Neuromuscular Diseases of the Newborn

Alex J. Fay, MD, PhD

The peripheral nervous system (PNS) is composed of motor neurons, nerve roots, plexuses,
peripheral nerves (motor, sensory and autonomic), neuromuscular junction, and skeletal
muscles. Disorders of the PNS in neonates most frequently cause weakness, hypotonia,
and contractures, which may be generalized or focal. Since these findings may also occur
with brain and spinal cord lesions, key features of the history and neurologic exam, together
with diagnostic testing, are helpful in reaching a diagnosis. This review covers the diagnos-
tic approach to PNS disorders in the neonate and includes a discussion of representative
diseases of the motor neuron, brachial plexus, peripheral nerves, neuromuscular junction,
and muscles. The importance of reaching a precise genetic diagnosis is highlighted with a
discussion of current and emerging treatments for neonatal PNS diseases, particularly spi-
nal muscular atrophy.
Semin Pediatr Neurol 32:100771 © 2019 Elsevier Inc. All rights reserved.

Introduction Muscle Tone in the Newborn

D isorders of the peripheral nervous system (PNS) affect

the motor neurons, peripheral nerves, neuromuscular
junction, or muscle, and in some diseases, may involve the
central nervous system (CNS) and other organs. Typical
manifestations of neuromuscular disorders in the newborn
include hypotonia, weakness (generalized or focal), multiple
contractures (arthrogryposis), respiratory failure, and feeding
difficulties. Weakness may be fixed, progressive, or episodic.
As these symptoms are not specific to dysfunction of the
PNS, the history, neurologic examination, and diagnostic
testing are all helpful in localizing to the peripheral nerves,
neuromuscular junction, and muscle. Electrodiagnostic test-
ing, such as nerve conduction studies (NCS) and electromy-
ography (EMG), muscle biopsy, magnetic resonance
imaging, and genetic testing can be useful as extensions of
the neurologic exam and as tools for establishing a precise
diagnosis. Current and emerging therapies for early onset
neuromuscular diseases, most notably spinal muscular atro-
phy, have placed inherited PNS disorders at the forefront of
targeted treatments.
Muscle tone in a newborn is assessed by a combination of
observation, provocative maneuvers and positioning, and
determination of velocity-dependent resistance to passive
range of motion. Normal tone depends on gestational age for
premature infants and can change with the state of the child
(sleeping, awake and quiet, or agitated).1 If only a single
examination is possible, as in the case of an outpatient visit,
assessment of the infant in the quiet, awake state is most
informative.
The examination of muscle tone should begin with an
understanding of the normal evolution of muscle tone with
gestational age (GA). Prior to 28 weeks’ GA, low axial and
appendicular tone is normal, without flexion of the arms or
legs in the quiet, awake state. By 32 weeks’ GA, flexor tone
begins to appear in the lower extremities, with full flexion of
the hips and knees appearing around 36 weeks’ GA. At 36
weeks’ GA, flexor tone starts to appear in the upper extremi-
ties, with full flexor tone at the elbows by 40 weeks’ GA.2

Department of Neurology, University of California, San Francisco, San
Francisco, CA.
Financial Disclosures: The author has no commercial, proprietary, or
financial interest in any products or companies described in this article.
Address reprint requests to Alex J. Fay, MD, PhD, Department of Neurology,
University of California, San Francisco, 1550 4th St., RH546, MB2922,
San Francisco, CA 94143. E-mail: alexander.fay@ucsf.edu
Neuromuscular Examination
Dysmorphic facial features with “myopathic facies,” where
the face is elongated, with dolichocephaly and sometimes
ptosis, may be seen in congenital myopathies, muscular dys-
trophies, and myasthenic syndromes. The examiner should
also note whether the palate is high-arched, a common find-
ing in congenital neuromuscular disorders.

https://doi.org/10.1016/j.spen.2019.08.007 1
1071-9091/11/© 2019 Elsevier Inc. All rights reserved.
2 A.J. Fay
The cranial nerve examination should focus on eye move-
ments, crying facies, and the vigor of crying and the sucking
and rooting reflexes. Limitation of extraocular movements
and/or ptosis may be seen in some congenital myopathies and
myasthenic syndromes. There may be reduced change in facial
expression with crying in children with the myopathic facies
mentioned above, asymmetric crying facies with absent
depressor anguli ori, or complete lack of facial movement in
M€ obius syndrome. A weak, hypophonic cry can be a sign of
bulbar weakness (cranial nerves IX and X) from a CNS or PNS
cause. The rooting and sucking reflexes are helpful to assess
the function of cranial nerves V, VII, and XII, and a weak suck
may correlate with feeding difficulties, though such difficulties
are common in CNS and systemic disease. The tongue should
be observed for fasciculations, as may occur in motor neuron
diseases such as spinal muscular atrophy.
Low axial and appendicular tone is characteristic of neuro-
muscular disorders, typically in a symmetric pattern. Marked
hypotonia and weakness in a single limb should raise con-
cern for a traumatic injury, such as brachial plexus palsy,
while congenital hemiplegia and diplegia are more likely due
to brain or spinal cord lesions. Muscle strength can be graded
on the Medical Research Council (MRC) scale if one carefully
isolates muscle groups, but it can be more helpful to define a
pattern of movement and weakness: limited proximal muscle
movement with relatively preserved movement of the fingers
and toes might be seen in an infant with spinal muscular
atrophy or a congenital myopathy, while more severe limita-
tion in distal muscle movement would be characteristic of
peripheral nerve dysfunction (Dejerine-Sottas) or distal
arthrogryposis. While some contractures, such as club foot,
may be obvious, others are apparent only with testing range
of motion.
The primitive reflexes may be incomplete or absent in a
child with low muscle tone, or asymmetric with focal CNS or
peripheral injuries. Asymmetry of the Moro reflex should be
apparent in a brachial plexus injury or unilateral CNS lesion,
while a muscle or motor neuron disease may result in a
response that is absent or incomplete. The plantar (Babinski)
reflex has little value in localization, unless there is marked
asymmetry. Combined with evaluation of response to gentle
pinprick, light touch, and cold temperature as a part of the
sensory examination, marked abnormalities may localize to
spinal cord or sensory nerves. Deep tendon reflexes are often
reduced proportionally to weakness and hypotonia in PNS
disorders. Reflexes may be reduced or absent following an
acute CNS injury, but there is typically a transition to hyper-
reflexia over days or weeks. Hypotonia, limb weakness,
hyporeflexia, and normal mental status in a newborn without
history suggestive of a CNS anomaly (such as perinatal hyp-
oxia, prolonged resuscitation, or CNS malformation) are con-
cerning for a PNS cause.
Hypotonia
Low muscle tone in the neonate can present a diagnostic
challenge, with a broad differential that includes acute and
chronic/developmental CNS disorders, systemic illness, med-
ication effects, and PNS disorders. It may occur together with
arthrogryposis or episodic weakness, which will be discussed
below.3 Hypotonia may be localized to the PNS by:
 Exclusion of CNS etiologies
 Positive exam findings:
○ symmetric, proximal or distal weakness
○ prominent facial or bulbar weakness
○ hyporeflexia/areflexia
 Diagnostic testing:
○ elevated creatine kinase level (muscular dystro-
phies)
○ EMG/NCS
○ muscle biopsy
○ imaging of muscle or nerves
Table 1 provides general patterns for disorders of the
motor neuron, peripheral nerves, neuromuscular junction,
and muscle. These categories are not rigid, as there is overlap
and there are exceptions to the rules (eg, distal myopathies).
Below, I discuss several representative disorders of each of
these parts of the PNS, and the reader should explore the
references for in-depth information about specific causes of
neonatal hypotonia. One should always consider reversible
causes of weakness and hypotonia, such as electrolyte and
endocrine abnormalities (hypokalemia, hypermagnesemia,
hypoglycemia, hypo-/hyperthyroidism) in the acute setting.4
Spinal Muscular Atrophy
 SMA is a motor neuron disease that causes proximal
weakness, initially sparing the eyes and face, and fasci-
culations.
 Disease onset and severity depend on the number of
copies of SMN2.
 Treatment with nursinersen is now available, with
additional treatments pending.
Spinal Muscular Atrophy5 is a disorder of the motor neu-
rons, most commonly caused by recessive loss of SMN1 pro-
tein expression, with disease severity determined by the
number of copies of the highly homologous SMN2 gene.
Thus, an individual with 4 or more copies of SMN2 may not
show symptoms until adulthood, while an individual with 1
or 2 copies of SMN2 will typically shows symptoms in utero
or in the first month of life. The age of onset and SMN2 copy
number allow for description of SMA subtypes: type 0 (1
copy SMN2, onset prior to birth), type 1 (2 copies SMN2,
onset prior to 6 months), type 2 (2-3 copies SMN2, onset
6-18 months), type 3 (3-4 copies SMN2, onset 18 months-
21 years), and type 4 (4-8 copies SMN2, onset >21 years).
Infants with type 0 typically die in the first month of life
from respiratory failure, while infants with type 1 never sit
independently, infants with type 2 never stand indepen-
dently, and children with type 3 exhibit a wide range of
motor ability, from standing only to walking independently.
Neuromuscular Disorders of the Newborn
Table 1 Characteristics Features of Disorders of the Peripheral Nervous System
Weakness Sensory
Localization Pattern Symptoms
Motor neuron Proximal No
Plexus Upper trunk, Distribution of
lower affected nerves
trunk, or both
Peripheral nerve Distal Yes
Neuromuscular Ocular, proximal, No
junction bulbar
Muscle Proximal, No
+/-facial
SMA type 1 is the most common subtype, and in natural his-
tory studies,6 is fatal in the first 2 years of life without inva-
sive ventilatory support. Initial manifestations of the disease
include axial and appendicular hypotonia, weakness in the
proximal more than the distal muscles with early sparing of
the muscles of facial expression, fasciculations in the tongue
and other muscles, low muscle bulk, chest circumference
smaller than head circumference, absent deep tendon
reflexes, and intact sensation.
In one of the most dramatic medical advances of the 21st
century, the development of nusinersen,7 a synthetic, stabi-
lized antisense oligonucleotide that targets splicing of SMN2
and increases formation of a more stable protein product,
has transformed SMA type I, from a fatal disease to a treatable
condition. Earlier treatment leads to better outcomes,8 with
initiation prior to symptom onset being associated with
nearly normal early motor development in some infants.9
Gene therapy, with a single intravenous infusion of an
adeno-associated virus vector carrying the full length SMN1
gene, showed promising results in early trials in infants with
SMA type I, and is now approved in the United States for
children under two years of age.10
Congenital Neuropathies
 Congenital neuropathies present with distal-predominant
weakness and contractures, sensory loss, and areflexia.
 NCS can distinguish between demyelinating and axo-
nal forms.
Peripheral neuropathies can be either dysmyelinating or
axonal, and most commonly affect both the sensory and
motor neurons, though there are forms that specifically
affect motor neurons (hereditary motor neuropathies)11 or
sensory and autonomic neurons (hereditary sensory and
3
Reflexes Other Disease Examples
Reduced/absent Atrophy, cramps, Spinal muscular atro-
fasciculations phy, acute flaccid
myelitis
Focally reduced Shoulder dystocia, Erb-Duchenne,
trauma, Horner’s if Klumpke palsies,
T1 root injured hereditary neuralgic
amyotrophy
Reduced/absent Pes Cavus, hammer Charcot-Marie-Tooth,
toes, +/- autonomic Guillain-Barr e
symptoms syndrome
Normal or Fatigability; improve Congenital myasthenic
reduced w/ ice, acetylcho- syndrome, botulism
linesterase
inhibitors
Normal or Myotonia, Congenital myopathy,
reduced pseudohypertrophy muscular dystrophy,
myotonia congenita
autonomic neuropathies).12 Early onset hypomyelinating
neuropathies are also referred to as Dejerine-Sottas syn-
drome,13 with marked slowing of nerve conduction veloc-
ities and elevated protein in the cerebrospinal fluid. Genes
with dominant mutations most commonly associated with
these hypomyelinating neuropathies include PMP22, MPZ,
and EGR2; several recessive forms exist, as well (EGR2,
periaxin mutations). Characteristic exam findings include
hypotonia, distal more than proximal weakness, club feet,
absent sensation, areflexia, and sometimes cranial neurop-
athies, including sensorineural hearing loss. Nerve con-
duction velocities (CV) may be in the range of 3-8 m/s
(normal neonatal CV are >20 m/s), often with loss of
compound motor action potentials (CMAP) due to sec-
ondary axon loss. Nerve biopsy typically shows absent,
thin, or abnormally folded myelin surrounding nerve
fibers. Recessive congenital hypomyelinating neuropathies
have also been reported (as part of the CMT4 category),
with mutations in genes such as GDAP1, SH3TC2, FGD4,
and EGR2. While in most cases, arthrogryposis is attrib-
uted to defects in motor neurons and Schwann cells, in
some cases, contractures appear to be due to sensory
neuron dysfunction (PIEZO2, NALCN).14 Giant axonal
neuropathy is a multisystem disease with global develop-
mental delay, ataxia, short stature, and kinked hair, with
gene therapy treatment currently in clinical trials after
promising preclinical studies.15 Many lysosomal storage
disorders also affect the peripheral nerves, and the reader
should explore references for more information on this
topic.16-18 Acquired, immune, and postinfectious neuropa-
thies have rarely been reported in the neonatal period, so
Guillain-Barre syndrome,19 chronic immune demyelinat-
ing polyneuropathy,20 and enterovirus-associated acute
flaccid myelitis21 should be considered in a previously
normal child who develops signs and symptoms of a dif-
fuse, peripheral neuropathy.
4 A.J. Fay

Congenital Myopathies and Muscular Examples include alpha-2-laminin,24 alpha-dystroglycanopa-

Dystrophies
 Congenital muscular dystrophies: progressive, limb-
girdle weakness, early respiratory involvement, ele-
vated CK, muscle biopsy shows replacement of muscle
fibers with connective tissue and fat.
 Congenital myopathies: static/slowly progressive,
prominent facial/ocular and limb-girdle weakness,
early respiratory involvement, normal CK, muscle
biopsy shows small fibers with distinct histological fea-
tures.
There are 2 broad categories of congenital muscle dis-
eases,22 which can be distinguished by examination findings,
creatine kinase level, EMG features, and muscle biopsy, and
which have distinct clinical courses and pattern of muscle
involvement over time (Table 2).
Dystrophies23 are progressive disorders that cause ongoing
degeneration and regeneration of muscle fibers, with gradual
accumulation of fibrotic tissue and fatty replacement of mus-
cle fibers over time. These pathologic features are best appre-
ciated with muscle biopsy, though a dystrophy may be
suspected if creatine kinase is markedly elevated and EMG is
consistent with an “irritable myopathy” (fibrillations and pos-
itive sharp waves with small, polyphasic motor unit poten-
tials). Weakness tends to be in a limb-girdle pattern, with
less facial/bulbar involvement than the congenital myopa-
thies and congenital myasthenic syndromes. Most of the con-
genital muscular dystrophies are associated with mutations
in genes that encode extracellular matrix proteins or sarco-
lemmal proteins associated with the extracellular matrix.
thies (proteins that affect glycosylation of alpha-dystrogly-
can),25 and collagen VI.26 Compared to the congenital
myopathies, the congenital muscular dystrophies are more
likely to affect other organs, particularly the brain27 and
heart.28 Walker-Warburg syndrome (a severe disorder of O-
glycosylation), for example, is associated with cobblestone
lissencephaly, microcephaly, microphthalmia, and severe
developmental delays.29 Alpha-2-laminin deficiency (also
known as merosin deficiency) may also manifest with epi-
lepsy and diffuse, symmetric white matter abnormalities on
brain MRI (typically present by 6 months of age), though the
neuromuscular manifestations of contractures, hypotonia,
and elevated creatine kinase are typically present at birth. Ull-
rich and Bethlem myopathies (collagen VI mutations) typi-
cally involve the skin (hyperkeratosis pilari, velvety palms/
soles) and may have a normal or only mildly elevated creatine
kinase level.
Congenital myopathies, by contrast, are typically non-
progressive or slowly progressive, and tend to spare
organs other than the skeletal muscle. Genes implicated
in congenital myopathies are primarily involved in excita-
tion or contraction, and include ryanodine receptor 1
(RYR1), actin (ACTA1), myotubularin-1 (MTM1), nebu-
lin, titin, and myosin.30 Creatine kinase is normal or only
slightly elevated, and muscle biopsy does not typically
show prominent degeneration-regeneration or fibrous-
fatty replacement; rather, there are characteristic muscle
histologic changes such as central nuclei, nemaline rods,
central cores, or fiber type disproportion. Muscle fibers
are small, which corresponds with the reduced muscle
bulk seen in patients with congenital myopathies. Facial

Table 2 Distinguishing Features of Congenital Muscle and Neuromuscular Junction Diseases

Congenital Muscular Congenital Myasthenic
Clinical Features Congenital Myopathy Dystrophy Syndromes

Weakness pattern Static/slow progression facial/ Progressive weakness, limb- Episodic, static/slow progres-
ocular/bulbar, limb-girdle girdle sion, ocular, facial/bulbar, limb-
girdle
Creatine kinase (CK) Normal/mildly elevated Marked elevation (exception: can Normal/mildly elevated
be normal in collagen VI
disorders)
Eye Ptosis, ophthalmoplegia common Eye structural changes (alpha- Ptosis, ophthalmoplegia common
dystroglycanopathies)
Heart Unaffected May be affected Unaffected
EMG/NCS Small, polyphasic motor unit Fibrillations, positive sharp Decremental response with
potentials waves, small, polyphasic motor repetitive nerve stimulation
unit potentials
Muscle biopsy Nemaline rods, central cores Degeneration/regeneration, Normal gross (EM may show
central nuclei, fiber type fatty/fibrous replacement of NMJ abnormalities)
muscle fibers
Proteins Excitation, contraction Extracellular matrix, ECM-inter- Neuromuscular junction ion
acting proteins, channels, receptors, ACh
O-glycosylation release
Treatment Gene therapy for MTM1 (in trial) Steroids? gene therapy? Acetylcholinesterase inhibitors,
albuterol, ephedrine
Ach, acetylcholine; ECM, extracellular matrix; EM, electron microscopy; NMJ, neuromuscular junction
Neuromuscular Disorders of the Newborn
and bulbar muscles are often weak, resulting in elon-
gated, “myopathic” facies, high-arched palate, and early
feeding difficulties, sometimes with ptosis or ophthalmo-
plegia. Early respiratory support31 may be necessary to
compensate for weakness of the diaphragm and accessory
muscles. The brain and heart are not typically affected.
With the increasing availability of next-generation
sequencing, muscle biopsy may no longer be necessary in
many cases for diagnosis of congenital myopathies and mus-
cular dystrophies, if the history and exam findings are consis-
tent with genetic testing results. Creatine kinase level and
EMG/NCS can be helpful in narrowing the differential in a
child with hypotonia, and brain and muscle MRI can
aid diagnosis in some cases. Muscle pathology may be
helpful when a clear genetic etiology cannot be identified.
Caution should be exercised when sedating children with
suspected congenital muscle weakness, as mutations in
RYR1, CACNA1S, STAC3, and several other genes have been
associated with malignant hyperthermia upon exposure to
inhaled anesthetics.32
Management of the congenital muscular dystrophies
and myopathies is largely supportive,33,34 with close
attention to respiratory and feeding complications. Physi-
cal and occupational therapy, orthotics, mobility equip-
ment, and corrective surgeries for contractures and
scoliosis may be necessary during childhood. Many of the
myopathies and muscular dystrophies affect neuromuscu-
lar junction transmission, so if there is fatigable weakness
or electrodecremental response to repetitive nerve stimu-
lation, a trial of acetylcholinesterase inhibitor and/or albu-
terol is reasonable.35 Small trials suggest that some
patients with congenital muscular dystrophies may show
improved strength with corticosteroids,36-38 similar to the
response seen in Duchenne muscular dystrophy, but at
this point, there are not enough data to support routine
use of steroids in newborns or infants with muscular dys-
trophy. Finally, there are emerging genetically targeted
therapies, including a gene therapy trial for centronuclear
myopathy due to MTM1 mutation.39 The rapidly chang-
ing therapeutic landscape makes reaching a genetic diag-
nosis increasingly important, as patients may be eligible
for trials of therapies that could change the course of
their disease.
While gene panels and whole exome sequencing may have
diagnostic yields approaching or exceeding 50%40,41 in some
neuromuscular disorders, it is important to recognize that
these tests may miss several conditions. The most common
of these is myotonic dystrophy, type I (DM1), while faciosca-
pulohumeral muscular dystrophy (FSHD) may also occur in
the neonatal period in its most severe manifestation. Each of
these requires specific testing: trinucleotide repeat sequenc-
ing in the case of DM1, and chromosome 4q D4Z4 repeat
contraction in FSHD. In addition, next-generation sequenc-
ing may take weeks to months to return results, so in treat-
able disorders such as infantile-onset Pompe disease (acid
maltase deficiency), enzyme testing should be sent early to
expedite diagnosis.
5
Special Cases: Pompe
 Pompe disease: Hypotonia, macroglossia, early cardio-
myopathy, elevated CK; treatable with enzyme
replacement
Pompe disease, also known as acid maltase deficiency or
glycogen storage disease type II, can present from the neona-
tal period to late adulthood, but the neonatal phenotype has
some distinguishing features from later onset forms and from
other forms of congenital muscular dystrophies. The severe
neonatal onset Pompe disease is associated with cardiomyop-
athy in almost all cases (>90%), and affects not only skeletal
and cardiac muscles, but also brain development.42 Affected
infants are typically hypotonic, with macroglossia, and crea-
tine kinase is elevated. Diagnosis is typically made by sending
acid maltase enzyme activity testing, and confirming with tar-
geted genetic testing. Muscle biopsy is rarely needed with the
rapid return of results from these tests, but in cases where it
is performed, shows glycogen accumulation on Periodic
Acid-Schiff staining. The course of Pompe disease is progres-
sive, and the neonatal form typically leads to death from car-
diac disease or respiratory failure in infancy without
treatment.41 With the advent of enzyme replacement ther-
apy, however, the course of disease can be slowed signifi-
cantly.43,44 Trials are underway to enhance uptake of
recombinant GAA enzyme using chaperones, and gene ther-
apy trials are also on the horizon, so the treatment landscape
may change significantly in the coming years.45
Special Cases: FSHD
 FSHD: Early facial involvement; requires specific test-
ing to make diagnosis
Facioscapulohumeral muscular dystrophy typically begins
to manifest in later childhood, adolescence, or early adult-
hood, but in its most severe form may present in the neonatal
period.46 Facial weakness is prominent at onset, and weak-
ness may be asymmetric. As noted above, FSHD1 cannot be
diagnosed by gene panels or whole exome sequencing;
rather, testing involves identification of a permissive allele on
the terminal part of chromosome 4q, with a reduced number
of D4Z4 repeats.47 Greater contraction of the number of
D4Z4 repeats is associated with earlier onset of disease, and
the shortened number of repeats is thought to weaken sup-
pression of a toxic downstream gene, DUX4.48 Although
muscle biopsy shows inflammatory changes, corticosteroids
have not been found to be effective in slowing the course of
disease. Several approaches to treat FSHD are under investi-
gation, aiming to suppress DUX4 expression.46 FSHD2 is
caused by dominant mutations in the SMCHD1 gene, and
may be diagnosed with individual gene testing, panel testing,
or whole exome sequencing.
6 A.J. Fay
Special Cases: Myotonic Dystrophy, Type I
(DM1)
 DM1: Profound hypotonia, distinct facies, early respi-
ratory failure and feeding difficulties; examine mother,
send specific trinucleotide repeat testing to diagnose
As with other trinucleotide repeat diseases, DM1 may have
a variable age of onset, depending on the number of repeats.
DM1, especially the congenital form, should be considered a
multisystem, degenerative disorder. The neonatal form is the
most severe and may lead to death from respiratory failure
during infancy.49 The presenting features include severe
hypotonia, respiratory and feeding difficulties, and a charac-
teristic facial weakness with a “fish-shaped” mouth. Hypoto-
nia is thought to be from CNS pathology in the neonatal
period, as creatine kinase is usually normal and muscle
biopsy does not show the dystrophic features that are typical
of more advanced disease. Myotonia, clinical and electro-
graphic, is not present until late childhood.50 Thus, examin-
ing the parents, particularly the mother, may be the most
helpful part of the neurologic examination: instability of
the repeat length is greater in women than in men, such that
the neonatal form of DM1 is typically inherited from the
mother.51 The mother of a child with DM1 may manifest
with grip or percussion myotonia (elicited by striking the
thenar eminence with a reflex hammer and watching for
delayed relaxation), cataracts, distal weakness (particularly
foot drop), or mild intellectual disability. Although prognosis
is poor for infants with congenital myotonic dystrophy, the
mother may benefit from diagnosis and referral to a cardiolo-
gist, as cardiac conduction defects cause early mortality in
later onset DM1.
Inborn Errors of Metabolism and the PNS
 Metabolic disorders may present with acute hypotonia,
encephalopathy, cardiomyopathy, with or without
metabolic acidosis, hypoglycemia.
 Work-up includes blood and urine metabolic studies,
brain MRI with spectroscopy.
A variety of defects in lipid, amino acid, glycogen, and
mitochondrial metabolism may lead to neonatal myopathies,
often with CNS and other organ involvement, including car-
diomyopathy and liver dysfunction.52 A detailed description
of each of these disorders is beyond the scope of this review
but some general principles are helpful in considering this
class of disorders. The importance of making diagnoses of
metabolic disorders is that many can be treated, or at least
mitigated, by dietary restrictions or by supplementing cofac-
tors. While newborn screening captures many metabolic
abnormalities on blood spots, especially among the amino
acidopathies, organic acidurias, and fatty acid oxidation dis-
orders, it must be recognized that many metabolic diseases
are missed by newborn screening, and may require specific
blood, urine, or CSF testing. Fatty acid oxidation defects and
disorders of glycogen storage or metabolism should be con-
sidered in a newborn with hypoglycemia, while encephalopa-
thy, and hypotonia, often with metabolic acidosis after
initiation of feeding, should prompt consideration of amino
acidopathies and organic acidurias. Mitochondrial disorders
may manifest with severe CNS abnormalities, such as
encephalopathy, seizures, and stroke-like episodes, or may
affect skeletal or cardiac muscle, peripheral nerves, eyes,
liver, or some combination of these tissues. Suggested initial
testing includes serum amino acids, urine organic acids, total
and free carnitine, acylcarnitine profile, ammonia, lactate and
pyruvate, uric acid, urine creatine metabolites, and urine
purines and pyrimidines. CSF analysis of lactate/pyruvate
ratio, amino acids, and MR spectroscopy should be consid-
ered in the setting of CNS symptoms. Muscle biopsy may be
helpful, and in the case of suspected mitochondrial disease,
it is preferable to perform sequencing of mitochondrial DNA
from muscle tissue instead of blood, due to differences in
heteroplasmy.53
Arthrogryposis
 Contractures at 2 or more joints (excluding club feet
and hips)
 Causes can include CNS, PNS, connective tissue;
acquired or inherited
Arthrogryposis is defined as the presence of contractures at
2 or more joints but not limited to club feet or hip dysplasia.
It is a syndrome, rather than a disease, and has diverse
causes, from CNS injuries and malformations, to maternal
and uterine factors such as oligohydramnios and uterine
bands, to connective tissue disorders and diseases of the
PNS.54 This section focuses on PNS causes but touches upon
CNS causes in identifying some of the distinguishing features
of neuromuscular disorders.
Hypotonia and arthrogryposis are more frequently due to
CNS causes, most commonly following perinatal hypoxic-
ischemic brain injury, than to PNS causes. The presence of
encephalopathy at birth, seizures, and characteristic findings
on brain MRI points to a CNS cause. In addition, contrac-
tures following perinatal CNS injury are not typically present
until weeks or months after birth. Reduced fetal movements,
contractures identified by antenatal ultrasound or present at
birth, and reduced muscle bulk at birth are more characteris-
tic of PNS disorders, though these findings can also be seen
in cases of CNS malformations or injury from TORCH infec-
tions. Club foot and hip dysplasia are relatively common and
are typically not associated with abnormal muscle or
peripheral nerve dysfunction, so they are not covered specifi-
cally in this section. Rather, I will review several PNS disor-
ders which present with prominent contractures at birth.
Any disorder that causes severely reduced movement in
utero, however, can lead to arthrogryposis. Pathologically,
Neuromuscular Disorders of the Newborn
arthrogryposis may be associated with increased connective
tissue at joints, and with muscle atrophy due to disuse.55
Amyoplasia
The most common cause of arthrogryposis multiplex conge-
nita, accounting for approximately one-third of cases, is
amyoplasia,56 which is thought to be an acquired disorder
that occurs sporadically because of vascular injury of the
motor neurons early in development. It is nonprogressive
but leaves affected individuals with severely restricted move-
ment as they grow up. Amyoplasia most commonly affects
all 4 limbs, but 3 limbs, upper extremity only and lower
extremity only involvement have been reported in case series.
Clubfoot deformities are seen in almost all cases, with other
common features including symmetric elbow extension con-
tractures, wrist flexion contractures, short limbs with
reduced muscle bulk, and midline forehead nevus flammeus.
Additional findings that may be associated with amyoplasia
include gastroschisis, bowel atresia, and partial absence of
fingers or toes. Muscle biopsy typically shows replacement of
muscle tissue with fat and fibrous connective tissue. Manage-
ment consists of casting, surgical tendon releases, and physi-
cal therapy. Since the injury is nonprogressive, and
amyoplasia does not typically involve any CNS injury, the
prognosis is good with diligent management of contractures.
Distal Arthrogryposis
The distal arthrogryposes cause club feet, ulnar deviation of
the hands with overlapping fingers and finger flexion con-
tractures, and may involve characteristic facial features, such
as the “whistling face” in Sheldon-Freeman syndrome.57
Most are dominant and caused by mutations in either muscle
or peripheral nerve genes.58,59 Club feet may be initially
treated with serial casting, though the response is typically
less than would be seen in idiopathic clubfoot, where there is
no underlying weakness.
Escobar Congenital Myasthenic Syndrome
Mutations in acetylcholine receptor subunits, particularly the
fetally expressed gamma subunit, may lead to multiple pte-
rygium syndrome, where reduced movement in utero leads
to webbing of skin (pterygia) across joints.60 Diffuse contrac-
tures may also be seen with recessive rapsyn mutations.61
When mutations are present in the gamma AChR subunit,
there is often improvement in strength in infancy and child-
hood, as the gamma subunit expression is reduced and the
delta subunit is expressed in mature muscle postsynaptic sar-
colemma.
Ullrich Congenital Muscular Dystrophy
Mutations in collagen VI genes (COL6A1, COL6A2,
COL6A3), both dominant and recessive, lead to a unique
syndrome of proximal contractures and distal joint hyperlax-
ity, called Ullrich congenital muscular dystrophy.62
7
Contractures may improve after birth, but recur progressively
later in childhood. While some children may achieve ambu-
lation, most do not, and progressive respiratory insufficiency
due to scoliosis typically occurs in childhood. Collagen XII
mutations have also been reported to cause a similar pheno-
type. Bethlem muscular dystrophy is a milder form of colla-
gen VI dysfunction, which may cause neonatal hypotonia,
but typically causes weakness and contractures in the infan-
tile period or later childhood. As collagen VI is also expressed
in skin, dermatologic features may include hyperkeratosis
pilari, keloid formation, velvety skin over the palms, and
atrophic scarring.
Episodic Weakness: Disorders of
the Neuromuscular Junction
 Congenital myasthenic syndromes: episodic weakness
(ptosis, ophthalmoplegia, and facial weakness), respi-
ratory failure, feeding difficulties; NCS with repetitive
nerve stimulation can aid diagnosis; treatment with
pyridostigmine, albuterol.
 Botulism and maternal myasthenia gravis are acquired
causes of neonatal weakness.
Congenital Myasthenic Syndromes
Fluctuating weakness in the neonate, particularly when it
affects facial and/or bulbar muscles, is most likely to be
caused by congenital myasthenic syndrome,63 hereditary dis-
orders of neuromuscular transmission. Some rare causes of
acquired neuromuscular junction disease, including botulism
and maternal myasthenia gravis, may also cause facial and
bulbar weakness that fluctuates. Episodic disorders of skele-
tal muscle, such as periodic paralyses and myotonias, do not
typically manifest until later in childhood, though the
sodium channel myotonias have been reported to present as
neonatal apnea64 or stridor65 and even sudden infant death
syndrome.66
In older children, a history of fatigability can often be eli-
cited, but this may be more challenging for parents to iden-
tify in neonates, who are less active. Progressive ptosis over
the course of waking hours and fatigue during feeding may
be present. The weakness pattern of ptosis with or without
ophthalmoplegia, facial weakness, and bulbar weakness,
superimposed on diffuse axial and appendicular hypotonia,
is typical of both congenital myopathies and congenital
myasthenic syndromes. With more dramatic symptoms,
such as episodic apneas, CNS causes (seizure, nonaccidental
trauma) and infectious syndromes like seizures, sepsis, or
meningitis, should be excluded first.
Diagnostic work-up for disorders of the neuromuscular
junction includes NCS with repetitive nerve stimulation and
EMG. CMAP amplitudes may be normal or slightly reduced,
while EMG is often normal or consistent with a nonirritable
myopathic process. Repetitive nerve stimulation at 2 Hz,
8 A.J. Fay
recording from a weak muscle, is usually sufficient to dem-
onstrate the diagnostic >10% electrodecrement, even in a
fussy newborn. Some presynaptic disorders, such as choline
acetyltransferase (ChAT) deficiency and botulism, require
higher frequency (10 Hz or more) stimulation.67 Repetitive
CMAPs, a unique feature of the slow channel myasthenic
syndromes (dominant acetylcholine receptor mutations) and
endplate cholinesterase deficiency (recessive ColQ muta-
tions), can be seen with standard NCS.
Several of the congenital myasthenic syndromes have char-
acteristic features that may raise suspicion before any diag-
nostic tests are performed. Escobar syndrome (multiple
pterygia) is discussed above. Recessive mutations in ColQ
can cause sluggish pupillary reactivity,68 which is not typi-
cally seen in other congenital myasthenic syndromes. Epi-
sodic apneas should raise suspicion for choline
acetyltransferase deficiency, sodium channel (SCN4A), or
rapsyn mutations. While most congenital myasthenic syn-
dromes selectively affect skeletal muscle, there are several
forms (SNAP25, DPAGT1, ALG2, ALG14, GMPPB, and
GFPT1) that may affect the CNS.69
The importance of diagnosing a congenital myasthenic syn-
drome is that these are treatable conditions.63 Most subtypes
are responsive to acetylcholinesterase inhibitors such as pyri-
dostigmine, with some exceptions: individuals with DOK7
mutations may show worsening weakness with pyridostig-
mine, while those with slow channel syndrome and endplate
cholinesterase deficiency (ColQ mutations) may worsen or not
respond to acetylcholinesterase inhibitors. Response to pyri-
dostigmine should be immediate with appropriate dosing.
Similarly, the potassium channel blocker 3,4-diaminopyridine,
used also to treat Lambert-Eaton myasthenia, can improve
symptoms rapidly, but should be avoided in DOK7 myas-
thenic syndrome and slow channel syndrome. Adrenergic ago-
nists, including albuterol and ephedrine, have also been
widely reported to improve strength and reduce fatigability in
myasthenic syndromes, though benefit is usually evident after
1-3 months of treatment. Other treatments include sodium
channel blocking medications (fluoxetine, quinidine, quinine)
for slow channel syndrome. A trial of one or more of these
treatments should be considered in children with congenital
myopathies and congenital muscular dystrophies,35 especially
if there is fatigable weakness and/or a decremental response
on repetitive nerve stimulation. Even with treatment, there is
typically residual weakness, which may gradually worsen over
many years.
Acquired Neuromuscular Junction Disorders
Mothers with untreated or undertreated myasthenia gravis
and elevated anti-AChR antibodies may pass these antibodies
transplacentally to the fetus, resulting in neonatal arthrogry-
posis and/or hypotonia with weakness and respiratory
depression.70 If there is uncertainty about the diagnosis, it
should be confirmed in the mother with anti-AChR antibod-
ies and electrodiagnostic studies. Symptoms resolve over sev-
eral weeks with supportive care and cholinesterase
inhibitors, such as pyridostigmine.
Botulism typically affects infants in the first 6 months of life
and may occasionally occur in newborns.71 It is a disease of
bacterial overgrowth by the anaerobe Clostridium botulinum (or
more rarely, other subtypes of clostridia), which releases a
toxin that enters the motor neuron presynaptic membrane,
where it cleaves proteins that are critical for calcium-depen-
dent release of acetylcholine into the neuromuscular junction.
Ingestion of C. botulinum spores from soil is the most common
exposure (more common than unpasteurized honey), and is
followed by bacterial replication and toxin release among the
infant’s immature gut flora. Clinical manifestations begin with
constipation, followed by bulbar weakness with poor feeding
and a weak cry, and progressing to diffuse hypotonia and
weakness, often with respiratory failure. A definitive diagnosis
is made by detection of toxin in the stool by ELISA, but, if
available, electrodiagnostic studies may help support the diag-
nosis more quickly than the stool toxin results. NCS show
reduced CMAP amplitudes, with an increase in CMAP ampli-
tude upon high frequency (10 Hz or greater) repetitive nerve
stimulation. EMG may be consistent with acute denervation,
with fibrillations, positive sharp waves, and a reduced recruit-
ment pattern, or may have more typically myopathic features
of small, polyphasic motor unit potentials and an early recruit-
ment pattern. Treatment, however, should not be delayed
when awaiting diagnostic testing results: human botulinum
antitoxin (BabyBIG) should be requested from the California
Department of Public Health, and given to the child as soon as
the diagnosis is suspected. BabyBIG treats only subtypes A
and B, by far the most common, but occasionally equine hep-
tavalent antitoxin (covers all subtypes, A-G) is necessary once
stool toxin results return.72 BabyBIG shortens hospitalization
and time on mechanical ventilation, and is cost effective.73
Prognosis for affected infants is excellent with prompt sup-
portive care and treatment.
Focal Weakness
Brachial Plexus Injury
The most common acquired brachial plexus injury is the Erg-
Duchenne palsy,74 often resulting from shoulder dystocia.
This upper brachial plexus injury may be due to stretching
the parts of the plexus deriving from the C5 and C6 roots
when the infant’s head and neck are stretched away from the
shoulder. The common pattern of weakness with this injury
manifests as arm adduction (deltoid and supraspinatus weak-
ness), internal rotation (infraspinatus weakness), extension at
the elbow (biceps weakness), often with a “waiter’s tip” posi-
tioning of the wrist in flexion. In most cases, the injury recov-
ers spontaneously in the first 3 months with physical
therapy, but with more severe injuries, such as nerve root
avulsion, surgical intervention may be necessary. Still, even
in cases that appear severe at birth, diagnostic testing (EMG/
NCS and MRI) is typically deferred until the child is 3
months of age, as spontaneous recovery may still occur.75
Lower plexus injury, leading to a Klumpke palsy,76 is
much less common that the Erb-Duchenne palsy, and may
Neuromuscular Disorders of the Newborn
result from forced abduction of the arm that puts tension
especially on the portions of the plexus derived from C8 and
T1. The resulting palsy leads to elbow flexion (triceps weak-
ness) with wrist and finger flexion and a “claw hand.” If the
sympathetic neurons that emerge from the T1 nerve root are
injured, a Horner’s syndrome may be seen on the affected
side. In the most severe cases of birth injury, the entire bra-
chial plexus may be injured, resulting in a flaccid arm and
Horner’s syndrome.
Mononeuropathies
Mononeuropathies are relatively uncommon at birth, but
may include radial nerve palsy and facial nerve palsy. Injury
to the facial nerve77 can occur with forceps delivery or in
utero compression, causing mechanical trauma to the facial
nerve, and leading to an asymmetric crying facies, often
involving the upper and lower face. This is not to be con-
fused with absence of the depressor anguli oris,78 which
causes asymmetry in displacement of the lateral lips with cry-
ing, but does not affect the nasolabial fold or upper face.
Recovery from facial nerve injury may lead to Frey’s syn-
drome,79 where there is unilateral facial flushing and hyper-
hidrosis with eating, due to aberrant reinnervation of blood
vessels and sweat glands as the facial nerve recovers from
injury. M€ obius syndrome80 involves hypoplasia or absence
of the facial nerve, unilaterally or bilaterally, typically associ-
ated with ipsilateral abducens nerve hypoplasia, and some-
times impairment of other cranial nerves or limb
malformations.
Radial nerve injury has also been reported perinatally,81,82
associated with intrauterine constriction, prolonged pressure
on the arm during delivery, or rarely, fracture of the humerus.
Clinical manifestations include wrist drop and inability to
extend the thumb and metacarpophalangeal joints. Prognosis
is excellent, with complete recovery in most children.
Disorders Affecting the Central
and PNSs
A newborn may have symptoms and signs indicative of both
CNS and PNS dysfunction, which can make the localization
of weakness and hypotonia a challenge. In the case of a child
with encephalopathy, seizures, or spasticity, which point to
CNS pathology, concurrent PNS disease should be consid-
ered especially when there is low muscle bulk, a proximal or
distal-predominant weakness pattern, hyporeflexia/areflexia,
or elevated creatine kinase. In some cases, a child may have a
rare genetic syndrome affecting the PNS, and coincidentally
develop hypoxic-ischemic encephalopathy from labor com-
plications. In others, a PNS disorder may lead to secondary
brain injury, as may occur from a prolonged apnea related to
neuromuscular weakness (congenital myopathies and myas-
thenic syndromes). Finally, there are conditions that impair
function of both CNS and PNS tissues.83 These include
inborn errors of metabolism, such as fatty acid oxidation
9
Table 3 Disorders Causing Both CNS and PNS Involvement
Motor neuron
 Acquired: Enterovirus encephalitis/acute flaccid myelitis
 Hereditary: Spinal muscular atrophy with pontocerebellar
hypoplasia, SMA with progressive myoclonic epilepsy
(ASAH1 deficiency)
Peripheral nerve
 Lysosomal storage diseases (eg, Krabbe, metachromatic
leukodystrophy, Farber’s)
 Congenital disorder of glycosylation, type 1a
 Peroxisomal diseases (Infantile Refsum’s, Zellweger’s dis-
ease)
 Hypomyelinating neuropathy (SOX10)
 Giant axonal neuropathy, infantile neuroaxonal dystrophy,
cerebral dysgenesis, neuropathy, ichthyosis, and palmo-
plantar keratoderma (CEDNIK), congenital disorder of
deglycosylation (NGLY1)
 Andermann syndrome
 Hereditary sensory and autonomic neuropathy, type 4;
Navajo sensory and autonomic neuropathy with
arthropathy
Neuromuscular junction
 Congenital myasthenic syndromes: SNAP25, DPAGT1,
ALG2, ALG14, GMPPB, GFPT1
Myopathy
 Congenital myotonic dystrophy
 Congenital Pompe disease (acid maltase deficiency)
 Congenital muscular dystrophy (alpha-dystroglycanop-
athy, LAMA2 deficiency)
 Inborn errors of metabolism (mitochondrial, fatty acid oxi-
dation disorders)
 Marinesco-Sjogren syndrome
 22q11.2 deletion with absent depressor anguli oris
disorders and mitochondrial disorders, which often affect
both brain and muscle. Congenital muscular dystrophies,
particularly alpha-2-laminin (merosin) deficiency and the
alpha-dystroglycanopathies, affect both the brain and mus-
cle, as do myotonic dystrophy and Pompe disease. The lyso-
somal storage and peroxisomal disorders, such as Krabbe
disease and infantile-onset Refsum disease, can be associated
with CNS white matter abnormalities and demyelinating
peripheral neuropathy. Table 3 lists examples of diseases that
cause both CNS and PNS dysfunction. Brain MRI is recom-
mended as part of the work-up for most children with con-
genital hypotonia to evaluate for CNS pathology, and
hypotonic infants should also be tested for inborn errors of
metabolism. Further work-up for suspected PNS disease is
discussed in the next section.
Diagnostic Approaches to
Neuromuscular Disorders
 Check CK: Marked elevation is indicative of a muscular
dystrophy
 EMG/NCS helps to localize, especially to motor neu-
ron, peripheral nerve, NMJ
10
 Genetic testing by single gene (SMA), panel (most
muscle, NMJ, and nerve diseases), or whole exome/
genome is replacing muscle biopsy, which is neverthe-
less still helpful in challenging cases
The PNS differs from the CNS in that it can be directly
and readily studied with electrophysiological techniques
and tissue biopsy. Electrophysiology for myasthenia and
muscle biopsy for immune myopathies, for example, is
still mainstays in diagnosis. EMG/NCS is an uncomfort-
able test at any age and is often challenging in newborns
because the signal amplitudes are smaller than those of
older children (a problem that is compounded by electri-
cal noise in intensive care unit settings) and the difficulty
in coaxing a young child to activate muscles during
EMG. Still, in certain settings, such as congenital myas-
thenic syndromes, demyelinating and axonal neuropa-
thies, and motor neuron diseases, even a limited study
may provide critical diagnostic information. In the setting
of a marked creatine kinase elevation (>5£ upper limit
of normal), however, EMG may be unnecessary, as the
laboratory value is already suggestive of an irritable
myopathy. Although muscle biopsy was once the main-
stay of diagnosing congenital myopathies and congenital
muscular dystrophies, this invasive procedure is no lon-
ger essential in all cases, with the availability of genetic
testing. With the growing use of ultrasound and MRI in
the diagnosis of inherited myopathies, imaging may pro-
vide enough information to make muscle biopsy unneces-
sary in some instances.
Newborn screening for spinal muscular atrophy is
already available in some states, and is being considered
for Pompe disease,84 as well. Gene panels are available
from many companies that cover most of the genes
known to be associated with inherited muscle and
peripheral nerve diseases.85 Comparative genomic hybrid-
ization/single nucleotide polymorphism arrays should be
considered if panel testing is negative, or if multiorgan
involvement or dysmorphic features (beyond those
explained by muscle weakness) are present. If gene panel
testing is negative, or if the child’s phenotype does not
seem to fit known phenotypes, whole exome sequencing
should be obtained, ideally along with at least 2 other
first degree relatives (a “trio,” to aid in filtering out non-
pathogenic polymorphisms). It may be reasonable to rec-
ommend muscle biopsy in the case of a negative gene
panel or whole exome sequencing, in order to establish a
diagnosis. Whole genome sequencing is currently per-
formed mostly on a research basis, though its availability
and yield can be expected to increase as costs come
down and more labs become comfortable with the inten-
sive data analysis. There have been some notable suc-
cesses in using whole genome and transcriptome
sequencing to identify intronic mutations in collagen VI,
titin, and other muscular dystrophy-associated genes.86
A.J. Fay
Current and Emerging
Therapeutics
The developments of nusinersen and gene therapy for spinal
muscular atrophy mark the forefront of therapeutics for neu-
romuscular diseases, but targeted therapies are under devel-
opment for many other conditions. Examples include
antisense oligonucleotide-mediated exon skipping for Duch-
enne muscular dystrophy (currently with conditional FDA
approval for exon 51 skipping), gene therapy for centronu-
clear myopathy (MTM1) and giant axonal neuropathy, and
CRISPR/Cas9-based gene editing87 studies for many disor-
ders, currently in the preclinical phase. Rapid developments
in therapeutics highlight the importance of achieving a pre-
cise genetic diagnosis for children with suspected inherited
neuromuscular disorders, as this will determine eligibility for
current and future clinical trials and treatments. This is a
hopeful and exciting time, with the expectation that the next
decade will bring more therapeutics that will transform life-
limiting and disabling disorders of the PNS into treatable
conditions.
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