.Clinical Management.

H YPOTONIA IN THE INFANT IS

usually associated with dimin-
ished active movement in addition to
The Hypotonic Infant: The infant’s physical exam was
remarkable for a left-sided abdominal
protuberance secondary to in utero
unusual posture, decreased resistance Case Study of Central positioning with legs flexed up on
of the joints to passive movement, the right side of the abdomen. Baby
and/or increased range of joint move- Core Disease M’s hips were flexed with contrac-
ment.1 By observing the infant’s tone tures, although there was full range
and level of activity, the examiner can Val Castrodale, RNC, NNP of motion in her knees and arms.
begin to determine the suspected site Bilateral clubfeet and scoliosis were
of dysfunction. Accurate diagnosis and C OLUMN E DITOR also present. The infant had
evaluation of the hypotonic infant are Angela Carlson, RNC, ND, NNP decreased muscle tone, weak sponta-
critical to providing necessary medical neous movement, and decreased
intervention, rehabilitation, and family muscle mass. The cranial ultrasound
support and counseling. was normal. An abdominal ultrasound showed abnormal
Because the presentation of the “floppy infant” can be rotation of normal abdominal contents.
associated with a wide variety of disorders, determining the At about 20 hours of age, the infant began to experience
cause of hypotonia in the newborn can be challenging. The oxygen desaturation to 70 percent. Sedation, pharmacologic
etiology of hypotonia includes neuromuscular disorders, cen- paralysis, increased ventilator settings, and manual positive
tral nervous system dysfunction, sepsis, metabolic disorders, pressure ventilation produced no improvement. There was no
and congenital myopathies.1 evidence of a pneumothorax on the chest x-ray. Baby M was
In this case study, the congenital myopathy, central core placed on high-frequency oscillatory ventilation and showed
disease, is discussed. Although central core disease is often- slight improvement in oxygenation. Because her clinical
times not appreciated in the newborn period, there are rare course seemed consistent with severe pulmonary hypoplasia,
accounts of the disorder that present with marked hypotonia extra corporeal membrane oxygenation was not a considera-
and weakness and respiratory failure.2 tion. The infant continued to have difficulty over the next few
hours, and the parents were allowed to hold her on the venti-
CASE STUDY lator. Because of the futility of continued care, the parents
Baby M was a 3,095 gm Caucasian female delivered at 38 requested that support be withdrawn when her color deterio-
weeks estimated gestational age by scheduled cesarean section rated and she started to develop bradycardia. The infant was
secondary to breech presentation to a 29-year-old gravida 1, extubated and expired minutes later. The autopsy was signifi-
para 0 mother. The pregnancy was complicated by decreased cant for lungs at 30 percent of normal weight for gestational
fetal movement, noted since 26–28 weeks gestation. An ultra- age and for a 2 cm intussusception of the small bowel proxi-
sound done at that time showed fetal akinesia, a small thorax mal to the ileocecal valve, which was thought to be a recent
(2.5 percentile), and the lower extremities held in a fixed event and not a factor in the infant’s demise.
position. The amniotic fluid level was normal. At birth, the
baby had a weak cry and required bag-and-mask ventilation. CLINICAL EVALUATION
She was intubated in the delivery room for continuing Differential diagnoses for this infant include hypoxic
cyanosis. Apgars were 5 at one minute and 7 at five minutes. ischemic encephalopathy (HIE), spinal injury, spinal muscular
In the neonatal intensive care unit, the infant was atrophy (SMA), congenital myasthenia gravis, acid maltase
placed on the ventilator on synchronized intermittent deficiency, congenital muscular dystrophy, congenital
mandatory ventilation (SIMV) on 100 percent oxygen, myotonic dystrophy, and congenital myopathy.
with a pressure of 22/4 and a rate of 40 breaths per Identifying the location of the functional disturbance within
minute. Initial oxygen saturations were between 70 and 80 the central nervous system (CNS) or the motor unit can be
percent. The initial arterial blood gas showed a pH of helpful in making a differential diagnosis. Each motor unit
7.26, PaCO2 53, PaO2 52, and bicarbonate 24. The chest consists of a motor neuron, its peripheral nerve fiber, and the
x-ray showed extremely low lung volumes with a bell- muscle fibers connected with the motor neuron through the
shaped chest (Figure 1). Arterial and venous umbilical neuromuscular junction. Normal movement and tone depend
lines were placed for arterial blood sampling and intra- upon the coordination of CNS pathways innervating function-
venous access. Baby M received one dose of surfactant ing muscle units. Disturbances in function at distinct points
(4 ml/kg) via the endotracheal tube. Oxygen saturation along these pathways can present with characteristic features,
levels gradually began to improve to 95 percent. which can be identified through history and physical exam.3

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FIGURE 1 ■ Admission x-rays show near complete opacification of lung fields and asymmetry of the abdomen with protrusion of loops of
bowel to the left.
The pelvis has an unusual configuration, most likely associated with in utero positioning of the infant’s contracted hips.
It is believed that skeletal-muscle tone results from nerve
impulses coming from the spinal cord, which in turn are con-
trolled partly by transmissions from the brain to the appro-
priate motor neurons and by impulses located within the
muscle itself.4 Postural tone in the newborn is best evaluated
by performing the ventral suspension maneuver or the pull-
to-sit maneuver and noting the degree of head control and
head lag.3,5
Muscle weakness in the infant can be difficult to assess, but
it can be evaluated by observing the infant’s ability to raise
and sustain a limb against gravity and by noting the with-
drawal response of a limb to painful stimuli.1 If the neuro-
muscular disorder is a primar y myopathy, the muscle
weakness tends to be proximal in location. Proximal weak-
ness, as seen in Werdnig-Hoffman disease, presents as paraly-
sis in the arms with sparing of the antigravity movement in
the hands or forearms.1,6 In a denervating disease, such as
congenital hypomyelinating neuropathy, there is a distal
weakness in the extremities, greater in the legs than arms.3,6
Likewise, measurements of tendon reflexes in the new-
born can be misleading, but there are some consistent find-
ings that can be informative. Infants demonstrating
hypotonia and weakness with normal reflexes may have dis-
orders of the central nervous system. Tendon reflexes are
spared in diseases of the neuromuscular junction, but they
are absent in the severe form of spinal muscular atrophy.
Presence of the Moro reflex and the tonic neck reflex indi-
cates that the motor unit is intact. The Moro reflex is pre-
N E O N ATA L N E T WO R K
54
sent until around six months of age, and its absence sug-
gests significant central or motor unit involvement.1,3 Time
of onset of symptoms can also be important when deter-
mining the etiology of hypotonia. A rapid onset of symp-
toms may be indicative of an infectious or inflammatory
myopathy, whereas diseases such as muscular dystrophy,
metabolic myopathy, and neurogenic disorders may present
with a progressive, more insidious clinical course.6 A histo-
ry of polyhydramnios, which may occur when the fetus has
difficulty swallowing amniotic fluid, decreased fetal move-
ment, and the presence of fixed deformities of the feet and
hands, is characteristic of antenatal onset.1 A family history
of muscle disease can be helpful in diagnosing hereditary
disorders. Features in the parents such as late age of first
walking and other clinical characteristics can have impor-
tant value in diagnosing neonatal myasthenia gravis, con-
genital myasthenia gravis, congenital myotonic dystrophy,
and congenital myopathies.
LABORATORY FINDINGS
Creatine phosphokinase (CPK) is a serum enzyme that
exists in relatively few organs, with higher concentrations
found in heart and skeletal muscle.7 Significant elevations of
CPK can be indicative of active muscle destruction or inflam-
mation, and CPK levels are usually elevated in infants with
acid maltase deficiency and can be increased in infants with
congenital muscular dystrophy.1,8 CPK levels for Baby M
were within normal limits.
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 Motor nerve conduction and electromyo-
gram (EMG) testing are also valuable screening
tools that differentiate myopathic from neuro-
pathic weakness. 1 Accurate EMG testing in
infants is extremely difficult, and the value of
these results depends on the age of the infant
and the skill and experience of the technician.
The significant background noise in the NICU
can impair the quality of the results of this test.3
EMG results in infants with congenital myopa-
thy may be normal or nonspecific, and normal
findings on an EMG do not exclude neuro-
muscular disorders other than congenital
myopathy.1,9
A muscle biopsy is indicated in any infant sus-
pected of having a neuromuscular disorder and
is essential in the diagnosis of congenital
myopathies and muscular dystrophy. A needle
biopsy can be performed under local anesthesia
and should not include an area that was recently
needled by EMG or a site of intramuscular injec-
tions. The sample should be obtained from a
muscle in which the disease is active but not
severely involved. Delay of the biopsy beyond
the newborn period, if possible, can improve the
sensitivity of diagnosis in some disorders, such as
the mitochondrial myopathies.3,6,10
DIFFERENTIAL DIAGNOSIS
Supraspinal Hypotonia
Hypoxic Ischemic Encephalopathy. Infants
with HIE may present with severe hypotonia,
depressed reflexes, and transient weakness. They
usually demonstrate associated seizure activity,
involvement of other organs such as the kidneys
or heart, a depressed level of consciousness,
and a histor y of perinatal asphyxia. Acute
encephalopathy secondary to perinatal asphyxia
is associated with sustained low Apgar scores
and multisystem failure. In Baby M’s case,
Apgar scores were 5 and 7; there was no seizure
activity or involvement of other organ systems,
thereby excluding the diagnosis of HIE.
Spinal Injury. Spinal cord injuries usually
occur following intrauterine malpositioning or
traumatic birth, and the perinatal history is
informative in these cases.11 When spinal cord
injuries occur, the infant can demonstrate poor
muscle tone, flaccid weakness, respirator y
depression, generalized hypotonia, and absent
deep-tendon reflexes.12 Although Baby M was a
breech presentation, her delivery history and
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clinical course were not consistent with a spinal
cord injury.
Motor Unit Hypotonia
Spinal Muscular Atrophy. The hypotonia
seen in SMA, a disorder of motor neurons,
occurs as a result of the degeneration of spinal
cord anterior horn cells.9 This is the most com-
mon neuropathy seen in the newborn period,
with an overall incidence of 1 in 10,000 live
births.3 SMA Type I (Werdnig-Hoffman dis-
ease) is characterized by muscular atrophy pre-
senting with a bell-shaped chest, marked
paralysis of the legs, almost complete immobili-
ty, and lesser paralysis of the arms.13 Although
their respiratory reserve is low, these infants sel-
dom require resuscitation or ventilator
support. 1 Other subtypes of SMA are late,
infantile presentation (Type II) and childhood
lower neuron disease (Type III). All three types
are related to mutations of the spinal motor
neuron gene on chromosome 5.13
Confirmation of SMA may be obtained by
chromosomal analysis indicating a deletion of
either exons 7 or 8 in the survival motor neuron
gene.13 The chromosome study from Baby M
showed a normal female karyotype, excluding
SMA as a diagnosis.
Congenital Myasthenia Gravis
Congenital myasthenia gravis is a disorder of
the neuromuscular junction. These infants pre-
sent with generalized hypotonia and weakness of
facial and oculomotor muscles and limbs, and
they demonstrate fatigue in sucking, swallowing,
crying, and facial and extraocular movement.3
All forms of myasthenia gravis demonstrate mus-
cle weakness that is responsive to anti-
cholinesterase medications.12 Baby M did not
exhibit restricted extraocular movement, facial
weakness, or ptosis, and the diagnosis of con-
genital myasthenia gravis was excluded.
Acid Maltase Deficiency
Acid maltase deficiency (glycogen storage dis-
ease Type II, or Pompe’s disease) is a disorder of
glycogen metabolism in which glycogen accu-
mulates in the tissue. It is characterized by hypo-
tonia, muscle weakness, cardiomegaly, and
macroglossia. These infants have elevated levels
of CPK. Death usually occurs by two years of
age due to cardiac failure. The diagnosis of acid
maltase deficiency can be confirmed by skeletal
55
TABLE 1 ■ Disorders Associated with Neonatal Hypotonia1,3,8,9,16
Disorder Skeletal Face Exam Tendon Muscle Chromosome R/D Special
Deformities Reflexes Biopsy Features
CNS
HIE Obligatory • Hypotonia Normal Normal • Seizures
trapping of • Hypertonia • Coma
thumbs into
hands • Low Apgar
scores

Spinal injury • Hypotonia Depressed Traumatic

• Weakness birth

SMA Bell-shaped Active, bright • Swallowing Absent Atrophic fibers 5 R/D Defect in
chest difficulties motor
• Paralyzed neuron
intercostal survival
muscles protein,
and/or
• Diaphragm neuronal
spared apoptotic
• Paralysis of protein
legs
• Immobility
NMJ
Congenital Bulbar, facial, • Fatigue in Normal Responsive to
myasthenia oculomotor swallowing, cholinesterase-
gravis muscle sucking, inhibiting
weakness crying drugs
• Limb
weakness
Acid maltase Macroglossia • Cardiomegaly •Vacuolar 19 R Elevated CPK
deficiency • HSM myopathy levels
•Accumulation
of glycogen
particles
Congenital • Contractures • Ocular • Weak Depressed, • Myofiber 19 D • Polyhydram-
myotonic • Arthrogryposis involvement respiratory normal, or atrophy nios
dystrophy • Weakness muscles increased • Failure of • Abnormalities
• Diplegia • Impaired fiber of labor
swallowing differentiation • Mental
• Tent-shaped
lip • Distal retardation
weakness
Congenital •Contractures Weakness • Marked, Depressed, Necrosis of 21 R • Condition
muscular •Arthrogryposis generalized normal, or fibers X-linked static or
dystrophy hypotonia increased improves
• Swallowing with time
difficulties • Needs
• Mild supportive
respiratory care
difficulties • Elevated CPK
levels

muscle biopsy.8,14 The muscle biopsy obtained
from Baby M failed to support this diagnosis.
Congenital Myotonic Dystrophy
Congenital myotonic dystropy is an inherited
myopathy characterized by progressive limb
weakness without histologic muscle abnormali-
ties. This disorder is expressed as generalized
hypotonia with arthrogryposis. Infants may
demonstrate respiratory and swallowing difficul-
ties and exhibit a tent-shaped appearance of the
upper lip. 12 Polyhydramnios is frequently

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TABLE 1 ■ Disorders Associated with Neonatal Hypotonia (continued)
Disorder Skeletal Face Exam Tendon Muscle Chromosome R/D Special
Deformities Reflexes Biopsy Features
Congenital
Myopathies
Central core • Pes cavus Weakness Mild or Decreased Well-circum- 19 R/D • Nonprogres-
disease • Congenital marked scribed sive or slowly
hip dislocation hypotonia, circular progressive
more regions • Associated
• Clubfeet prominent in with
• Scoliosis proximal malignant
• Small stature extremities hypothermia

Nemaline • Joint • Elongated • Weak cry Decreased or Nemaline rods 1 R/D • Non-
myopathy contractures face • Hypotonia absent progressive,
Severe • Scoliosis • High, arched generalized
• Poor suck weakness
neonatal • Clubfeet palate and swallow
congenital • Malocclusion • Cardiomegaly
myopathy • GER

Myotubular Contractures • Diplegia • Hypotonia Decreased Nuclear 28 R/D • Polyhy-

myopathy • Weakness • Severe abnormalities X-linked dramnios
respiratory • Fatal in
difficulty infancy

Key: R=recessive; D=dominant; NMJ=neuromuscular junction disorders; HSM=hepatosplenomegaly; GER=gastroesophageal reflux; CPK=creatine phos-
phokinase; SMA=spinal muscular atrophy; HIE=hypoxic ischemic encephalopathy.

characteristic of the pregnancy, with a maternal history of CENTRAL CORE DISEASE

spontaneous abortions and premature birth. Muscle weakness
can be severe enough in the newborn period to cause death.
The prenatal and maternal histories and physical examination
in Baby M’s case were not consistent with congenital
myotonic dystrophy.
Congenital Muscular Dystrophy
Congenital muscular dystrophy in the neonate presents as
generalized trunk and limb weakness with facial involve-
ment. CPK levels in these infants are usually elevated, and
electroencephalogram and cranial computed tomograpy
findings are abnormal, demonstrating a decrease in white
matter density due to hypoplasia of myelin.12 Baby M did
not present with facial involvement, and her CPK levels
were normal.
Congenital Myopathy
Hypotonia associated with congenital myopathies results
from aberrant inner vation within the muscle fibers. 9
Although many myopathic disorders can present in the new-
born period, only a few account for the vast majority of
reported cases (Table 1). The most frequently reported disor-
ders in the newborn period include central core disease,
nemaline myopathy, and myotubular myopathy.15 The biopsy
of Baby M’s skeletal muscle showed changes that were com-
patible with the diagnosis of central core disease.
Pathophysiology
Central core disease was the first congenital myopathy to
be specifically recognized as a distinct clinical syndrome based
on structural changes noted in histologic analyses of biopsied
muscle.16 In normal muscle, most striated muscles are parti-
tioned into bunches of fibers that are surrounded by a sheath
of connective tissue. The muscle fiber or cell is multinucleated
and cylindrically shaped.17 Muscle cell cytoplasm is called sar-
coplasm and the cell membrane is the sarcolemma.18 Each
muscle fiber is composed of subunits called myofibrils.
Myofibrils are deeply embedded in the sarcoplasm, where the
contractile myofibrils are bathed in adenosine 51-triphos-
phate, produced by mitochondria.17
Central core disease results from an abnormality of the
ryanodine receptors in the sarcoplasmic reticulum. These
receptors, which normally regulate the release of calcium,
allow excess calcium into the muscle fibers, where it damages
the mitochondria. The interior of affected myofibrils contains
cylindrical cores that extend throughout the length of the
myofiber. These cores are central or eccentric in location and
appear pale in contrast to the periphery of the muscle fiber
because of the absence of mitochondria and a loss of intermy-
ofibrillar substance (Figure 2).4,15 Cores may increase in num-
ber over the years, and solitary cores may be observed in
normal muscle.15,16

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FIGURE 2 ■ Muscle biopsy displaying small, numerous myofibrils
with pale central cores.
Central core disease almost always presents with a predom-
inance of Type I fibers (red muscle).15 Type I fibers contain a
large amount of myoglobin, which is an oxygen-storing, red
pigment similar to hemoglobin in the red blood cell. Type I
fibers are specialized for aerobic respiration and long, sus-
tained contractions. White muscle, or Type II fibers, have
fewer mitochondria but possess an abundance of glycogen
stores. These fibers are more suited to anaerobic respiration
and rapid contractions of short duration.6 The proportion of
Type I and Type II fibers varies according to function and
anatomic location, but ideally most muscles contain 35–40
percent Type I fibers and 60–65 percent Type II fibers. Cores
seem to most frequently involve Type I fibers.16
During embryologic development, early muscle cells
express type-specific proteins. Type I fibers appear by 22–24
weeks gestation, and their number normally increases after
birth. After 30 weeks gestation, Type II fibers begin to differ-
entiate. The Type I fiber predominance in central core disease
may result from the fusion of myotubes during the 24th to
28th week of gestation, caused by the arrested development
of Type I fibers or by the abnormal conversion of Type II to
Type I fibers. There is also speculation that fiber differentia-
tion may be related to a change in the pattern of motor neu-
rons or muscle activity.16
Clinical Features
In the newborn period, central core disease presents with
hypotonia and weakness. The severity and distribution of
involvement can be variable, and some infants may be asymp-
tomatic and not demonstrate muscle disease until months
N E O N ATA L N E T WO R K
58
later. Muscle weakness is usually proximal, symmetric, and
more severe in the lower extremities.15 Breech presentation at
birth is a frequent finding.16 Infants may present with congen-
ital hip dislocations, facial weakness, thoracic deformities,
kyphoscoliosis, contractures, pes cavus, flexion deformities of
the fingers, skeletal anomalies, and short stature.9,16 Baby M
presented with decreased muscle tone and weakness, a bell-
shaped chest, hip contractures, scoliosis, and bilateral clubfeet.
She was delivered by cesarean section for breech presentation.
Prognosis
The course of the disease varies from nonprogressive to
slowly progressive. Infants can attain motor milestones,
although they may not walk until three or four years of age.
Their intellectual performance is often above normal.
Adolescents and adults afflicted with central core disease have
very thin muscles and may complain of muscle stiffness and
cramps with moderate exertion, although most patients
remain fully active throughout their lives with a normal life
expectancy.16
Autosomal dominant inheritance is most often observed,
although sporadic cases have been reported. The gene for
central core disease has been mapped to chromosome 19, and
malignant hyperthermia is thought to be an allelic disorder of
the same gene. Because an association between central core
disease and a susceptibility toward malignant hyperthermia
seems to exist, all family members of patients with central
core disease should be considered at risk for malignant hyper-
thermia.9,15,16
Management
There are no specific treatments for patients with central
core disease. Therapeutic interventions such as prevention of
contractures and symptomatic physical therapy are important,
as is orthopedic treatment of skeletal anomalies. Patients with
respiratory muscle weakness may require ventilatory support.9
Baby M’s presentation was atypical for central core disease,
although a similar death in a neonate had recently been report-
ed in the same community. Severe hypotonia and contractures
are rarley reported in central core disease. As noted earlier, pro-
found weakness with respiratory failure is infrequent. 16
Certainly, the severe degree of pulmonary hypoplasia contribut-
ed greatly to Baby M’s poor clinical course. Hers was thought
to be a sporadic case, and her parents were counseled that the
chance of recurrence in subsequent offspring was the same as
for the normal population. They now have a healthy toddler.
SUMMARY
Causes of hypotonia in the newborn can be broadly cate-
gorized into two classifications. Hypotonia with a supraspinal
origin may be seen with systemic disease, hypoxic ischemic
encephalopathy, cerebral malformations, syndromes (for
example: Down, Prader-Willi, Lowe, Zellweger, Smith-Lemli-
J A N U A RY / F E B R U A RY 2 0 0 3 , VO L . 2 2 , N O . 1
Opitz), and c-spine injury. Disorders of the motor unit that 16. Engle A, and Franzini-Armstrong C. 1994. Myology, 2nd ed.
present with hypotonia in the newborn period include SMA, New York: McGraw-Hill, 1488–1494.
congenital myotonic dystrophy, congenital myasthenia gravis, 17. Rubin E, and Farber J. 1998. Pathology, 3rd ed. New York:
and congenital myopathies.10 Lippincott Williams & Wilkins, 1415–1426.
Central core disease is one of the classic congenital 18. Anthony C. 1967. The Textbook of Anatomy and Physiology, 7th
myopathies that can be differentiated based on characteristic ed. St. Louis: Mosby, 47.
histologic findings. Muscle fiber samples from patients with
central core disease possess distinct morphology that can be About the Author
diagnostic. Many infants may not exhibit muscle weakness in Val Castrodale is a neonatal nurse practitioner in the intensive care
the newborn period, although there have been rare cases of nursery at St.Vincent Hospital’s Family Life Center in Indianapolis,
profound hypotonia and respiratory failure. Indiana. She was a staff nurse for 23 years in Level III nurseries and
graduated from the neonatal nurse practitioner program at Children’s
Clearly, muscle biopsy is the gold standard and is indicated
Hospital in Columbus, Ohio, in 1998.
for any infant with marked hypotonia that is not thought to
The author wishes to thank Drs. Howard Harris, Kathy Clark, Jose
be supraspinal in origin. Bonnin, and John Bodensteiner for their assistance in the preparation of
this article. Special acknowledgment to Angela Carlson, RNC, ND,
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