Neonatal Hypotonia

Elissa Yozawitz, MD,*† Leslie Delfiner, MD,*† Solomon L. Moshé, MD*†‡

*Saul R. Korey Department of Neurology, †Department of Pediatrics, ‡Dominick P. Purpura
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY

Education Gaps
1. Clinicians should recognize that generalized hypotonia is a common clinical
presentation in the neonate that may be a manifestation of systemic illness,
central nervous system dysfunction, or peripheral nervous system dysfunction.
2. With the introduction of newer therapeutic modalities, some of the causes
of neonatal hypotonia are now treatable. Therefore, recognizing
symptoms and pursuing appropriate and timely evaluation may positively
affect outcomes.
3. An understanding of the localization-based differential diagnosis is
important in the approach to the evaluation of these infants.

AUTHOR DISCLOSURE Drs Yozawitz and

Delfiner have disclosed no financial
relationships relevant to this article. Dr Moshé Abstract
is the Charles Frost Chair in Neurosurgery and
Neurology and is partially funded by grants Neonatal hypotonia represents a commonly encountered issue in the NICU
from the NIH (U54 NS100064 and NS43209),
US Department of Defense (W81XWH-13-1- and newborn nursery. Low tone is not a diagnosis in itself but, rather, a
0180), CURE Infantile Spasms Initiative, symptom. This review focuses on the special case of diffuse hypotonia
the Heffer Family and the Segal Family
presenting in the neonatal period. Etiologies are broad and include systemic
foundations, and the Abbe Goldstein/Joshua
Lurie and Laurie Marsh/Dan Levitz families. He illness, dysfunction of the central nervous system, or dysfunction of the
is serving as associate editor of Neurobiology peripheral nervous system and motor unit (ranging from disorders of the
of Disease and is on the editorial board of Brain
and Development, Pediatric Neurology, and anterior horn cell to primary muscle disease). In this time of rapidly expanding
Physiological Research. He receives annual therapeutic options for many diagnoses causing hypotonia, expeditious
compensation from Elsevier for his work as
evaluation is crucial. Careful physical examination, thorough history, and
associate editor for Neurobiology of Disease
and royalties from 2 books he has coedited. appropriately selected ancillary testing guides the diagnostic process.
He receives consultant fees from Eisai,
Mallinckrodt, and UCB. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
Objectives After completing this article, readers should be able to:

1. Describe the key components of the history and physical examination

ABBREVIATIONS
CK creatine kinase relevant to the assessment of the hypotonic infant.
CMS congenital myasthenic syndrome
2. Discuss the differential diagnosis of generalized hypotonia in the neonatal
CMT Charcot-Marie-Tooth neuropathy
CNS central nervous system
period.
EMG electromyography 3. Identify major treatable causes of neonatal hypotonia that should not be
HIE hypoxic-ischemic encephalopathy
MRI magnetic resonance imaging
missed.
PNS peripheral nervous system
SMA spinal muscular atrophy
WES whole exome sequencing

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 INTRODUCTION histories provide critical information that can help narrow
the differential diagnoses.
The classic “floppy baby” represents a challenging clinical
scenario for pediatricians and child neurologists alike.
Although spasticity generally indicates dysfunction at the PHYSICAL ASSESSMENT OF THE NEONATE
level of the brain or spinal cord, low tone in an infant is a
The neurologic examination of a neonate is a complex task.
nonspecific sign that is not localizing. Hypotonia may be a
Observation is a key aspect of the physical examination.
manifestation of systemic illness, central nervous system
Although the approach to examination is the same when
(CNS) dysfunction, or peripheral nervous system (PNS)
assessing for generalized or focal hypotonia, we will focus
dysfunction. Within the category of PNS dysfunction, cli-
specifically on the diffusely floppy neonate.
nicians must consider disorders of the anterior horn cell,
The presence of dysmorphic facial features or other
peripheral nerve, neuromuscular junction, or muscle. Addi-
general examination features, including organomegaly, micro-
tional causes include systemic conditions such as meta-
cephaly, skin abnormalities, and early joint contractures or
bolic disorders, infection, hypothyroidism, and chromosomal
arthrogryposis, may suggest multisystem involvement. The
anomalies. The differential diagnosis evolves as the infant
mental status will inform the differential diagnosis and guide
ages. This review focuses on the evaluation of diffuse hypo-
further evaluation. Recognition of a sleepy, encephalopathic
tonia in the neonatal period, considering first systemic
newborn should trigger an evaluation for systemic illness
involvement, CNS dysfunction, and finally PNS dysfunction.
such as infection, metabolic derangement, hypoxic-ischemic
At first glance, a neonate with an epileptic encephalop-
encephalopathy (HIE), or some other process causing diffuse
athy may be indistinguishable from a neonate with a con-
CNS dysfunction. A diagnosis of HIE is more likely if the
genital myopathy. These 2 infants (and families), however,
history indicates that there was an acute perinatal or intra-
require different care and counseling. The clinical history
partum event. Because infants are more sedated after they
and examination findings narrow the differential diagnosis
eat, the physical examination should also mention when they
and guide further evaluation. With careful assessment and
were examined in relation to a feeding.
use of appropriate ancillary testing, clinicians can often
Certain physical examination features aid in the locali-
identify the etiology of the hypotonia. In a time of rapidly
zation of muscle weakness. Evaluation of facial strength
expanding treatment opportunities, accurate and timely
(grimace, ability to fully bury eyelashes), ability to suck and
diagnosis is crucial. This is perhaps best exemplified by
swallow, strength of cry/cough, and eye movements serve to
the development of a new therapy for spinal muscular
evaluate bulbar function. Prominent abnormality in one of
atrophy (SMA), a previously untreatable and life-limiting
these functions may suggest a neuromuscular or multisys-
disorder in its infantile form. (1)(2) An organized, system-
tem disorder, though these abnormalities can be found in
atic approach to evaluation aids the diagnostic process.
CNS dysfunctions as well.
Here, we review a localization-based differential diagnosis
The examiners should also observe the complexity of
for the diffusely floppy infant. An overview of this approach
movements. This serves as an assessment of neurologic
is summarized in the Fig.
maturity. Normal patterns consist of a variable sequence of
movements involving the arms, legs, and trunk. (3) Typical
movements should be asynchronous and involve all extrem-
OBTAINING THE HISTORY
ities. Movements should not be asymmetric and should not
A careful perinatal and birth history helps guide the eval- occur en bloc. Signs of pathology and hypotonia would be
uation. It is important to inquire about the frequency, as well suggested if the movements are not complex or variable in
as any changes, in fetal movements during the pregnancy. nature. The lack of movements is correlated with the degree
The history should also include the patient’s gestational age, of hypotonia.
Apgar scores (because appropriate tone varies based on Tone is defined as the internal state of the muscle (tone is
gestational age), and medications prescribed to the patient. fiber tension within individual muscles and muscle groups),
The Apgar score and delivery history aid in determining if or the degree of muscle tension or resistance during rest in
the hypotonia is an acute or semiacute process, and if there response to stretching. Both postural (central) and periph-
was any clear precipitating event. Knowledge of maternal eral tone must be assessed. It is therefore necessary to assess
serologic testing and infectious exposures (eg, exposure to pronation/supination to bypass the flexor predominance in
varicella, cytomegalovirus, or Zika virus) may raise suspi- the neonatal period. It is important to observe the infant
cion for a congenital infection. Maternal and family medical when the head is in the midline position; this prevents

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 Figure. An approach to a neonate with generalized hypotonia. CNS¼central nervous system; CK¼creatine kinase; HIE¼hypoxic-ischemic
encephalopathy; PNS¼peripheral nervous system. 1Loss of anal sphincter tone or wink is not specific for spinal cord dysfunction and may also be
abnormal in some PNS disorders such as myotonic dystrophy.

activation of the tonic neck reflex, which would cause a false gestationally mature counterparts, such that gestational age
asymmetry in tone. The normal resting posture of a healthy must be taken into account when judging tone.
newborn is characterized by flexion in the arms and legs. Assessing motor function of the arms and legs begins
The hypotonic infant may be placed with arms in extension with passive range of motion in the full-term infant. The
and hips in abduction (“frog leg posture”). Manual muscle examiner should rotate each joint to feel the resistance and
strength cannot be tested in a neonate. the range of motion. Assessment of arm supination and
Axial tone is assessed by evaluating for head lag and slip pronation allows for evaluation without misinterpretation of
through. To assess head lag, the infant is placed supine and the normally predominant flexor tone seen in newborns.
pulled by the arms to the sitting position. If the infant has Arm recoil is tested by holding the arms in flexion for a
neurologically normal examination findings, the arms will few seconds then quickly extending and releasing the
remain partially flexed at the elbows. The infant’s head arm. The arm should return to the original flexed posi-
should lag behind the body but should not be fully flexed tion. Similarly, assessment of leg recoil starts with flexion
backward. Vertical suspension should allow for the infant to of the legs onto the abdomen for a few seconds. One can
be held by the examiner under the arms and around the also measure the popliteal angle (the angle between the
chest without the infant “slipping through” his/her hands. thigh and the leg), which is typically 90 degrees. A wider
Premature neonates are expected to have lower tone than angle suggests hypotonia.

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 Tone of the shoulder girdle is evaluated by moving the type 2) represents a now treatable disorder. Severely affected
infant’s hand to the opposite shoulder. In a neurologically infants can present in the neonatal period with hypotonia,
appropriate infant, the infant’s hand does not pass the cardiomyopathy, and hepatomegaly. Treatment with enzyme
shoulder and the infant’s elbow cannot cross the midline replacement improves ventilator-free survival and leads to
of the chest. The “scarf sign” is defined by the hand reaching improvements in cardiac function, though there have been
past the shoulder, an indication of hypotonia in a full-term no randomized controlled trials with placebo to firmly estab-
infant. (4) lish long-term benefits. (6) In addition to Pompe disease,
The reflexes being normal, increased, or absent can help other metabolic disorders that present in the neonatal period
distinguish between an upper motor versus a lower motor include peroxisomal disorders (Zellweger syndrome), mito-
neuron lesion. Reflexes should be tested after the assess- chondrial cytopathies, and disorders of creatine metabolism.
ment in tone to avoid upsetting the infant and falsely Organic acidurias, amino acidopathies, fatty acid oxidation
increasing the tone. Hyperreflexia may be characterized disorders, and urea cycle defects may present early as well.
by pathologic spread of reflexes (eg, finger flexion on test- Infants with inherited metabolic disorders are often medically
ing of the brachioradialis reflex) or sustained clonus. This sick, and laboratory abnormalities can help further direct the
suggests upper motor neuron dysfunction related to a pro- evaluation. Although statewide newborn screening can help
cess affecting the brain or spinal cord. Asymmetry of identify many of the treatable inherited metabolic disorders,
reflexes indicates a focal process. Asymmetric hyperreflexia panels vary among states and the results are not immediately
may indicate a focal lesion of the CNS, whereas asymmetric available. Clinical concern for a metabolic disorder warrants
hyporeflexia may reflect injury of a nerve root or plexus. immediate evaluation in the NICU.
In addition to the deep tendon reflexes, newborn reflexes
should be tested. These include the Moro reflex, tonic neck Central Nervous System
reflex, and withdrawal reflex. It is helpful to recognize the Brain. Clinical signs to suggest central hypotonia include
infant’s gestational age to determine which reflexes are encephalopathy, seizures, dysmorphic features, multiorgan
expected to be present. The palmar grasp and Moro reflex abnormalities, hyperreflexia, or known genetic/chromo-
first appear at 28 weeks’ gestation, though they are weak. somal abnormalities. A careful history may also aid in the
The asymmetric tonic neck reflex, stepping reflex, and a diagnosis. Pregnancy history should assess for complica-
stronger sucking reflex emerge at 34 weeks’ gestation. The tions including decreased fetal movements, polyhydram-
healthy term infant has a strong grasp, full Moro reflex, and nios, maternal exposures (drugs and infections), and
placing reflex. gestational age. The delivery history must include type of
By identifying signs and patterns that accompany hypo- delivery, Apgar scores, and need for resuscitation. Evidence
tonia, a tailored differential diagnosis can be developed. of hypoxia and low Apgar scores are suggestive of HIE.
Several entities are associated with an acute injury that
can have hypotonia as a prominent feature, such as HIE.
LOCALIZATION-BASED ASSESSMENT OF HYPOTONIA
HIE is a clinical syndrome that evolves after an acute
Multisystem and Systemic Disorders peripartum or intrapartum event, resulting in disruption
Hypotonia does not imply a purely neurologic disorder. The of the fetoplacental circulation and subsequent decreased
triad of areflexia, hypotonia, and weakness in a neonate is brain perfusion. Clinical findings include cardiorespiratory
not specific to a single class of disease and can localize failure, altered sensorium, hypotonia, poor feeding, and/or
throughout the motor unit. Abnormally low tone and weak- seizures. (7) This is one of the first diagnoses to consider
ness can be a manifestation of systemic illness or a chro- when there is a history of hypoxia, acidemia, and low Apgar
mosomal anomaly. Change in tone may be a heralding sign scores. We often characterize this as a brain disease, but it is
of sepsis in a neonate. Exposure to drugs/medications a multisystem effect of global hypoxia that results in hypo-
should also be considered. For example, an infant born to a tonia. Physical examination, blood gas, and head ultraso-
mother treated with magnesium sulfate for preeclampsia nography may be used to assess the severity of the cerebral
may display hypotonia at birth that improves over time. edema. In the first 10 days after birth, several distinct
Profound hypotonia in an infant without other signs of imaging patterns of brain injury have been identified in
systemic illness should prompt consideration of Prader affected infants. Typical patterns of injury involve motor
Willi syndrome. (5) Inborn errors of metabolism deserve tracts and may have long-term sequelae on muscle tone.
consideration as well. The early infantile form of Pompe Such areas affected include the deep gray matter (basal
disease (acid maltase deficiency, glycogen storage disease ganglia and thalamus), hippocampus, brainstem, watershed

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 areas, and mixed patterns. (8)(9) At birth, the infant is of myelomeningocele is the lumbosacral region and is
typically floppy and encephalopathic. Clinically, loss of associated with segmental hypotonia. The lumbosacral me-
muscle tone is an immediate response to severe brain ningomyelocele affects bladder and bowel function with
injury. Depending on the site, extent of injury, and age of partial or complete paralysis of the legs. Infants who have
the infant, increased tone appears as hemiplegia or quad- a sacral dimple larger than 5 mm in diameter, located more
riplegia in the term infant and diplegia in the preterm than 2.5 cm above the anal verge, or associated with cuta-
infant. These deficits are typically permanent and nonpro- neous findings, should undergo further evaluation. Myelo-
gressive. Therapeutic hypothermia is now the standard of meningocele repair is traditionally performed within 72
care for term and near-term infants with moderate to severe hours of birth to minimize the risk of meningitis.
HIE.
Intracerebral and intraventricular hemorrhage may also Disorders of the Motor Unit: From Anterior Horn Cell to
affect the infant’s muscle tone depending on the severity/ Muscle Fiber
extent of the bleeding. Intraventricular hemorrhage with Disorder of the Anterior Horn Cell. A previously untreatable
periventricular leukomalacia can be seen in premature neurodegenerative disorder, SMA deserves special atten-
infants. Such injury can be associated with motor and tion. In its classic form, SMA is an autosomal recessive
cognitive deficits depending on the location and extent of disorder caused by loss (or less commonly mutation) of both
the injury. copies of the SMN1 gene. Severity of the clinical presenta-
Cerebrovascular accidents (ischemic or hemorrhagic) can tion is determined by the copy number of SMN2, a rescue
occur perinatally and lead to focal brain lesions that can protein; patients with fewer copies of SMN2 display a more
cause asymmetry/abnormality on an infant’s motor exam- severe phenotype.
ination. The infant may present with generalized hypotonia Infantile-onset SMA (type 1 SMA, Werdnig-Hoffman
or focal weakness depending on the size and location of the disease) may present in the early neonatal period with
lesion. Such an infant may demonstrate an asymmetry in hypotonia, areflexia, poor suck/feeding, or respiratory weak-
tone that can ultimately result in lateralized signs of upper ness. Arthrogryposis should also prompt consideration of
motor dysfunction, such as hemiparesis, over time. Alter- this diagnosis. Mental status is unaffected unless a second-
natively, these infants may remain asymptomatic during the ary issue is at play, such as hypercarbia in the setting of
first few months of age. Development of early hand prefer- respiratory failure. Examination reveals hypotonia, weak-
ence during the first year after birth, seizures, or both, may ness, and areflexia. Fasciculations of the tongue may or may
be the first sign of their impairment. not be present initially. Bulbar dysfunction may be prom-
Other conditions that can present with hypotonia (often inent. Respiratory weakness may manifest as tachypnea,
without evidence of an acute injury) include malformations increased work of breathing, or even paradoxical breathing.
in cortical development. These are often caused by disrup- (10) It should also be noted that infants often present beyond
tion of neuronal proliferation, neuroblast migration, and the neonatal period, after an initial honeymoon phase in the
neuronal organization. Resulting abnormalities include first weeks to months of age; a neonate born to 2 parents
microcephaly, megalencephaly, cortical dysplasia, periven- known to be carriers of SMA should still be tested after birth
tricular heterotopia, lissencephaly, or band heterotopia that even if examination findings are normal. In fact, SMA can
can be seen on magnetic resonance imaging (MRI) of the present throughout the lifespan.
brain. (8) Clinically, these patients present with hypotonia With the advent of treatment for SMA, this has become a
and difficulty feeding. Genetic testing should be performed “do not miss” diagnosis. Nusinersen, an antisense oligo-
to aid in prognosis and family planning. nucleotide, became available in late 2016. This intrathecal
Spine. Spinal cord dysfunction should be suspected in therapy allows for production of more full-length SMN
severely hypotonic infants with paraplegia with hyper- or protein by altering transcription of the SMN2 gene. (11)(12)
hyporeflexia and bowel/bladder dysfunction (abnormalities Treated infants have been found to have clinically signifi-
in rectal tone). Spinal cord trauma caused by a contusion or cant improvement in motor milestones and in ventilator-
transection of the cord is rare in infants but can lead to free survival. Clinical trials are also under way for single-dose
severe sequelae. Other causes include a spinal cord tumor, gene therapy using an adeno-associated viral vector; phase I
paraspinal infection, syrinx, or spinal dysraphism including studies are encouraging. (13) Currently, a phase III trial is
a myelomeningocele of the distal spinal cord and spinal under way and actively enrolling patients.
column. Lesions in the cervical area may present with Without treatment, type 1 SMA leads to loss of motor mile-
generalized hypotonia early in life. The most common site stones and either death or need for mechanical ventilation

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 by 2 years of age. With newer therapies, the clinical course of findings in the infant may be nonspecific, examination of
this disease is now forever changed. Rapid diagnosis and the mother may be useful; fluctuating, alternating ptosis,
initiation of treatment is crucial to improve outcomes, such facial weakness, or fatigable extremity weakness may point
that diagnosis of SMA in a newborn should be considered a toward this diagnosis. Treatment of the infant with acetyl-
neuromuscular emergency. Genetic testing is readily avail- cholinesterase inhibitors (pyridostigmine), respiratory sup-
able and can be quickly performed so as to expedite initi- port, and feeding support may be necessary until symptoms
ation of treatment. begin to improve. Transient neonatal myasthenia has even
Disorders of Peripheral Nerve including Congenital been reported in mothers with seronegative myasthenia
Hypomyelinating Neuropathy and Hereditary Sensory and gravis. (17) Rare cases of arthrogryposis have also been
Autonomic Neuropathies. Hereditary neuropathies can pre- described in infants born to women with myasthenia. (18)
sent in the neonatal period. The classic example of this is a Congenital myasthenic syndrome (CMS) represents a
congenital hypomyelinating neuropathy and the more com- separate entity. (19) This group of disorders represents
monly known Dejerine-Sottas disease, both considered sub- inherited/genetic defects of neuromuscular transmission
types of Charcot-Marie-Tooth neuropathy (CMT). Although caused by a mutation in genes responsible for the neuro-
many genes have been implicated in the various forms of muscular junction (presynaptic, postsynaptic, or synaptic).
hereditary neuropathy, PMP22, MPZ, and ERG2 are the most Multiple genes have been implicated in CMS. Children
commonly involved causative genes in the neonatal forms of affected by CMS can present in childhood or as early as
CMT neuropathy. (14). Although CMT can be inherited in an the newborn period. Features such as (fluctuating) ptosis,
autosomal dominant or recessive manner, mutations are also bulbar dysfunction, and weakness can make this class of
often spontaneous in infantile-onset cases. In addition to disorder challenging to differentiate from other neuromus-
hypotonia and weakness, bulbar dysfunction and respiratory cular causes of hypotonia. Repetitive nerve stimulation can
weakness may be prominent. Early contractures or even be useful but is nonspecific, and may be abnormal in other
arthrogryposis may be seen. (14)(15) A hypotonic, areflexic conditions such as mitochondrial disorders. Electromyog-
neonate with prominent dysautonomia should prompt con- raphy (EMG) may be misleading, because EMG findings can
sideration of a hereditary sensory and autonomic neuropathy appear myopathic in some cases. Careful clinical assess-
(including the Riley-Day syndrome). (14)(15) Electrodiagnos- ment paired with electrodiagnostics and genetic evaluation
tics may be of use when considering the rare possibility of a can help make this diagnosis. (19)(20) Like children and
hereditary neuropathy presenting very early in life. adults with autoimmune myasthenia gravis, precautions
Neuromuscular Junction. Dysfunction of neuromuscu- must be taken to avoid medications that may cause wors-
lar transmission can present in the neonatal period and ening of myasthenic symptoms.
includes transient neonatal myasthenia, the rare congenital Infantile botulism, a disorder of the presynaptic neuro-
myasthenic syndromes, and botulism. Neuromuscular muscular junction, does not usually present in the imme-
junction disorders can result from pathology at the pre- diate neonatal period. Onset of bulbar weakness with
synaptic, synaptic, or postsynaptic level. Regardless of eti- descending appendicular weakness and loss of reflexes
ology or localization within the junction, infants with these raises concern for this diagnosis in an infant. Loss of the
disorders can present with hypotonia, poor feeding, ptosis, pupillary light reflex is classic but not requisite. Constipa-
and respiratory weakness. tion may be an early sign. Consideration of this disorder
Transient neonatal myasthenia refers to the passively allows for early initiation of therapy (intravenous botulism
acquired, self-resolving disorder of infants born to mothers immunoglobulin; Baby-BIG). (21) Diagnosis may be sup-
affected by autoimmune myasthenia gravis. Transplacen- ported by electrodiagnostics and, if early in the course, stool
tally acquired antibodies cause postsynaptic impairment of testing; in some cases, empirical treatment may be consid-
neuromuscular transmission. Symptoms include ptosis, ered while test results are pending. (21)(22)
hypotonia, weak cry, bulbar weakness, and respiratory dif-
ficulty or failure. (16) Affected infants generally present Primary Disorders of Muscle
within the first 2 days after birth, though longer times to The differential diagnosis includes congenital myopathies,
onset have been reported. (17) congenital muscular dystrophies, congenital myotonic dys-
It should be noted that transient neonatal myasthenia has trophy, and multisystem disorders such as muscle-eye-brain
been diagnosed in infants born to mothers without pre- disease. Key features may provide clues to examiners about
existing myasthenia diagnosis, because myasthenia gravis subcategories of muscle disease, though there is significant
is an underrecognized disorder. Because the examination overlap (Table).

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 TABLE. The Overlapping Features of Primary Muscle Disease Presenting
in the NICU
CONGENITAL NEUROMUSCULAR CONGENITAL
MYOPATHY MUSCULAR DYSTROPHY JUNCTION DISORDER MYOTONIC DYSTROPHY

Hypotonia þ þ þ þ
Eye movement abnormality – Not commonly – –
Ptosis – – þ (not always) –
Bulbar dysfunction – – – –
Creatine kinase level Often normal Usually elevated (not always) Usually normal Can be elevated
Brain malformation or – – – –
hydrocephalus

The congenital myopathies are a heterogeneous group of disorder, categorized as a muscle disease, is actually a
disorders characterized by low tone, early muscle weakness, multisystem disorder. The congenital form is generally as-
and developmental delay. Facial weakness is often prom- sociated with more than 1,000 CTG repeats in the DPMK
inent. The creatine kinase (CK) level is usually normal. gene, inherited with anticipation and usually via the mother.
These disorders have traditionally been classified on a histo- (26) These neonates may have depressed mental status and
pathologic basis. Examples include core and centronuclear are at risk for both cerebral atrophy with ventriculomegaly
myopathies, congenital fiber-type proportion myopathies, and hydrocephalus. The cardiac manifestations in the neo-
and nemaline myopathies. (23) A long list of genes has been natal period include pulmonary hypertension and rarely car-
identified as causative in these disorders, and some genes diomyopathy; cardiac conduction abnormalities generally
have been found to be causative in more than 1 form of become a concern later in life. Examination of the parents
myopathy. Mutations in the RYR1 gene, for example, can cause (almost always the mother) may reveal distal hand/foot
both central core disease and centronuclear myopathy. weakness, facial weakness with an elongated face, and grip
(23)(24) Limitations in eye movement (external ophthalmo- and percussion myotonia. Clinical myotonia is absent in
plegia) may suggest centronuclear myopathy or multicore neonates. (26) Diagnosis is made with genetic testing.
disease. Diagnosis of these disorders can be approached with
a combination of genetic testing and, if needed, muscle
biopsy. DIAGNOSTIC TOOLS FOR ASSESSMENT
Elevated CK levels (hyper-CKemia) in a hypotonic infant
Ancillary testing can be useful when clinical examination
with early joint contracture may suggest a form of congen-
and history do not reveal a clear cause. Some of the available
ital muscular dystrophy, another broad category of pri-
diagnostic modalities are reviewed here.
mary muscle disease. These disorders can be variable in
presentation, but the phenotype is often severe. (25) They
usually have an autosomal recessive pattern of inheritance. Laboratory Studies
Consideration of these disorders is important, as clinical Acute hypotonia raises concern for infection. Standard cul-
trial opportunities may become available. Diagnosis can be tures (blood, urine, and cerebrospinal fluid) and laboratory
approached with a combination of genetic testing using studies are performed as part of the evaluation for infections.
commercially available panels and muscle biopsy. Biopsy General laboratory studies to consider in the evaluation
reveals dystrophic changes without the characteristic struc- of any hypotonic infant include thyroid function tests to
tural abnormalities seen in myopathies. (25) exclude hypothyroidism (a treatable disorder) and a screen-
Congenital myotonic dystrophy, a triplicate-repeat disor- ing CK level. CK levels may be elevated in congenital
der with autosomal dominant inheritance, should be con- muscular dystrophies, but normal serum CK levels do not
sidered in the evaluation of a profoundly hypotonic infant exclude another form of neuromuscular disorder. An ele-
who may have characteristic tenting of the upper lip, facial vated CK level may be repeated in case the original elevation
weakness, and an elongated facial/temporal atrophy. This was related to the birth process.

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 The possibility of an inborn error of metabolism may be are not monogenic in origin and genetic testing should be
supported by acidosis on basic chemistries, hyperammonemia, used in combination to further classify these disorders.
and persistent unexplained hypoglycemia. Further testing
may include quantitative testing of urine organic acids and Targeted Genetic Testing
serum amino acids to diagnose organic acidurias and amino In addition to chromosomal studies such as karyotyping,
acidopathies. An acylcarnitine profile can be used in the fluorescence in situ hybridization, and microarray-based com-
diagnosis of fatty acid oxidation disorders. A very long chain parative genomic hybridization, use of gene panels (usually via
fatty acid profile helps in the diagnosis of the peroxisomal next-generation sequencing and deletion/duplication screen-
disorders. ing when appropriate) may allow for more targeted diagnosis.
(29) Whole exome sequencing (WES) is also commercially
MRI of the Brain/Spine available and clinically useful in the evaluation of multisys-
Brain and spine MRI can exclude structural CNS etiolo- tem disorders; WES is now becoming a more commonly
gies of hypotonia if the clinical examination suggests CNS used tool. (30) Consultation with a geneticist is especially
localization. (8)(9)(27) Imaging is performed easily and important when WES is considered for diagnostic purposes,
noninvasively in the neonatal period, when it can be per- (7)(8) because testing may reveal other clinically important
formed without sedation. The challenge of interpreting genetic changes that may affect the patient later in life and
neonatal brain imaging should be mentioned. Brain myeli- influence the parents’ future family planning decisions.
nation begins in the fifth fetal month and continues until
2 years of age. The evolving appearance of the normal neo- CONCLUSIONS
natal brain on MRI should be taken into account when
assessing the findings. Hypotonia in the neonate should be considered a symptom
If a brain or spinal cord etiology is suspected, MRI of the and not a diagnosis in itself. Low tone may be a manifes-
brain or spine is performed to rule out structural lesions (ie, tation of systemic illness, dysfunction of the CNS, or a
HIE, malformation in cortical development, intracerebral disorder of the motor unit (from anterior horn cell through
hemorrhage, stroke, spinal cord tumor, paraspinal infec- the muscle fibers). In this time of rapidly expanding treat-
tion, a syrinx, or spinal dysraphism). (27) ment options for previously incurable disorders, efficient
and accurate diagnosis is paramount.
A focus on treatable etiologies is encouraged when creat-
EMG/Nerve Conduction Studies ing a differential diagnosis and plan of evaluation. Infection
Electrodiagnostics, if available, may be helpful in the assess- in an encephalopathic, floppy neonate is hopefully treatable
ment of the hypotonic infant, though these tests may not be and reversible, such that an opportunity should not be
available in every center. (28) Nerve conduction studies can missed. Metabolic disorders including urea cycle defects,
assess for hereditary neuropathies. Because the conduction organic acidurias, and amino acidopathies require treatment
velocity of peripheral nerves does not reach adult range until 3 with specialized diets to reduce morbidity and improve
to 5 years of age, involvement of a clinician experienced in developmental outcome in some cases. Acid maltase defi-
pediatric EMG/nerve conduction studies is important. Needle ciency (Pompe disease), a lysosomal storage disease, can be
electromyography can be used to distinguish between myo- treated with enzyme replacement, which has been found to
pathic (dystrophies, myopathies) and neurogenic (spinal mus- improve both motor and cardiac function, in addition to
cular atrophy) processes. Repetitive nerve stimulation or prolonging survival. (29) Finally, the case of SMA deserves
single-fiber EMG may also be useful in the consideration of highlighting. This unrelenting, neurodegenerative disorder
possible neuromuscular junction disorders. had been untreatable until recently; the newly available ther-
apies have significant clinical benefit and have changed the
Muscle Biopsy prognosis for patients with SMA. (13)(14)
Though less commonly performed in this age of readily In each of these treatable disorders, early initiation of ther-
available genetic testing, muscle biopsy plays an important apy improves outcome. Although the list of potential causes
role in the diagnosis of muscle disease. Congenital myop- for neonatal hypotonia is long and unwieldy, a thorough history
athies such as central core disease, centronuclear myopathy, and careful examination can significantly narrow the differ-
nemaline myopathy, and myotubular myopathy are charac- ential diagnosis and allow for a targeted, efficient evaluation.
terized by their unique pathologic findings on biopsy. Finally, a word of caution—infants in the NICU are
(23)(24) It should be noted that most of these disorders likely to require procedures under sedation at some point.

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 Neuromuscular precautions for anesthesia are recom- 9. Barkovich AJ, Westmark K, Partridge C, Sola A, Ferriero DM.
Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J
mended when caring for infants with suspected muscle
Neuroradiol. 1995;16(3):427–438
disease. All patients with muscle disease may be susceptible
10. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular
to complications such as rhabdomyolysis when exposed to atrophy. Orphanet J Rare Dis. 2011;6:71
certain anesthetic agents, and the possibility of myopathy/ 11. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset
dystrophy should be shared with the anesthesiology team so spinal muscular atrophy with nusinersen: a phase 2, open-label,
that appropriate precautions can be taken. dose-escalation study. Lancet. 2016;388(10063):3017–3026
12. Finkel RS, Mercuri E, Darras BT, et al; ENDEAR Study Group.
Nusinersen versus Sham Control in Infantile-Onset Spinal
Muscular Atrophy. N Engl J Med. 2017;377(18):1723–1732
American Board of Pediatrics
13. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement
Neonatal-Perinatal Content therapy for spinal muscular atrophy. N Engl J Med.
Specifications 2017;377(18):1713–1722

• Know the normal integrated (primitive) reflexes that are present 14. Amato A, Russell J. Charcot-Marie-Tooth disease and other related
disorders. In: Neuromuscular Disorders. 2nd ed. New York, NY:
in the newborn infant (such as Moro, tonic neck, rooting, and
McGraw-Hill Education; 2016;chap 11
grasping) and their maturation.
15. Landrieu P, Baets J. Early onset (childhood) monogenic
• Know how a newborn infant’s posture, spontaneous activity, and neuropathies. Handb Clin Neurol. 2013;115:863–891
elicited movements are influenced by postmenstrual age and
16. Peragallo JH. Pediatric myasthenia gravis. Semin Pediatr Neurol.
neurologic status.
2017;24(2):116–121
• Identify the various maneuvers used to evaluate active and 17. Townsel C, Keller R, Johnson K, Hussain N, Campbell WA.
passive tone in newborn infants, and know how they change with Seronegative maternal ocular myasthenia gravis and delayed
maturation. transient neonatal myasthenia gravis. AJP Rep. 2016;6(1):e133–e136
• Know the significance of persistent neuromotor abnormalities in 18. Midelfart Hoff J, Midelfart A. Maternal myasthenia gravis: a cause for
infancy (including asymmetries). arthrogryposis multiplex congenita. J Child Orthop. 2015;9(6):433–435
• Recognize normal deep tendon reflexes (DTRs) in newborn 19. Beeson D. Congenital myasthenic syndromes: recent advances.
infants, including unsustained clonus. Curr Opin Neurol. 2016;29(5):565–571

• Know the basis for (including genetic), clinical and laboratory 20. Engel AG, Shen XM, Selcen D. The unfolding landscape of the
congenital myasthenic syndromes. Ann N Y Acad Sci.
features (including associated abnormalities), differential diagnosis,
2018;1413(1):25–34
management, and outcomes of neonatal hypotonia/neuromuscular
21. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL.
weakness.
Human botulism immune globulin for the treatment of infant
botulism. N Engl J Med. 2006;354(5):462–471
22. Amato A, Russell J. Other disorders of neuromuscular
transmission. In: Neuromuscular Disorders. 2nd ed. New York, NY:
References McGraw-Hill Education; 2016; chap 26
1. Gillingwater TH. Dawn of a new therapeutic era for spinal muscular 23. Mah JK, Joseph JT. An overview of congenital myopathies.
atrophy. Lancet. 2016;388(10063):2964–2965 Continuum (Minneap Minn). 2016;22(6, Muscle and
2. Groen EJN, Talbot K, Gillingwater TH. Advances in therapy for Neuromuscular Junction Disorders):1932–1953
spinal muscular atrophy: promises and challenges. Nat Rev Neurol. 24. Sparks SE, Quijano-Roy S, Harper A, et al. Congenital myopathy
2018;14(4):214–224 overview. GeneReviews. https://www.ncbi.nlm.nih.gov/books/
3. Einspieler C, Prechtl HF. Prechtl’s assessment of general movements: NBK1291/. Accessed May 1, 2018
a diagnostic tool for the functional assessment of the young nervous 25. Schorling DC, Kirschner J, Bönnemann CG. Congenital muscular
system. Ment Retard Dev Disabil Res Rev. 2005;11(1):61–67 dystrophies and myopathies: an overview and update.
4. Dubowitz LM, Dubowitz V, Goldberg C. Clinical assessment of Neuropediatrics. 2017;48(4):247–261
gestational age in the newborn infant. J Pediatr. 1970;77(1):1–10 26. Sansone VA. The dystrophic and nondystrophic myotonias.
5. Muralidhar B, Butler MG. Methylation PCR analysis of Prader-Willi Continuum (Minneap Minn). 2016;22(6, Muscle and
syndrome, Angelman syndrome, and control subjects. Am J Med Neuromuscular Junction Disorders):1889–1915
Genet. 1998;80(3):263–265 27. Sorantin E, Robl T, Lindbichler F, Riccabona M. MRI of the neonatal and
6. Chen M, Zhang L, Quan S. Enzyme replacement therapy for paediatric spine and spinal canal. Eur J Radiol. 2008;68(2):227–234
infantile-onset Pompe disease. Cochrane Database Syst Rev. 28. Pitt MC. Nerve conduction studies and needle EMG in very small
2017;11:CD011539 10.1002/14651858.CD011539.pub2 children. Eur J Paediatr Neurol. 2012;16(3):285–291
7. Fatemi A, Wilson MA, Johnston MV. Hypoxic-ischemic encephalopathy 29. Lalani SR. Current genetic testing tools in neonatal medicine.
in the term infant. Clin Perinatol. 2009;36(4):835–858, vii [vii.] Pediatr Neonatol. 2017;58(2):111–121
8. Sanyal S, Duraisamy S, Garga UC. Magnetic resonance imaging of 30. Smith LD, Willig LK, Kingsmore SF. Whole-exome sequencing and
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 NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://
www.aappublications.org/content/journal-cme.

1. Tone is defined as the internal state of the muscle (tone is fiber tension within individual NOTE: Learners can take
muscles and muscle groups), or the degree of muscle tension, or resistance during rest in NeoReviews quizzes and
response to stretching. Both postural (central) and peripheral tone are assessed during the claim credit online only
normal neurologic examination of the newborn. Which of the following is CORRECT when at: http://Neoreviews.org.
performing an assessment of tone in a newborn?
To successfully complete
A. The head position of the infant does not affect the examination. 2018 NeoReviews articles
B. It is necessary to assess pronation and supination to bypass the flexor pre- for AMA PRA Category 1
dominance in the neonatal period. CreditTM, learners must
C. In a neurologically intact term infant, the head is expected to be fully flexed demonstrate a minimum
backwards for 1 to 2 seconds during assessment of the head lag. performance level of 60%
D. Axial tone can be assessed by evaluating slip-through with the infant in horizontal or higher on this
suspension. assessment, which
E. A popliteal angle of 60 degrees is indicative of hypotonia in a term infant. measures achievement of
2. A 1-day-old male infant born at 39 weeks’ gestational age after an uncomplicated the educational purpose
pregnancy and delivery is transferred to your NICU for evaluation of generalized and/or objectives of this
hypotonia. Which of the following findings on your neurologic examination points to activity. If you score less
upper motor neuron dysfunction? than 60% on the
A. Inability to fully bury eyelashes. assessment, you will be
B. Asymmetric hyporeflexia. given additional
C. Abnormal arm recoil. opportunities to answer
D. Hyperreflexia. questions until an overall
E. The presence of a scarf sign. 60% or greater score is
achieved.
3. You are evaluating a 1-day-old infant born at 40 weeks’ gestational age for hypotonia. The
pregnancy was noted to be uncomplicated with good prenatal care. The infant was This journal-based CME
delivered via spontaneous vaginal delivery, and Apgar scores were 9 and 9. Your activity is available
examination reveals generalized hypotonia, areflexia, and poor suck. In addition, the infant through Dec. 31, 2020,
exhibits signs of respiratory distress with tachypnea, increase in work of breathing, and however, credit will be
paradoxical breathing. Which of the following is the most likely diagnosis? recorded in the year in
A. Congenital hypomyelinating neuropathy. which the learner
B. Transient neonatal myasthenia. completes the quiz.
C. Spinal muscular atrophy type 1.
D. Congenital myotonic dystrophy.
E. Congenital muscular dystrophy.
4. Transient neonatal myasthenia results from the postsynaptic impairment of
neuromuscular transmission by transplacentally acquired antibodies in infants born to
2018 NeoReviews now is
mothers affected by autoimmune myasthenia gravis. Symptoms include ptosis, hypotonia,
approved for a total of 10
weak cry, bulbar weakness, and respiratory difficulty or failure. What is the most common
Maintenance of
time of symptom onset in these neonates?
Certification (MOC) Part 2
A. Immediately after birth. credits by the American
B. Within the first 2 days after birth. Board of Pediatrics
C. Between 72 hours and 5 days after birth. through the ABP MOC
D. In the second week after birth. Portfolio Program.
E. At age 2 to 4 months. Complete the first 5 issues
or a total of 10 quizzes of
journal CME credits,
achieve a 60% passing
score on each, and start
claiming MOC credits as
early as May 2018.

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 5. Congenital myotonic dystrophy, a triplicate-repeat disorder, should be considered in the
evaluation of a profoundly hypotonic infant with tenting of the upper lip, facial weakness,
and an elongated facial/temporal atrophy. How is this condition inherited?
A. Autosomal dominant inheritance.
B. Autosomal recessive inheritance.
C. X-linked inheritance.
D. Maternal inheritance of mitochondrial DNA.
E. Genomic imprinting.

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