This document discusses the approach to evaluating and diagnosing a hypotonic infant. It begins by defining hypotonia and noting that determining the cause can be challenging. A detailed history and physical exam are important to localize the cause as central or peripheral. Differential diagnosis involves considering central nervous system, genetic, infectious, metabolic, and muscular causes. Basic lab tests include screening for infection and metabolic/genetic disorders. Imaging, EMG/NCV, muscle biopsy and genetic testing can further evaluate potential peripheral and muscular etiologies. The case presented is of a newborn with hypotonia, absent reflexes, and no family history or dysmorphic features to suggest a cause.

1. Approach to HypotonicApproach to Hypotonic
InfantInfant
Dr. Vinayak Kodur
3rd year DM resident
L.T.M.M.C. Sion Mumbai

2. Hypotonic InfantHypotonic Infant
• Defined as decreased resistance to passive
movement, and may or may not be associated
with decreased muscle strength or weakness.
• Recognition of hypotonia in the newborn may be
straightforward, but determining the cause may
be a challenge.
• The physical examination, including a detailed
neurologic examination, is important in localizing
the site of a defect within the nervous system
(ie, central vs peripheral).

3. Hypotonic InfantHypotonic Infant
• History along with basic laboratory testing and
imaging aids in the differential diagnosis.
Identification of the cause is essential for
determining the prognosis for the infant,
associated morbidities, and the recurrence risk.

4. CaseCase
• A newborn term infant presents with poor
respiratory effort and abnormal suck and
swallow after a pregnancy complicated by
decreased fetal movement.
• Born by cesarean section because of breech
presentation.
• Physical examination shows no dysmorphic
features but significant hypotonia, without
tongue fasciculations and absent deep tendon
reflexes.

5. CaseCase
• The family history is negative for any muscle or
neurologic disease, early infant deaths, or
consanguinity.
• Examination of the mother is normal
(specifically evaluating for signs of myotonia).

6. AlgorithmAlgorithm
• History and physical examination
• Localization of hypotonia to
• central (ie, the brain and brainstem, either
diffusely or focally)
• peripheral (any component of the motor unit:
anterior horn cell, peripheral nerve,
neuromuscular junction, muscle itself)

7. HistoryHistory
• The history in conjunction with the physical
examination may give clues to the cause.
• The history includes prenatal, perinatal/birth,
and family history.

8. Family HistoryFamily History
• Neuromuscular disorders
• Maternal myotonia (shake mom’s hand to
assess for myotonia; slow release) Congenital
myotonic dystrophy
• Advanced maternal age: increased risk of
chromosomal aneuploidy
• Advanced paternal age: increased risk of de
novo mutations and new dominant diseases
• Consanguinity: Autosomal recessive disorders.
• Early infant deaths

9. Antenatal HistoryAntenatal History
• Maternal infection
• Teratogen exposure
• Polyhydramnios
• Maternal diseases (GDM/PIH)
• Maternal systemic lupus erythematosus
• Maternal Myasthenia Gravis.
• Decreased fetal movement
• Breech presentation.
• Shortened umbilical cord

10. Birth HistoryBirth History
• Breech Delivery
• Instrumentation
• Perinatal asphyxia
• Trauma/delivery complications
• Maternal delivery medications
• Need for resuscitation, ventilator support

11. Physical ExaminationPhysical Examination

12. Physical ExaminationPhysical Examination
• Differentiating central from peripheral hypotonia.

13. Physical ExaminationPhysical Examination
• Syndromic Vs non-syndromic cause.
• If an infant with hypotonia has dysmorphic facial
features, congenital malformations, or both, the
standard of care is to obtain a chromosomal
microarray (by either single nucleotide
polymorphism or comparative genomic
hybridization) to evaluate for chromosomal
deletions and duplications.

14. Syndromic CausesSyndromic Causes
• Trisomies 21/13/18
Prader Wili
Syndrome
Feeding difficulties, FTT,
Hypogonadism hyperphagic
obesity; almond-shaped palpebral
fissures; small hands and feet;
mild to moderate MR
FISH analysis of
SNRPN gene Ch 15
Smith Lemli
Opitz Synd
Microcephaly, Ptosis, anteverted
nostrils, low set ears,
micrognathia, 2-3 toe syndactyly
7 Dehydrocholesterol
reductase deficiency
with elevated serum
7-dehydrocholesterol
Zellweger
and other
peroxisomal
disorders
High forehead with flat facies,
Hepatomegaly,
Very Long chain fatty
acids and
plasmalogens
analysis

15. Physical ExaminationPhysical Examination
• Once an infant is determined to be hypotonic and
nondysmorphic, weakness or strength should be
evaluated.
• May be difficult to demonstrate if there are systemic
symptoms (ie, infection, altered mental status) or if the
baby is on systemic medications such as neuromuscular
blocking agents and sedatives.
• There is no direct measurement of muscle strength in
infants, but it may be assessed by observing the
awake/alert infant.

16. Differential DiagnosisDifferential Diagnosis
• Central hypotonia
• May have altered mental status, increased
deep tendon reflexes, Babinski sign,
persistent infantile reflexes
• HIE, Premature birth, difficult delivery
• Intracranial hemorrhage, Cerebral
malformations May be noted on prenatal
ultrasonography

17. Differential DiagnosisDifferential Diagnosis
• Chromosomal abnormalities
• Peroxisomal disorders Dysmorphic features
• Inborn errors of metabolism Metabolic acidosis,
hypoglycemia, hyperammonemia, lactic acidosis
• Maternal and infant drug effects
• Congenital infections or Acquired infections

18. Differential DiagnosisDifferential Diagnosis
• Spinal cord
• Birth trauma
• HIE
• Syringomyelia
• Anterior horn cell: Spinal muscular atrophy

19. Differential DiagnosisDifferential Diagnosis
• Neuromuscular junction
1. Myasthenia gravis:
• Transient acquired neonatal myasthenia
• Congenital myasthenia gravis
• Easy fatigability, recurrent aspiration,
feeding difficulty
• EMG Responds to anticholinesterase
Inhibitors ECG may show heart block

20. Differential DiagnosisDifferential Diagnosis
• Neuromuscular junction
2. Infantile botulism
• Facial weakness and pupillary abnormality
• Presence of toxin in food
2. Drug toxicity (magnesium, aminoglycosides)
History of drug exposure Plasma and urine
drug levels

21. Differential DiagnosisDifferential Diagnosis
• Peripheral nerves diagnosed by DNA
sequencing
1. Hereditary motor and sensory neuropathies
• Diminished/absent DTRs, absent Babinski and
infantile reflexes
• EMG/NCV may be helpful
1. Congenital hypomyelinating neuropathy
• Family history
1. Giant axonal neuropathy
• Family history

22. Differential DiagnosisDifferential Diagnosis
• Muscular Causes: may have family history and
require muscle biopsy for diagnosis
1. Muscular dystrophies
• May have elevated serum CK and aldolase, ALT
and AST may be elevated from muscle rather than
liver
1. Congenital myopathies
2. Metabolic myopathies
• May have elevated serum CK, aldolase, ALT, and
AST
1. Congenital myotonic dystrophy
• Maternal myotonia
• CTG-repeat analysis of DMPK gene

23. Physical Examination
CNS
Causes
Neuro-
imaging
Genetic
Studies
Biochemi
cal
Studies
Peripheral
Causes
CPK
EMG
NCV
Muscle
Biopsy
Genetic
Studies

24. Basic LAB StudiesBasic LAB Studies
• Septic screen
• ABG for metabolic acidosis
• Sugar levels for hypoglycemia,
• Serum electrolytes (specially sodium) and
calcium.
• Ammonia, orotic acid and plasma amino acids
for urea cycle defects,
• Urine organic acids and acyl carnitine profile for
organic acidemias,

25. LAB StudiesLAB Studies
• Plasma acyl carnitine and total carnitine for fatty acid
oxidation defects,
• Plasma lactate, pyruvate for disorders of
carbohydrate metabolism and mitochondrial
disorders.
• Laboratory testing of creatine kinase (CK) and
aldolase
• Helpful if there is a muscular dystrophy, but often
is normal in infants with hypotonia.
• In addition, it can be falsely elevated after difficult
deliveries.
• Elevated alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) may be an indication of

26. Genetic StudiesGenetic Studies
• Chromosomal analysis (routine karyotype for
Down syndrome [trisomy 21]
• Analysis for microdeletions/duplications either
by chromosomal microarray or specific testing
by FISH)
• Methylation analysis of the chromosome region
of 15q11-q13 for Prader-Willi syndrome (PWS)
(detects 99% cases vs 70% with FISH)

27. NeuroimagingNeuroimaging
1. Neurosonogram
2. CT brain
3. MRI brain and Spine
4. MR spectroscopy
• Corpus callosal agenesis
• Migration defects
• Signal abnormalities in the white matter and
basal ganglia
• Congenital malformations
• Spine defects

28. EMG NCVEMG NCV
• Helpful in localizing the defect
• Technically difficult
• EMG is very accurate in the diagnosis of SMA
• NCV is helpful in investigating hereditary motor
sensory neuropathies by distinguishing between
axonal and demyelinating conditions.
• These studies can also be helpful in distinguishing
between a neuronal and a myopathic process15 and in
the diagnosis of a neuromuscular transmission defect
(congenital myasthenia gravis).

29. EMGEMG
• Though useful for muscular dystrophies and
congenital myopathies, EMG may missed
metabolic myopathies.
• A resting muscle does not show recordable
electrical potential but with increase force of
contraction, amplitude of potential increases.
• EMG detects electrical potential generated by
muscle cells when these cells are electrically or
neurologically activated.
• EMG shows fibrillation and muscle denervation
in SMA.

30. EMGEMG
Pattern of EMG Record Findings
Resting activity Muscle relaxed &
needle not moving
No activity
Insertion Activity Needle is moved to
various sampling spots
within insertion tract
Brief action potentials
Motor Unit Potential Needle is not moved
while patient makes
slight contraction.
A few motor unit action
potentials, biphasic or
triphasic,short duration
Recruitment Subject makes
progressively stronger
muscle contraction
until reaching
maximum force
Increase number of
functioning movements
until the baseline is
obscured

31. EMGEMG
• Motor unit potential (MUP)
• The sum of the action potentials produced in the
muscle.
• Characterized by its duration, number of phases,
amplitude, & rate of rise of first component

32. EMGEMG
Duration •measured from the initial take-off to the point of
return to the baseline
•5-15 ms
Phases •portion of the MUP between the departure & the
return to the baseline
•triphasic(positive, negative, positive)
•Polyphasic-MUP with more than four phase (5-15%)
Phases •measured from maximum peak of negative phase to
maximum peak of the positive phase
•0.5mV to 2mV
Rise Time •duration from the initial positive to subsequent
negative peak
•normal ↓ 500 μs

33. EMGEMG
Fibrillation Fasiculation
Contraction of individual
muscle fibre
Contraction of individual motor
units
cannot be seen through the
skin
visible through the skin
when muscle fibers lose
contact with their innervating
axon
occurs as a result of additional
nerve impulses generated
10-100 μV in amplitude, 1-2
ms in duration & 10 Hz in
frequency
50-500 μV in amplitude, 2-4
ms in duration & 2-20 Hz in
frequency
Neuropathy, myopathy Neuropathy

34. EMGEMG

35. Muscle BiopsyMuscle Biopsy
• If muscular dystrophy or myopathy is
suspected.17
• Basic histology can identify myopathic,
neuropathic, and dystrophic changes.
• Immunohistochemical techniques using
antibodies against muscle-specific proteins are
helpful in the diagnosis of muscular dystrophies
and myopathies.
• Electron microscopy can identify abnormalities
of organelles (such as mitochondria), and
identify inclusions and storage material.

36. Congenital Myotonic
dystrophy
• Mother previously
diagnosed in 50% cases
• Presents at birth
• Hypotonia, facial diplegia
with “tenting” of upper lip
• Frequently severe
respiratory distress
secondary to intercostal
and diaphragmatic muscle
weakness
Transient Neonatal
Myasthenia
• Mother usually previously
diagnosed
• Presents at birth or within
few days
• Muscle fatiguability,
generalised weakness,
hypotonia, weak cry, poor
feeding, respiratory
distress, ophthalmoplegia,
ptosis (in 15%)

37. Congenital Myotonic
dystrophy
• Poor suck, GI dysmotility
• Reduced muscle mass,
contractures
• Maternal history: spont
abortions, polyhydramnios,
↓ fetal movement, PPH,
delayed 2nd
stage
• Triplet repeat Chr 19: AD
Transient Neonatal
Myasthenia
• Normal pupils, normal
DTR
• Due to transplacental
passage of maternal
antibodies against acetyl
choline receptor
• Diagnosed by
edrophonium test
• Resolves in weeks

38. SMASMA
• A group of autosomal-recessive disorders
characterized by progressive weakness of the
lower motor neurons.
• In the early 1980s, Werdnig and Hoffman
described a disorder of progressive muscular
weakness beginning in infancy that resulted in
early death, though the age of death was
variable.

39. SMASMA
• Incidence 1 in 10,000 live births with a carrier
frequency of approximately 1 in 50.
• Male individuals are most frequently affected,
especially with the early-onset forms of spinal
muscular atrophy, ie, types I and II.
• SMA type I, the median survival is 7 months,
with a mortality rate of 95% by age 18 months.

40. SMA - TypesSMA - Types
• Acute infantile (SMA type I, or Werdnig-Hoffman
disease) onset birth to 6 months, Never sits
• Chronic infantile (SMA type II), 6-18 months,
Sits but can`t walk,
• Chronic juvenile (SMA type III or Kugelberg-
Welander disease), after 18 months, can walk.
• Adult onset (SMA type IV) forms. Mid 30.
• The genetic defects associated with SMA types
I-III are localized on chromosome 5q

41. SMA - PathophysiologySMA - Pathophysiology
• Each individual has 2 SMN(Survivor Motor
Neuron) genes, SMN1 and SMN2.
• More than 95% of patients with spinal muscular
atrophy have a homozygous disruption in the
SMN1 gene on chromosome 5q, caused by
mutation, deletion, or rearrangement.
• However, all patients with spinal muscular
atrophy retain at least 1 copy of SMN2, which
generates only 10% of the amount of full-length
SMN protein versus SMN1.

42. SMA - Clinical FeaturesSMA - Clinical Features
• 95% of patients symptomatic by 3 months.
• They have severe, progressive muscle
weakness and hypotonia.
• Bulbar dysfunction includes poor suck ability,
reduced swallowing, and respiratory failure.
• Patients have no involvement of the extraocular
muscles
• Facial weakness is often minimal or absent.
• No evidence of cerebral involvement, and
infants appear alert.

43. SMA - DiagnosisSMA - Diagnosis
• The creatine kinase (CK) level is typically
normal in SMA type I and normal or slightly
elevated.
• EMG shows fibrillation and muscle denervation.

44. SMA - DiagnosisSMA - Diagnosis
• Homozygous SMN1 gene deletion is 95%
sensitive and nearly 100% specific for the
diagnosis of SMA.
• The accuracy of prenatal prediction by means of
chorionic villi sampling and amniocentesis was
88-99%.

45. SMA - DiagnosisSMA - Diagnosis

46. Thank YouThank You