deformity of thefeet and, later, weakness of the hand muscles.

MSHP type III, Déjerine-Sottas disease, consists of arare and severe congenital form, with hypotonia since birth,eating and breathing difficulty, as well as arthrogryposis,from time to time, and the classic infantile form, beginningbefore the age of two and coursing with a moderateretardation in motor development, never presenting a severecongenital pattern, with increased invalidism when thechild survives.

Molecular genetic analyses of these polyneuropathies,with different types of inheritance, evidenced a change inthe function of two proteins implicated in myelin metabolism:peripheral myelin protein 22 (PMP22) associated with the17p11.2-12 locus, and myelin protein zero (P0), associatedwith the 1q22-23 locus. Several types of mutations in thesetwo loci connect, through a mechanism of gene dosage, todifferent effects with regard to phenotypic severity; Déjerine-Sottas is the most severe and characteristic form in children,and it can be dependent on mutations in both genes.

In MSHP, EMG is an essential exam to detect reductionin the speed of nerve conduction; today, with the help ofmolecular tests, biopsy of the peripheral nerve is oftendispensable.

Among acquired polyneuropathies,12 inflammatorydemyelinating acute polyneuropathy or Guillan-Barrésyndrome, is an autoimmune disorder; its diagnosis isrelatively common in children older than 2-3 years (1.5 to2/10,000) and it should be considered when acute or subacuteparalysis, with an ascending pattern, is present, usuallypreceded by gastrointestinal or respiratory infection, andaccompanied by intense pain, which possibly prevents thechild from walking and being handled. Classic findings ofnormal CSF cellularity in the presence of spinalhyperproteinemia and great reduction in the speed of nerve

Jornal de Pediatria - Vol. 78, Supl.1 , 2002 S97Neuromuscular disorders - Reed UC

conduction at EMG allow for a relatively easy to establishdiagnosis, also helping to establish the treatment, whichvaries according to the intensity of clinical manifestationsand the potential risk of respiratory involvement, possiblyrequiring plasmapheresis or the administration of intravenousgammaglobulin.

Occasionally, inflammatory demyelinating poly-neuropathy can present a slowly progressive chroniccourse,12,14 without pain and with weakness, alternatingbetween predominantly distal and proximal, essentiallysimilar to the clinical status seen in myopathies, but with amore evident and generalized areflexia.

Differential diagnosis is based on EMG showing adecrease in the speed of nerve conduction, and on the CSF,showing protein-cell dissociation. Treatment is withcorticosteroids or intravenous injection of gammaglobulin.

Severe myasthenia and congenital myasthenic syndrome

Acquired severe myasthenia presents an autoimmunenature, and is dependent on a postsynaptic defect inneuromuscular transmission. It occurs more often duringthe pubertal period, although it can also manifest itself inpre-school or school age children. In the NB, we observe thetransient form of severe myasthenia or nonautoimmunecongenital myasthenic syndrome, which is geneticallydetermined, with different subtypes, and can also occur ininfants.

The neonatal transient form affects 10% to 15% of NBsof mothers with generalized myasthenia. The onset occursin the first hours of life, exceptionally up to the third day; theNB presents a weak cry and facial involvement or generalizeddebility, with breathing difficulty. Palpebral ptosis is rare.This form occurs due to the transmission of cholinergicantireceptor antibodies from the mother to the fetus, andshould be considered when a sibling has already presenteda similar problem, or when the mother presents an elevatedrate of circulating antibodies. Diagnosis is established withthe use of 0.1 Tensilon (edrophonium bromide), viasubcutaneous or IM route and, in case no significant responseis observed, prostigmin is used via IM route (0.05 mg) orpyridostigmine (0.3 mg). Acknowledgment of this situationmust be immediate, with the administration ofanticholinesterase drugs: pyridostigmine bromide(Mestinon) or neostigmine bromide (Prostigmin), both viaoral route, in order to prevent respiratory insufficiency. Thedaily total dosage of pyridostigmine bromide varies from 5mg to 25 mg in four or five doses, one hour and a half beforemeals, depending on personal response; the daily totaldosage of neostigmine bromide varies from 5 mg to 10 mg.Out of precaution, the treatment must be maintained up tothe eighth week.

Nonautoimmune congenital myasthenic syndromecomprises different subtypes, which can occur from birth orbe identified during childhood.15,16 Different defects inpresynaptic, synaptic or postsynaptic levels result in different

types of deficiencies: in cholinergic receptors, inacetylcholinesterase, or in the levels of response and affinitywith acetylcholine, sporadically presenting familialrecurrence, dominant autosomal inheritance or recessiveautosomal inheritance. Recently, this field has becomemore complex, with the identification, in all mutationalsubtypes, of several genes that codify both structural andfunctional changes of the neuromuscular junction.15,16

Most subtypes of the congenital myasthenic syndromeusually do not respond to common anticholinesterase drugs;these conditions are characterized by a variable combinationof muscular hypotonia and focal signs, such as palpebralptosis and weak cry, and also by the involvement of thecervical, facial and bulbar musculature. The condition canremain localized or become generalized during childhood.In one of the subtypes, slow channel syndrome, whichpresents a fluctuating course - with exacerbation andremission, as seen in the juvenile form - clinical andelectrophysiological improvement are said to occur withthe use of quinidine sulfate.17

The juvenile or autoimmune form is characterized bythe occurrence of acute generalized weakness, with bulbarand ocular musculature involvement (palpebral ptosis orcomplete extrinsic ophthalmoplegia). Occasionally, theclinical status is not so dramatic, combining, in variableforms, excessive fatigue in different muscle groups,suggested by a fluctuating pattern along the day. Diagnosiscan be made using the edrophonium bromide test; EMG anddosage of acetylcholine antireceptor antibodies do notpresent the same specificity seen in adults. Treatment usesanticholinesterase drugs and, depending on the case,corticoid therapy and other immunosuppressive measures,intravenous gammaglobulin and, occasionally, thymectomy.

Major genetically determined primary myopathies

Among muscular disorders of childhood, sex-linkedPMD in the form Duchenne syndrome is the most commonlyfound. This disorder becomes evident and slowly progressivefrom the age of four. In addition to Duchenne PMD,myopathies of childhood that course with congenitalmuscular hypotonia and early muscular weakness arecongenital muscular dystrophy, congenital myopathies,metabolic myopathies, and congenital myotonic dystrophy(congenital Steinert�s disease). In extremely rare situations,other PMD, such as girdle syndrome and fascio-scapulo-humeral dystrophy, may occur in infants or school agechildren.

Muscular dystrophy

Muscular dystrophy is a primary, genetically determinedmyopathy, that is clinically characterized by intense variationin phenotype and severity, and anatomopathologically, bythe finding of a nonspecific dystrophic pattern in the musclefiber. Since the 1990s, continuous advances in molecular


Defined phenotypes with molecular basis

Fukuyama-type CMD: locus 9q31 (fukutin)Classic merosin-deficient CMD: locus 6q2 (merosin)CMD with early rigid spine: locus 1p35Finland-type CMD (muscle-eye-brain): locus 1p32Saudi Arabian family with girdle syndrome and merosin deficiency:

locus 1qHypotonic-sclerotic form (Ullrich): absence of collagen type VI

(chromosome 2? 21?)

Undefined phenotypes

Walker-Warburg syndromes: the most severe form of CMD withhighly specific phenotype

Merosin-positive CMD: heterogenous subgroup, with someapparently specific clinic phenotypes that can constitutegenetically and biochemically different subtypes

Merosin-deficient CMD not related to 6q: with or without mentaldeficiency and neuroimaging alterations

Table 7 - Classification of congenital muscular dystrophy


genetics and immunohistochemistry have allowed for theclassification of muscular dystrophies according to the typeof muscle disorder.12,18,19 Most of known musculardisorders involve the function of the dystrophin-associatedglycoprotein complex, which connects the subsarcolemmalcytoskeleton to the extracellular matrix of the skeletalmuscle, allowing for the stabilization and reinforcement ofthe muscle fiber membrane. Partial or total deficit ofdystrophin proteins, alpha-2 laminin of the extracellularmatrix (merosin) and sarcoglycane correspond, respectivelyto, Duchenne and Becker DMP, the most severe form ofclassical congenital muscular dystrophy, and to part of thegirdle syndromes. Other proteins are implied, whose deficitsoriginate uncommon dystrophic myopathies in children.

Congenital muscular dystrophy (CMD)

CMD is an heterogeneous group of degenerative, primaryand progressive, disorders of the skeletal muscle, with onsetduring the intrauterine period or the first year of life, whichare characterized as follows: clinically, by an accentuatedmuscular hypotonia, generalized weakness with delay inmotor development, intense and early fiber-tendonretractions and, often, respiratory disorders and eatingdifficulty; histologically, by dystrophic changes in muscles(intense variability in the caliber of fibers, proliferation ofinterstitial tissue, variable degree of necrosis anddegeneration of muscle fibers), in the absence of specificstructural abnormalities.

CMD is an entity with a recessive autosomal inheritanceor sporadic occurrence, with a prevalence of 1:60,000births, and 1:100,000 in the general population.20,21 SeveralCMD subtypes have an already defined genetic locus;20-24

among CMDs with normal merosin, the wide clinicalvariability probably represents genetically and biochemicallydistinguished entities, still unidentified.20-24

The currently accepted classification of CMD includesfour entities22,23: classic or pure CMD, with normalintelligence and without changes in the CNS, although 40%to 50% of these cases, which are merosin deficient, showchanges in the white matter; Fukuyama CMD (FCMD),with mental deficiency and structural changes in the cerebralcortex; muscle-eye-brain (MEB), also called Finnish type,and Walker-Warburg (WW), with mental deficiency andbrain structural changes and ocular defects. The three laterforms of CMD, generically called oculo-cerebral, are severe,both in terms of muscle and mental involvement; thesechildren can exceptionally walk without assistance and, dueto cerebral and ocular malformations are, in their majority,non-trainable, not surviving up to maturity. In these threeforms, cerebral malformations belong to type II lissencephalycomplex, represented by agyria in WW, and pachygyria/polymicrogyria in the other two forms. The three formspresent retinal abnormalities and, in muscle-eye-brain andWW syndromes, several defects in the anterior chamberand microphtalmia can be observed.4

In patients with the classic form, the majority of merosin-positive patients present a moderate clinical status and areable to walk, while almost all merosin-negative patientshave a more severe clinical status and are not able to walk.Thus, among our 40 merosin-positive patients, only 1/3could not walk, while among the 30 merosin-negativepatients only two were able to ambulate. Merosin-positivechildren present a wide variety of phenotypes: atrophy andmild or moderate muscular weakness, with a predominantlyproximal pattern and predominantly distal retractions; fewchildren present more diffuse retractions and kyphoscoliosis,or show the same severity seen in merosin-negative patients,although facial dysmorphism is not so evident.Arthrogryposis is occasionally reported and, regardless ofthe severity, its course is non-progressive or presents anextremely slow progression, with normal or slightly increasedCPK levels.

Part of merosin-positive patients present clinical orneuroradiological manifestations, suggesting a CNS-relatedinvolvement25: mental deficiency in 10%; epilepsy in 25%;neuroradiological chances, such as cortical atrophy; changesin white matter, such as in merosin-negative children;cerebellar hypoplasia; and cortical dysplasia out of thecontext of a type II lissencephaly.

The discovery of merosin or alpha-2 laminin deficit, themain component of the extracellular matrix, expressedespecially in muscles, Schwann cell, skin and placentaltrophoblast,28 and easily identified by immunocytochemicalmethods, has impelled new progresses in infantile myology.Merosin-negative patients present a characteristicphenotype20,21,24,26: dysmorphism and bilateral facialdebility (Figure 4), high-arched palate, pronounced anddiffuse muscular hypotonia (usually level three), generalized


and early fiber-tendon retractions, intense muscular atrophywith kyphoscoliosis, moderate or marked increase of CPK,normal or poor intelligence, and neuroradiological examsshowing diffuse changes, rarely focal, of the cerebral whitematter. In the NB, respiratory and eating disorders canoccur and, in the first year of life, a severe muscularhypotonia is observed, as well as a delay in motordevelopment; the child�s only ability is to sit down withoutany assistance. In the beginning of the second decade,kyphoscoliosis contributes to aggravating respiratoryintercurrent diseases, possibly leading to death. Certaintypes of mutations in 6q originate a partial merosindeficiency, which is usually associated with a milder clinicalstatus and with a later onset. Whether diffuse or focalalteration in the cerebral white matter is associated withmerosin deficiency is still unknown; however, since merosinhas already been identified in the basal membrane of cerebralvessels, it is possible that its absence is implicated in somepossible alteration of the blood-brain barrier and,consequently, of the myelin metabolism.20,21,24 Prenataldiagnosis is possible, through immunohistochemical analysisof merosin in chorion villous or through the identification ofthe deletion in families in which a type of deletion is alreadyknown.20,21,24

In conclusion, despite the advance in molecular genetics,the clinical-genetic correlation of the different forms ofCMD is not still perfectly known, and several other non-classifiable forms, especially of the merosin-positive type,exist.

Dystrophinopathies: sex-linked PMD, Duchenne(DMD) and Becker (BMD)

Different types of mutations in the dystrophin gene inXp21 can be observed in two thirds of the cases of DMD,and in 75% of the cases of BMD.18 Some deletions result ina non-functioning protein and in more severe cases ofDMD; others lead to a milder clinical status and a later onsetof BMD. DMD has a high prevalence (3:100,000) andincidence (3:1,000 births of boys), while BMD is ten timesless frequent.18

Women carrying the syndromes can be asymptomatic,with or without an in increase in CPK level, or symptomaticin different levels: calf hypertrophy, cardiopathy or mildmyopathy.

Classic clinical status of DMD and BDM is uniform. Inshort, DMD is usually observed in the pelvic girdle betweenthe ages of two and four, although it becomes evidentbefore, showing classical calf hypertrophy (Figure 2a); atinitial stages, Gowers� sign or myopathic rising and toewalking, with pelvic oscillation, are characteristic findings;scapular girdle involvement occurs around the ages of sixand seven, and the ability to walk is lost between the ages ofnine and twelve; death, caused by respiratory or cardiacinsufficiency, occurs by the end of the second decade of life,or shortly afterwards. The onset of BMD, on the other hand,occurs around the ages of seven and ten, or later; the ability

to walk is lost around the age of twenty, or later, showing avariable survival rate, and even reproduction. Mentalretardation occurs in approximately 1/3 and 1/10 of boyswith DMD or BMD, respectively. In more than half of thecases, myocardiopathy is observed, affecting the postero-lateral wall of the left ventricle, leading to valvularinvolvement and rhythm disorders. In patients with BMD,due to a better prognosis, cardiomyopathy ends up beingmore restrictive than in patients with DMD, sometimesbeing even more valued than the motor deficit.

Diagnosis of dystrophinopathy is highly suggested bythe sex-linked inheritance, by the particular chronology ofthe clinical status, and especially in DMD, by the high levelsof CPK, usually above 10,000 IU/l. It can be confirmed bymeans of molecular analysis and, if necessary, by molecularbiopsy, recommended for 1/3 of patients in whom mutationcannot be identified. Dystrophin analysis in muscle biopsycan be performed through histochemical or Western Blottechniques, considering that the amount of residualdystrophin is always the best indication of the severity of theclinical status.

For prenatal diagnosis, molecular analysis is safer thanthe immunohistochemical detection of dystrophin; theprocedure is always successful in cases in which deletionshave already been identified in another affected sibling.18

Treatment of dystrophinopathies includes palliativemethods, such as physical therapy, corrective orthopedicsurgeries of fibro-tendon retractions and spinal columndeformities, in addition to treatment with corticoids,especially in DMD cases; a number of ongoing studies haveaimed at finding effective treatment schemes, such as, forinstance, myoblast transplantation and gene therapy.18,29

Corticoid therapy with prednisolone or deflazacort,which presents fewer side effects, is being universally usedto reduce the speed of muscle strength loss, delaying, in oneto three years, the need to use a wheel chair and theprogression of kyphoscoliosis. The effect of such therapy isbelieved to be maintained for three or more years; the ideais to �buy� the patient some time before he/she receivesefficient therapy. Thus, therapy should start around the agesof 5-6, when muscles are still preserved and the stage of fastmuscle deterioration has not begun. A careful monitoring ofthe several possible side effects is required but, generally,based on our experience with 80 patients under corticoidtreatment, we can consider that side effects are not veryextensive, and seldom require treatment discontinuation.

Fascio-scapulo-humeral PMD (internationalabbreviation FSH)

FSH muscular dystrophy, an extremely rare dominantautosomal inheritance, presents a molecular defect in locus4q . Extension of the deletion and severity of the clinicalstatus, as well as age of onset, are related; an anticipationphenomenon is also observed, with more extensive deletionsbeing observed in subsequent generations.11,18

S100 Jornal de Pediatria - Vol. 78, Supl.1, 2002 Neuromuscular disorders - Reed UC

The classic clinical status of FSH appears by thebeginning of adolescence and is associated with a proximalinvolvement of the scapular girdle with facial involvement.Winged scapula and tapir mouth are frequently observed.The involvement of the pelvic girdle is variable. CPK levelis usually slightly elevated. Diagnosis is confirmed by amolecular study. Pediatric forms, with early onset, can beextremely severe, both in the face (which becomes almostentirely paralyzed), and in the limbs, in such a way that thepatient becomes invalid by the end of the first decade of life.Occasionally, FSH is associated with deafness and Coat�ssyndrome, an oxidative vascular degeneration of the retina.18

Congenital myopathy (CM)

CM is a subgroup of primary muscular disorders, usuallyinherited, clinically characterized by an early onset and abenign, non-progressive or slowly progressive course.Histopathologically, CM is characterized by structuralabnormalities defined at muscle biopsy. Etiopathogeny ofthis type of myopathy has not yet been clarified, but it isprobably dependent on abnormalities in the developmentand maturation of muscle fibers.

In spite of this classic concept, the classification of CMis difficult, strictly following morphological criteria.30

Basically, structural and non-structural CM is recognized,depending on whether the abnormalities are derived or notfrom normal components of the muscle fibers; mixed CMcan also be found.12

Clinical status is multiform and not necessarily benign;it can present severe forms, even fatal, in addition to lateonset forms and adult forms. Genetically, several types ofinheritance and loci can be observed, even for the sameclinical manifestation. Among the several subforms ofcongenital myopathies, central core, nemaline andmyotubular are the best defined in terms of the type ofstructural abnormality.

In central core myopathy, the specific presentation ofmuscle fibers shows central areas of anomalous myofibrils,which are stained by specific methods. In spite of beingbasically benign, with a reduced involvement of the scapulargirdle and, occasionally, of the facial muscles, CM isfrequently associated with a congenital hip luxation,sometimes requiring surgical correction. In any surgicalprocedure in patients with central core myopathy, the highrisk of malignant hyperthermia during the anestheticinduction with halothane and succinylcholine must beconsidered. Predisposition for this severe - and often fatal- phenomenon, whose prevention is intensively investigatedin multicenter studies, is associated with locus 19q ascentral core. The gene codifies proteins that regulateintracellular calcium metabolism, which, when modified,triggers cytotoxic reactions with cellular death and extensiverabdomyolysis, in addition to hyperthermia.

In nemaline myopathy, the specific finding is the presenceof rods, which are prolonged structures, composed mainly

of alpha-actinin and desmin, derived from the Z-disk.Inheritance can be both dominant or recessive autosomal,with a wide range of clinical severity levels, including:extremely severe pre- or neonatal forms; typical congenitalforms, with onset during childhood and variable severity,often compromising breathing and swallowing; intermediateforms between neonatal and congenital; and also late onsetforms, which are more benign. Facial dysmorphism iscommon and extremely characteristic. Today, at least fourgenes implied in this process are known (2q22, nebulin;1q22 alpha-tropomyosin; 9p13, beta-tropomyosin; 1q42,alpha-actin). The pronounced clinical and geneticheterogeneity promotes several studies in moleculargenetics.31-33

In centronuclear myopathy, the specific finding is thepresence of centrally disposed fetal myotubules, structuresthat suggest a delay in the maturation of the sarcotubularsystem.34 Different clinical forms can be found. In sex-linked inheritance, genetic locus is in Xq28, and themyotubularin protein is implied with mechanisms that affectlate myogenesis. This form is extremely severe, causingdifficulty in eating and breathing since birth; fetal diagnosisand identification of carriers are possible. In less severeforms, with recessive or dominant autosomal inheritance, avariability in clinical status is observed. Severe formspresent an early onset with a significant developmentalretardation; insidious forms present a late onset and fewrestraints. A frequent finding of palpebral semiptosis and anoccasional association with CNS involvement (seizuresand mental retardation) are indicative signs for the diagnosis.

Congenital myotonic dystrophy

Myotonic dystrophy, or Steinert�s disease, is caused byan abnormal unstable DNA sequence in locus 19q (5,36). Insuccessive generations, a progressive expansion of theaffected gene fragment is observed, and, through theanticipation phenomenon, the onset of symptoms occursearlier, and the clinical status becomes more severe. Thus,patients presenting the congenital form, extremely severe,present wider bands of abnormal DNA, while adult patients,with a mild involvement, present slightly larger bands thannormal individuals.35,36

Advances in molecular genetics allow for the recognitionand, therefore, the genetic counseling of asymptomatic orminimally affected subjects, as well as fetal diagnosis of thecongenital form.

Since, more often than not, the mother is affected by thecongenital form, detection of asymptomatic or minimallyaffected female fertile patients is essential in order toprevent this severe clinical status; however, the risk of amother in such conditions giving birth to a child with thecongenital form is relatively low, approximately 10%.When a pregnant woman presents a severe multisystemicstatus, the risk is of approximately 80%. Clinical status ofcongenital myotonic dystrophy is severe, with neonatal or


prenatal onset, possibly presenting congenital multiplearthrogryposis, stillbirths and polyhydramnios. Pronouncedmuscular hypotonia is observed, with predominantlyproximal involvement, as well as the involvement of themuscles of the face, tongue, pharynx and diaphragm; patientsalso present difficulty to eat, caused by poor suck ordysphagia, and respiratory complications, with a high rateof deaths in the first month. During the neonatal period, themyotonic phenomenon is not apparent, not even throughEMG. When the child survives, a global retardartion inneuropsychomotor development and mental deficiency canoccur, although the disease does not tend to progress duringa long period, suggesting motor and intellectual deteriorationonly after the second or third decade. In older children facialdiplegia is evident, with protracted lips and speechdifficulties. Systemic changes of the disease are not seen inthe congenital form, except for, occasionally, cardiacinvolvement.

Metabolic myopathies

Metabolic myopathies occur due to modifications in themetabolism of glycogen, mitochondria or ionic channels(channelopathies). In general, these myopathies constitutesevere pathologies, with onset during the neonatal period orearly childhood, presenting dramatic manifestations, suchas eating and breathing difficulties, frequently fatal metabolicdisturbances and multisystemic disorders. Moderate ormild forms can evolve with a chronic myopathic status,presenting variable severity, or with acute, recurrent andreversible outbreaks of muscle weakness, intolerance toexercises, cramps and, occasionally, myotonic phenomenonand myoglobinuria.

Among the glycogenoses,1,38,39 type II, caused by adeficiency of acid maltase (Pompe�s disease), with recessiveautosomal inheritance, is the most severe disorder, presentinga subtype that can be evident in a few months or since birth,through multisystemic involvement (muscular, cardiac,visceral, CNS and peripheral nervous system).

Mytochondriopathies38-41 represent a vast and complexset of clinically and genetically heterogeneous disorders,dependent on defects in the mitochondrial metabolism,which can present different forms. In mostmitochondriopathies, muscle involvement is absolutelyheterogeneous: generalized, possibly severe and early fatal;predominating in girdles, fascio-scapulo-humeral, or ocularmusculature; static, progressive or with intolerance outbreaksduring exercises, with or without myoglobinuria andmetabolic disorders. In addition to muscle involvement,mitochondriopathies are usually multisystemic, affectingCNS, retina, heart, liver, pancreas and endocrine system.Genetical heterogeneity is expressed through sporadic cases,maternal inheritance associated with multiple mutations ofmitochondrial DNA, dominant autosomal inheritance,recessive, and sex-linked recessive inheritance.

In some mitochondriopathies, abnormal proliferation ofmitochondria can be observed at muscle biopsy (modifiedGomori trichrome), represented by ragged red fibers, whichare, histochemically, succinate-dehydrogenase positive. Indaily practice, cases compatible with mitochondripathies,showing an increase of serum or CSF lactate, and ragged redfibers at muscle biopsy, present a difficult biochemical orgenetic identification. In spite of that, some treatmentstrategies are tested, offering absolutely irregular results.Especially in disorders of the respiratory chain, the combinedadministration, in high doses and variable proportions, ofthe following drugs is recommended: succinate (2 to 5 mg/day), K3 vitamin (20 to 80 mg/day), C vitamin (4 to 5 g/day), Q10 coenzyme (100 to 150 mg/day), riboflavin (100to 300 mg/day), nicotinamide (0.5 to 1 mg/day), E vitamin(400 to 1000 IU/day), and tiamin (200 mg/day)38,39.

Mitochondriopathies caused by defects in the deliveryand subsequent oxidation of fatty acids to the interior ofmitochondria are denominated ß-oxidation disorders.38,39

Among these, primary deficit of carnitine, which associatesmyopathy with myocardiopathy, presents a positive responseto oral administration of carnitine. A deficit of carnitine-palmityl-transferase II in older children and teenagerspresents a benign clinical status, similar to glycogenosis,with outbreaks of muscular pain following physical exercisesor prolonged fasting. In the remaining defects that affect themetabolism of short, medium, long or very long chain fattyacids, the onset can occur at any age, gradually showing apredominantly proximal muscular debility and, occasionally,involvement of the muscle innerved by cranial nerves,polyneuropathy and retinopathy. In some patients, the clinicalstatus is severe, or even fatal, with early outbreaks ofhypoketotic hypoglycemia and hepatic, cardiac andencephalopathic involvement. Treatment is based on a low-fat diet, using medium-chain triglycerides, which do notdepend on carnitine to enter the mitochondria. Musclebiopsy shows lipid accumulation in type I fibers and, insome cases, an evident improvement is seen with theadministration of carnitine, in a 100 mg/kg/day dosage. Partof the ß-oxidation defects can be diagnosed throughlaboratory analysis at large centers, by means of abiochemical profile of the ß-oxidation or other moresophisticated methods.

Periodic paralysis caused by abnormalities in muscleion channels (channelopathies) are rare metabolicmyopathies, particularly in childhood, presenting a verysuggestive clinical status.42 Hyperkalemia, an autosomalinheritance associated with chromosome 17 and withdifferent types of mutations leading to an abnormality insodium channels, is more frequently observed in children.This type of myopathyt is benign and is characterized byoutbreaks of muscle weakness, lasting up to 4 hours, generallyrestricted to the limbs, without respiratory intercurrentdiseases. Potassium levels are increased during the outbreak,but often do not surpass the upper normal limit. Restingimmediately after a prolonged exercise is usually a triggering


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factor; therefore, a regular, and not extenuating, physicalactivity is recommended. Preventive treatment consists ofthe administration of diuretics, such as chlorothiazide and,more rarely, acetazolamide, which causes a greater numberof side effects. In more severe clinical status, intravenousglucose can be administered, associated or not withsubcutaneous insulin.

Among acquired myopathies, autoimmune inflammatorymyositis is an easily recognizable entity when it showscharacteristic acute and subacute signs, with predominantlycervical weakness, muscular pain, erythema in the malarand palpebral areas with periorbital edema, as well as apronounced increase in the levels of CPK and other muscleenzymes. Muscle biopsy presents, in addition to thecharacteristic inflammatory infiltrate, perifascicular atrophy,since autoimmune aggression to muscular microvasculaturecauses atrophy in the most peripheral fibers of the fasciculus.Treatment is traditionally long and, in typical cases, it canbe initiated with corticoids, even before the results ofmuscle biopsy, adopting, when required, more drasticimmunosuppressive measures, such as azathiprine,cyclophosphamide, methotrexate and cyclosporin.43 Inchronic cases, without cutaneous changes and consistentincreases in enzymatic levels, differential diagnosis ofdifferent forms of PMD can be difficult. In a myogenicalteration pattern, EMG and muscle biopsy show somepeculiar characteristics and, therefore, these two tests mustbe performed before treatment is introduced.

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Corresponding author:Dra. Umbertina C. ReedHospital das Clínicas - Departamento de NeurologiaAv. Enéas de Carvalho Aguiar, 255/5031CEP 05403-900 � São Paulo, SPTelephone/fax: +55 (11) 3062.0063E-mail: [email protected]

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Neuromuscular disorders - JPED · main neuromuscular disorders in children, that include the diseases affecting the motor unity, i.e. spinal motor neurons, peripheral nerves, neuromuscular