Hypotonia - the floppy baby

SMA

Spinal Muscular Atrophy

הצגת מקרה – מ.ג'

לאחר הריון תקין,42נולדה בשבוע •

בלידה - מים מקוניאלים•

9 דק' - 5 , 7 דק' -1אפגר •

34.5, היקף ראש – 3030משקל לידה -•

במשפחה – הורים בני דודים דרגה ראשונה, • – איחור 5לא ידוע על מחלות. אח בן

התפתחותי על רקע לא ברור.

הצגת מקרה – מ.ג'

בבדיקה גופנית :• 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:•1180 מוגבר – CPKבמעבדה : – 2 קטן : בגדר הנורמה ליום PFO ו PDAאקו לב – –

של חיים. חדרים בגודל תקין, התכווצות תקינה.בדיקת עיניים – תקינה––US מוח – תקין –EMGסימני דהנרווציה במידה בינונית – SMA type 1בדיקה גנטית – –

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

• 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

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.

DNRמוגדרת •

תודה