Motor Neuron Disease


SMA Type (incidence as % of total SMA)

Age at onset

Life span

Highest motor milestone achieved

Other features

EMG findings

Type I (60%): Type IA

Prenatal

<6 months

Mostly unable to achieve

motor milestones

 • Severe weak-ness at birth

 • Profound hypotonia

 • Facial diplegia

 • Areflexia

 • Early respiratory failure

 • Joint contractures

 • SNAPs and CMAPs can be normal in the early stage

 • CMAPs usually lowest among all SMAs but SNAPs are normal

 • Fibrillation potentials and PSWs are common

 • Fasciculation potentials are rare

 • Long duration and large amplitude motor unit potentials can be present but not frequently

 • Spontaneous motor unit firing is common

Type IB, Type IC

Type IB

(0–3 months)

Type IC

(3–6 months)

<2 years without respiratory support

Never sits unsupported

 • Weakness

 • “Frog leg” posture, hypotonia

 • Tongue fasciculations

 • Hyporeflexia, areflexia

 • Suck and swallow difficulties

 • Respiratory failure

Type II

(27%)

6–18 months

>2 years

~70% alive at 25 years of age

Sits independently but never walks

 • Proximal weakness, hypotonia

 • Postural hand tremor

 • Hyporeflexia

 • Average or above average intellectual skills by adolescence

 • Scoliosis

 • CMAPs are lower than in Type III

 • Spontaneous motor unit firings can be seen in younger patients

 • Fibrillation potentials are frequent

Type III

(12%)

>18 months

Type IIIA (prior to 3 years)

Type IIIB (after 3 years)

Almost normal

Walks independently

 • May have hand tremor

 • Resembles muscular dystrophy

 • CMAPs are of higher amplitude, especially in ambulatory patients

 • Duration and amplitudes of motor unit potentials are highest

 • Smaller and poly-phasic, myopathic looking units can be seen

 • Fibrillation, fasciculations and complex repetitive discharges can be seen

Type IV

(1%)

>21 years

Normal

Normal

 • Minimal weakness
 



Type I SMA


SMA type I (previously known as Werdnig-Hoffmann disease) has been further subdivided into three groups: type IA (or Type 0 in certain reports[11]) with onset in utero and presentation at birth, type IB with onset of symptoms between birth and 3 months of age, and type IC with onset between 3 and 6 months of age. Infants with SMA type I have progressive proximal weakness that affects the legs more than the arms. They have poor head control with hypotonia, leading to a severe head lag, frog-leg posture when supine, slip through on vertical suspension, and draping on ventral suspension, along with areflexia. They are never able to sit independently and are thus also known as “non-sitters” (Table 16.1 ). Intercostal muscle weakness with relative sparing of the diaphragm produces a bell-shaped chest and a paradoxical pattern of abdominal breathing. They exhibit tongue fasciculations and eventually develop dysphagia, risk of aspiration, and failure to thrive. Other cranial nerves are not as affected, although facial weakness does occur at later stages of the disease. Cognition is usually normal [1, 12, 13].


Type II SMA


Patients with type II SMA, also known as intermediate SMA or Dubowitz disease, are able to sit unsupported at some point and are thus also known as sitters, but they are never able to walk independently (Table 16.1 ). The onset of symptoms is typically between 6 and 18 months of age. They have progressive proximal weakness affecting legs more than arms, along with hypotonia and areflexia. They also develop progressive scoliosis, which in combination with intercostal muscle weakness results in significant restrictive lung disease as they grow older. They develop joint contractures and can have ankylosis of the mandible [1315]. Cognition is normal and verbal intelligence may be above average [16]. Patients may live into the third decade, but life expectancy is shortened due to the risk of respiratory compromise [2, 14].


Type III SMA


In 1956, Kugelberg and Welander described a much milder form of SMA characterized by prolonged ambulation [17]. Patients with type III SMA, also known as Kugelberg-Welander disease, are able to walk independently at some point and are thus also referred to as “walkers”. The onset of symptoms usually occurs after the age of 18 months. This subset has further been subdivided into type IIIA (onset between 18 months and 3 years) and type IIIB (onset after 3 years). Type III patients have progressive proximal weakness affecting legs more than arms and may ultimately need to use a wheelchair, especially the IIIA group, but they generally develop minor or no respiratory muscle weakness or scoliosis. Loss of ambulation increases the risk of these complications. Type III patients may have tremor or polyminimyoclonus of the hands, which can also be seen in type II or even type I patients [14, 18]. Sometimes, the calves of type III patients can be prominent, and hence type III SMA can be confused with Becker muscular dystrophy. Creatine kinase levels are often elevated, usually no more than fivefold, and may lead to an erroneous evaluation for myopathy. Life expectancy is not significantly different compared to the normal population (Table 16.1) [2, 14, 19].


Type IV SMA


A milder, adult-onset SMA, or type IV SMA, has also been described, with onset of symptoms after age 21 years and essentially normal life span [10].


Electrodiagnostic Testing in SMA


Prior to the identification of the genetic loci for SMA, electrodiagnostic studies were the primary diagnostic tools for suspected cases. Genetic testing has largely supplanted EMG for the diagnosis of SMA. However, there are circumstances in which EMG still plays an important role in the diagnostic evaluation. Genetic testing, even when expedited, often takes several days to return results, whereas EMG is often available the same day, with results reportable immediately. For example, an undiagnosed child who is acutely ill in a critical care setting may benefit from EMG testing. EMG can also help point to the correct diagnosis when there are atypical presentations, especially in some cases of SMA type III [20], and when patients have non-5q related SMAs [1, 21].

Motor nerve conduction studies can be completely normal in the early stages of SMA [21, 22]. With the progression of the disease, nerve conduction studies typically show features of chronic motor axonal loss, specifically reduction of compound muscle action potential (CMAP) amplitudes [23, 24]. Conduction velocities are generally preserved, but mild slowing of conduction velocities secondary to loss of faster conducting fibers can be seen. Distal motor latencies and F wave latencies may similarly be slightly prolonged. Sensory nerve action potentials (SNAPs) are usually preserved throughout the course of disease, even in infants with SMA type I [25, 26].

CMAP amplitudes have been shown to correlate with clinical severity, age, functional status and progression of disease. CMAP amplitudes are most often reduced in SMA type I. Accordingly, SMA type II subjects have lower CMAP amplitudes compared to SMA type III and non-ambulatory SMA type III patients usually have lower CMAP amplitudes than ambulatory type III patients [23, 24]. In some reports, CMAP amplitudes have been shown to decline over time, specifically in SMA type II. Initial CMAP amplitude has been suggested to predict functional outcome [23].

Although SMA is primarily a pure motor neuron disorder with preserved SNAPs, sensorimotor involvement has been described in a few cases [26, 27]. In a small number of infants with SMA type I, sensory action potentials can be reduced, preferentially in the sural nerve, secondary to loss of sensory fibers and ganglion cells [22, 27, 28]. Most of the reported cases of sensory involvement in SMAs involve axonal neuropathy, though occasionally demyelinating neuropathy or mixed axonal and demyelinating features can be seen [26, 29, 30].

Motor unit number estimation (MUNE), an electrophysiologic method to estimate the number of lower motor neurons innervating a specific muscle, has shown motor unit loss in SMA patients [3133]. The number of functional motor units in some patients progressively decreases, though occasionally an increment in the number of motor units has been noted, suggesting a degree of spontaneous recovery [23, 24, 34]. Please refer to Chap. 12 for a more detailed discussion of MUNE.

In addition, repetitive stimulation studies may show a decremental response with correction after post exercise testing [35]. Decremental responses have also been reported in patients with SMA types II and III at 2–3 Hz repetitive stimulation without facilitation at higher frequency stimulation [35, 36]. Similarly, single fiber EMG may show increased jitter and blocking [37]. It is still uncertain whether these changes are related to a defect in neuromuscular transmission or to a secondary effect of chronic denervation and re-innervation. Typically, these features are uncommon in other motor neuron diseases with more rapid denervation and reinnervation, such as amyotrophic lateral sclerosis [1].

Needle EMG in SMA shows motor neuron or motor axon loss in the form of active denervation and chronic reinnervation. Based on the severity and stage of the disease, as well as the rapidity of disease progression, the proportions and patterns of denervation and reinnervation vary, and different electrophysiological patterns can be seen [38, 39].

In infants with SMA type I, needle EMG shows active denervation in the form of fibrillation potentials and positive sharp waves (PSWs), and residual voluntary motor units are mostly of normal size. Collateral reinnervation is usually absent. In these patients, detection of higher amplitude and normal duration MUAPs does not necessarily indicate collateral sprouting. Several factors may result in such high amplitude, normal duration MUAPs; these factors include loss of smaller motor units, muscle fiber hypertrophy, and other anatomical changes such as contraction of motor unit cross-sectional territory with atrophy of intercalated fibers bringing additional motor units closer to the EMG electrode [15, 21, 38, 39].

Collateral sprouting from the adjacent nerve fibers of healthy neurons is the main reinnervation process that leads to type grouping in cases of partial denervation and reinnervation. At the stage of chronic denervation and successful collateral reinnervation, such as in older infants and children with milder forms of SMA, fibrillation potentials and PSWs, which are usually few, may even disappear. MUAPs are reduced in number and are of giant size [15, 21, 39]. In advanced cases with end-stage individual muscles, MUAPs can be of reduced amplitude and duration, lose their clear neurogenic features, and mimic myopathic units [40].

An unusual form of spontaneous motor unit firing (MUF) at 5–15 Hz has been reported. These continuous potentials can be distinguished from fasciculation potentials by their regular pattern of firing, persistence for long periods and occurrence during sleep. The source of these potentials has not been defined. They are more frequent in SMA type I and in younger type II patients [38, 39]. Fasciculation potentials are absent in most cases of SMA, particularly in type I, but can be seen rarely in later stages of the disease in proximal muscles, particularly the quadriceps [39].

Accurate assessment of EMG features can be difficult in children. They may not be able to cooperate fully, and hence the assessment of number, size, and firing rates can be limited. Secondary to slow progression of SMA, occasionally reinnervation can be complete, features of fibrillation and PSWs can be absent, and abnormalities can be found only in the MUAPs with reduced number, higher amplitude, longer duration and polyphasia. Occasionally, satellite potentials can also be seen. Moreover, in milder SMA, such as SMA type III, MUAPs can appear myopathic with low amplitude and many high frequency components [40]. Some forms of SMAs are focal, and EMG of some muscles is normal [21]. In light of the variability of diagnostic findings, several muscles should be tested in multiple extremities (including genioglossus), if tolerated by the child, to maximize the accuracy of the study.

It is noteworthy that in the early stages of SMA, even in the presence of early weakness, EMG may sometimes be normal. The typical electrophysiologic features of SMA in those cases will emerge later [21]. Therefore, a normal EMG study does not entirely rule out the possibility of SMA, depending upon the circumstances including the extent of needle examination. The degree of electrophysiological abnormality may also not accurately reflect the clinical status. Thus, electrophysiological features should be interpreted carefully. Occasionally, electrophysiologic findings in a patient with SMA can mimic those found in other neuromuscular diseases, such as critical illness neuropathy or Guillain-Barré syndrome [29, 30]. Thus it is important to correlate EMG findings with the clinical context.



Other “Spinal Muscular Atrophies”



Non-5q Spinal Muscular Atrophies


Non-5q SMAs are genetically heterogeneous, clinically diverse and rare compared to 5q SMA [41]. Phenotypic classification may be based on distribution of weakness (distal, proximal or bulbar) and mode of inheritance (Table 16.2) [42, 43]. This classification system, however, does not include all non-5q motor axonopathies or neuronopathies, excludes SMA plus syndromes, and in particular excludes conditions with uncertain nosology or those with no gene/locus information [41].


Table 16.2
Clinical features and EMG findings in major non-5q spinal muscular atrophies (SMA)


































































Gene/locus

Disease/phenotype, selected distinguishing features

EMG findings

Distal spinal muscular atrophy/distal hereditary motor neuropathy or neuronopathy (DSMA/distal HMN)

Autosomal recessive

IGHMBP2

SMA with respiratory distress (SMARD) or diaphragmatic SMA

 • Low birth weight, typically presents within 3–6 months of life with diaphragmatic paralysis

 • Hypotonia, distal > proximal weakness, sensory and autonomic involvement

 • Ventilator dependence

 • Marked reduction or complete absence of CMAPs (prominent in lower extremities)

 • Similar but milder findings in sensory studies

 • Initially EMG shows denervation in distal muscles, later diffuse changes

PLEKHG5

Lower motor neuron syndrome with childhood onset

 • Early involvement of foot and hand muscles.

 • Rapid progression and early loss of ambulation

 • Cranial nerves are spared

 • SNAPs are present but can be of reduced amplitude, motor and sensory conduction velocity can be mildly slow

 • EMG shows denervation changes

Autosomal dominant

GARS

Distal SMA with upper-limb predominance, Type VA

Charcot-Marie-Tooth disease 2D

 • Predominant upper-limb weakness

 • Selective atrophy of the thenar and FDI muscles

 • Peroneal atrophy and weakness

 • Reduced vibration senses in CMT 2D

 • Absent or markedly reduced CMAPs from APB

 • Preserved CMAPs from ADM

 • CMAP amplitudes from peroneal < 2 mV

 • SNAP amplitudes and conduction velocities are usually normal except sural can be affected

 • Large MUAPs, reduced recruitment in thenar muscles

BSCL2

Distal SMA with upper-limb predominance, Type VB

Silver syndrome/SPG17

 • Hand muscle weakness and wasting

 • Stiffness in lower limbs and foot deformities

 • Gait abnormalities but ambulation usually maintained

 • Reduced CMAPs with occasional chrono-dispersion, partial conduction block and slowing of conduction velocity

 • Ulnar is less affected

 • Chronic denervation with large MUAPs

 • Usually no spontaneous activities

Proximal spinal muscular atrophy (+/- distal involvement)

Autosomal dominant

TRPV4

Congenital Distal SMA with arthrogryposis, contractures, asymmetric atrophy and non-progressive weakness with lower limb predominance

Scapuloperoneal SMA with scapular winging, laryngeal distribution of weakness, distal muscle wasting and absent reflexes

Charcot-Marie-Tooth, Type 2C with vocal cord and phrenic nerve paralysis

 • Normal conduction velocities

 • Reduced CMAPs

 • Polyphasic or giant MUAPs

 • Predominantly motor axonal neuropathy

DYNC1H1, BICD2

SMA with lower extremity predominance (SMA-LED)

 • Abnormal cortical development and epilepsy is common in DYNC1H1 mutation.

 • Wasting and contracture is common in BICD2, especially around ankle

 • NCS can be normal

 • Mild reduction of CMAPs (especially in common peroneal in BICD 2 mutation)

 • Chronic denervation in both proximal and distal leg muscles (quadriceps are most affected in DYNC1H1 mutation)

Other non-5q spinal and bulbar muscular atrophies, SMA plus types

Autosomal recessive

RFT2 (C20ORF54)

Brown-Vialetto-van Laere syndrome

Fazio-Londe disease, bulbar palsy

 • Primarily involves lower cranial nerves

 • Present with ponto-bulbar palsy

 • Sensorineural deafness in BVVLS

 • Respiratory failure

 • can be normal initially

 • repeat testing can suggest MND

EXOCS3 (30–40%),

VRK 1, TSEN54,

RARS2

Pontocerebellar hypoplasia with SMA,

PHC1

 • Progressive microcephaly combined with brainstem and cerebellar hemispheres atrophy

 • Relative sparing of the cerebellar vermis.

 • Severe cognitive and motor limitations, seizures.

 • Anterior horn cell degeneration

 • Neurogenic EMG

 • In most of the patients no neuropathy

 • In some EXOSC3 negative patients marked reduction or loss of SNAPs and CMAPs with marked slowing of conduction velocity

GLE1

Lethal arthrogryposis with anterior horn cell disease or lethal congenital contracture syndrome
 

X-linked recessive

Androgen receptor

Bulbar SMA, Kennedy disease

 • Atrophy and weakness of the facial, bulbar and proximal muscles

 • Bulbar symptoms

 • Fasciculation

 • Mild to severe hyper-CK-emia

 • Gynecomastia

 • Testicular atrophy and reduced fertility

 • Weakness often starts in the lower extremities

 • CMAPs and SNAPs are usually reduced with milder involvement of conduction velocities.

 • In CAG repeat (≥47), CMAPs reduced

 • In CAG repeat (≤ 47), SNAPs reduced

 • EMG shows chronic denervation and reinnervation with abnormal spontaneous activities

UBA1

Infantile SMA with arthrogryposis

 • White matter abnormalities on MRI

 • Prominent motor and sensory involvement

 • Cerebellar involvement

 • SNAPs and CMAPs can be absent

 • EMG shows reinnervation or denervation


Distal SMAs (DSMA)


Distal SMAs present with predominantly distal weakness. They exhibit significant phenotypic overlap with distal hereditary motor neuropathies or neuronopathies (dHMN).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by mutations in the gene IGHMBP2, which encodes the immunoglobulin μ-binding protein. Most patients with SMARD1 have low birth weight and present within the first 3 to 6 months of life with diaphragmatic paralysis, hypotonia, distal more than proximal weakness, and sensory and autonomic involvement, followed by ventilator dependency [44, 45]. Life expectancy is usually limited primarily due to the severe respiratory weakness [45]. Respiratory failure between 6 weeks and 6 months combined with the presence of diaphragmatic eventration or preterm birth is a good predictor of the presence of IGHMBP2 mutations [44]. Patients with SMARD1 usually have normal serum CK levels and no primary cardiomyopathy, but severe autonomic dysfunction can lead to secondary cardiovascular collapse [45, 46]. In a series of 141 patients with respiratory distress and diaphragmatic and intercostal weakness, three distinct phenotypes were noted: (1) SMARD-congenital: arthrogryposis multiplex congenita with associated respiratory failure at birth, (2) SMARD1-like: respiratory distress with onset between 6 weeks to 6 months along with hip flexion weakness with minimal or no movements of the distal muscle groups, and (3) SMARD-late: respiratory distress after age 6 months without multiple congenital contractures; however, the phenotype can be more variable [44, 47].

EMG in SMARD1 shows marked reduction of or complete absence of CMAPs and markedly slow conduction velocities, more predominantly in the lower extremities. Similar but milder findings may be seen in sensory studies [48, 49]. Needle EMG initially shows a denervation pattern only in distal muscles, but diffuse changes can be seen later. EMG of the diaphragm, if performed, may show denervation changes [45, 48, 49].

HMN5A and Charcot-Marie-Tooth type 2D (CMT2D) are allelic conditions caused by mutations in GARS [50, 51]. The clinical distinction between HMN5A and CMT2D is usually based on whether sensory abnormalities are present [50]. Patients with GARS mutations usually present in their twenties with predominantly upper-limb weakness, most notably including selective atrophy of the thenar eminence and first dorsal interosseous (FDI) muscles. The hypothenar eminence is usually spared until later in the course of the disease. Peroneal weakness and atrophy and reduced vibration sensation are usually present in all patients with CMT2D and about half of the patients with HMN5A [52]. EMG shows a motor axonopathy with typical features of absent or markedly reduced CMAPs recording abductor pollicis brevis (APB) and preserved CMAPs recording abductor digiti minimi (ADM). CMAP amplitudes from peroneal muscles are typically below 2 mV and below 1 mV when leg atrophy is clinically evident. SNAP amplitudes and conduction velocities are usually normal, although sural SNAP amplitude can be reduced. Even in presymptomatic mutation-carrying individuals, large long-duration motor unit potentials with reduced recruitment pattern can be seen in the thenar muscles. Similarly, chronic partial denervation can be seen in the ADM and extensor muscles of the legs even in the absence of apparent muscle atrophy [50, 51].

Mutations in BSCL2 gene result in allelic phenotypes including spastic paraplegia with amyotrophy of hands and feet (Silver syndrome/SPG17), congenital generalized lipodystrophy, type 2, distal SMA with early hand involvement (dHMNV), and dHMN beginning in the legs (dHMNII) [53, 54]. Phenotypes can be variable, but common features include hand muscle weakness and wasting, gait abnormalities, stiffness in the lower limbs, and foot deformities. Ambulation is usually preserved [53]. EMG shows reduced CMAPs, predominantly in the lower extremities, with occasional temporal dispersion and partial conduction block, and slowing of conduction velocity in the demyelinating range, suggesting that demyelination compounds a presentation that is otherwise predominantly axonal. In the upper extremities, median nerve CMAPs and conduction velocities are typically more affected than the ulnar nerve. EMG shows chronic denervation with large motor unit potentials with or without polyphasia, and without any abnormal spontaneous activity [53].


Non-5q SMAs with Proximal or Diffuse Weakness


SMA with lower extremity predominance (SMA-LED) is caused by dominant mutations in the dynein gene (DYNC1H1) encoding a microtubule motor protein in the dynein-dynactin complex and mutations in BICD2, which encodes a dynein adaptor protein. Features of SMA-LED with DYNC1H1 mutations include congenital or very early onset, severe weakness in the proximal legs, specifically quadriceps, and a static or minimally progressive course [43, 55]. In BICD2 mutations, onset may be in utero, at birth, or in early childhood. The typical presentation consists of delayed motor milestones, along with predominantly lower limb non-length-dependent weakness, with a variable amount of wasting and contractures. Contractures are most commonly found in the ankle. Of note, arthrogryposis or contractures are uncommon in DYNC1H1mutations. In some patients, scapular winging is present. A subset of patients can have upper motor neuron signs, but all patients usually have stable or only slowly progressive lower motor neuron disease, and most remain ambulatory throughout their lives [56]. In contrast to DYNC1H1 mutations, abnormal cortical development and epilepsy are not typical features of BICD2 mutations [56, 57].

Nerve conduction studies in DYNC1H1-associated SMA-LED may be normal. In older patients, mild CMAP amplitude reductions in the lower extremities may occur. EMG usually shows chronic denervation in both proximal and distal leg muscles [43]. Similar findings may be seen in BICD2-associated SMA-LED. CMAP amplitudes are occasionally reduced, especially in the common peroneal nerve. Nerve conduction velocities and SNAPs are usually normal or borderline reduced. Needle examination shows chronic denervation and large motor units with or without polyphasia [56].

TRPV4-related disorders are another example of diverse phenotypes: (1) congenital distal SMA with arthrogryposis and asymmetric atrophy and weakness, in the lower extremities, (2) scapuloperoneal SMA with scapular winging, laryngeal distribution of weakness, distal muscle wasting and weakness with absent deep tendon reflexes, and (3) CMT2C associated with vocal cord and phrenic nerve paralysis. EMG usually shows normal conduction velocities with reduced CMAP amplitudes and some polyphasic or giant motor units with evidence of a predominantly motor axonal neuropathy [5862].


Bulbar SMA


Brown-Vialetto-van Laere syndrome (BVVLS) and Fazio-Londe disease are clinically overlapping motor neuron diseases involving primarily lower cranial nerves; they present with ponto-bulbar palsy, sensorineural deafness in BVVLS, and respiratory failure. BVVLS and Fazio-Londe disease have been linked to mutations in the RFT2 (C200RF54) gene with defective riboflavin transport; riboflavin supplementation has been reported to be helpful in some cases [63, 64]. Early in the course, electrophysiological testing may be normal, but repeat examinations at later time points may detect motor neuron disease with greater sensitivity [6466].

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Nov 18, 2017 | Posted by in PEDIATRICS | Comments Off on Motor Neuron Disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access