Download Hypotonia - the floppy baby

Hypotonia - the floppy baby
SMA
Spinal Muscular Atrophy
‫הצגת מקרה – מ‪.‬ג'‬
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‫נולדה בשבוע ‪ 42‬לאחר הריון תקין‪,‬‬
‫בלידה ‪ -‬מים מקוניאלים‬
‫אפגר ‪ 1‬דק' ‪ 5 , 7-‬דק' ‪9 -‬‬
‫משקל לידה ‪ ,3030-‬היקף ראש – ‪34.5‬‬
‫במשפחה – הורים בני דודים דרגה ראשונה‪ ,‬לא‬
‫ידוע על מחלות‪ .‬אח בן ‪ – 5‬איחור התפתחותי על‬
‫רקע לא ברור‪.‬‬
‫הצגת מקרה – מ‪.‬ג'‬
‫•‬
‫בבדיקה גופנית ‪:‬‬
‫–‬
‫–‬
‫–‬
‫–‬
‫–‬
‫–‬
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‫היפוטוניה בולטת‪.‬‬
‫לא הופקו החזרים‬
‫גידיים‪.‬‬
‫בכי חלש‪.‬‬
‫יש מציצה‪.‬‬
‫נשימה בעיקר סרעפתית‪.‬‬
‫נצפו פסיקולציות בלשון‪.‬‬
‫עירנית‪ ,‬עוקבת עם‬
‫תגובות ראיה ושמיעה‬
‫טובות‪.‬‬
‫הצגת מקרה – מ‪.‬ג'‬
‫• בירור שבוצע‪:‬‬
‫– במעבדה ‪ CPK :‬מוגבר – ‪1180‬‬
‫– אקו לב – ‪ PDA‬ו ‪ PFO‬קטן ‪ :‬בגדר הנורמה ליום ‪2‬‬
‫של חיים‪ .‬חדרים בגודל תקין‪ ,‬התכווצות תקינה‪.‬‬
‫– בדיקת עיניים – תקינה‬
‫– ‪ US‬מוח – תקין‬
‫– ‪ – EMG‬סימני דהנרווציה במידה בינונית‬
‫– בדיקה גנטית – ‪SMA type 1‬‬
Hypotonia - the floppy
baby
Hypotonia in the newborn
• Almost any condition that affects the
central or peripheral nervous system can
be expressed by a reduction of tone.
• Most acute or multisystem illness in
neonated is accompaied by some degree
of hypotonia therefore: sepsis, organ
failure, metabolic dysfunction or other
systemic illness must be ruled out.
Diagnosis - Hx
• Detailed family, obsteteric, and delivery
history.
– Polyhydramnios
– Decrease in fetal movement
– Malpresentation
– Birth trauma / Asphyxia
Diagnosis – Phys. exam.
• General appearance
• Skin – pallor, trauma, bruising, petechias
• Dysmorphic features, Weight, length and head size and
shape, Respiratory – rate, pattern, Cardiovascular,
Organomegaly, Genitalia, cotractures
• Neurologic examination – alertness, fixes or follows,
posture and spontaneous movements, cranial nerves –
eye movements, fisting, abnormal primitive reflex,
character of deep tedon reflexes (upper vs lower),
sensation, ability to suck ad swallow, character of cry,
tongue fasciculations
SPINAL MUSCULAR ATROPHY
SMA –spinal muscular atrophy
• The spinal muscular
atrophies (SMAs) are
characterized by
degeneration of the
anterior horn cells in
the spinal cord and
motor nuclei in the
lower brainstem.
HISTORY
• Was first described in the 1890s by Guido
Werdnig of the university of Viena and
Johann Hoffmann of Heidelberg University.
Frequency:
• The acute infantile-onset SMA (type I)
affects approximately 1 per 10,000
live births.
• The chronic forms (types II and III), 1
per 24,000 births
Clinical features – TYPE 1
• Werding Hoffman / infantile onset SMA
• Weakness and profound hypotonia – first
few months of life
• Normal social awareness and interaction
• Limited spontaneous movement
• Deep tendon reflexes are absent
• Sphincter tone and sensation are intact
Clinical features – TYPE 1
• Muscle trembling can be seen in
fingers and fasciculitations are often
present in the tongue
• Pectus excavatum and flaring of the
lower ribs (weak intercostal muscles)
• Feeding difficulties – FTT
• Aspiration
• Rarely survive beyond 2 yrs
Clinical features – TYPE 2
• Milestones are usually normal until onset –
6-18 months.
• Legs are weaker then arms – failure to
walk
• Deep tendon reflexes – variable pattern
• Usually sit without support, some walk with
bracing
• Survive into adolescence and beyond
• Good pulmunary function
Clinical features – TYPE 3
•
•
•
•
Kugelberg-Welander disease
Independent ambulation acheived
Normal survival
Onset of weakness after 18 mo – often
late childhood or adolecence
• Waddling gait with lumbar lordosis
• Decrease in motor units over time has
been documented (despite clinical picture)
Diagnosis
• Clinical, physical exam, family Hx
• Lab:
– CK level is usually normal in SMA type I and
normal or slightly elevated in the other types
– Cerebrospinal fluid findings are normal
– Genetic testing, both prenatally and
postnatally
Diagnosis
• Nerve conduction studies – normal or
slightly decreased velocities, the sensory
nerve action potentials are normal.
• Electromyography – abnormal
spontaneous activity with fibrillations and
positive sharp waves. The mean duration
and amplitude of motor unit action
potentials are increased.
Histology
• Muscle biopsy: large groups of
circular atrophic type 1 and 2 muscle
fibers intersperseded among
fascicles of hypertrophied type 1
fibers. The enlarged fibers have
been reinnervated by the sprouting
of surviving nerves and are 3-4 times
larger than normal.
Genetics
• Autosomal recessive
disorder caused by
homozygous
deletions or mutations
of the SMN1 gene at
the 5 q11 locus.
• There are two copies
of the smn gene on
chrom. 5q that code
for SMN protein –
SMN1 and SMN2.
Genetics
Genetics
• All SMA patients have reduced fl-smn
protein :
– Type 1 – 9%
– Type 2 – 14%
– Type 3 – 18%
– Carriers – 45 -55%
• When levels approach 23% - motor
neuron function is normal.
Genetics
• SMA type I: Mutations
– Mostly SMN1 deletions
– Few missense point mutations
in SMN1
– SMN2 gene copy number:
Often 2
• SMA type II
– Mutations convert SMN1 gene
to SMN2
– SMN2 gene copy number: > 3
– Missense point mutations
more common
• SMA type III
– SMN2 gene copy number: > 3
– Missense point mutations
more common
Genetics
SMN protein
• Expressed in most tissues
• High levels are found in spinal motor
neuron
• SMN exist in the cell as a part of a large
complex that regulates the assembly of a
specific class of RNA protein complexes which is essential for pre-mRNA splicing.
• The function of SMN protein is linked to
the control of protein synthesis.
Why are only motor
neurons and muscle are
affected in SMA ?
The Role of SMN in SMA -1
•
SMA is a direct consequence of a defect
in pre-RNA splicing:
•
The affected motor neurons, being large,
high energy requiring cells, have a lower
tolerance for depleted SMN levels and are
uniquely sensitive.
The Role of SMN in SMA - 2
•
SMA is a consequence of a motor
neuron specific function of the SMN
protein:
– From observations demonstrating the
accumulation of the SMN protein in the
axons and growth cones of neuron like cells
in vitro and anterior horn cells in vivo.
Potential for Therapies
Potential for Therapies
• The disease phenotype is proportional to
the amount of fl-SMA.
• Mechanisms for potential therapies:
– Enhanced expression of SMN2
– Altering SMN2 transcript splicing to increase
the level of fl-SMN RNA
– Other strategies to increase the level or
activity on SMN.
Potential for Therapies
• In was found that histone deacetylase
(HDAC) inhibitors can increase the level of
fl-SMN.
• Studies with other agents also show
promise – sodium butyrate, valproic acid.
‫הצגת מקרה – מ‪.‬ג'‬
‫• כעת בת חודשיים וחצי‪.‬‬
‫• שלושה אשפוזים במחלקתינו‪:‬‬
‫– דלקת ריאות ימין (אספירציה?)‬
‫– ירידה ביכולת אכילה ובמצבה הכללי – שוחררה לביתה‬
‫עם זונדה‪.‬‬
‫– דלקת ריאות ימין על רקע אספירציה‪ ,‬התדרדרות‬
‫נשימתית‪ ,‬שוחררה עם חמצן‪.‬‬
‫• מוגדרת ‪DNR‬‬
‫תודה‬