Spinal muscular atrophy

What type of disease is SMN?

It is a degenerative disorder of spinal motor neuron.

What causes SMN? 

Homozygous mutation of SMN1 gene on exon 7 of chromosome 7

AR and X linked are also present but rare

What is the most common casue of infant mortality among AR disorders?

Spinal Muscular atrophy

Which is the most prevalent AR disorder at birth?

Cystic Fibrosis f/b SMA

What is the function of SMN1?

SMN protein appears to play a role in mRNA synthesis in motor neurons and also may inhibit apoptosis.

What determines the activity of SMN1 gene & phenotypic expression of SMA?

Modifying gene called SMN2

Loss of the SMN1 protein is partially compensated by SMN2 protein synthesis, a mechanism that explains some but not all of the phenotypic variability in patients with SMA.

Disease severity in SMA generally correlates inversely with SMN2 copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein. 

The presence of >3 copies of SMN2 is associated with a milder phenotype

What are the types of SMA?

SMA0

SMA1

SMA2

SMA3

SMA4

Which cranial nerves and spinal nerves are spared?

Motor neurons of cranial nerves III, IV, and VI to the extraocular muscles, as well as those of the sacral spinal cord innervating striated muscle of the urethral and anal sphincters, are selectively spared. 

The upper motor neurons (layer 5 pyramidal neurons in the cerebral cortex) also remain normal.

What is the pathological hallmark of SMA? 

The pathologic hallmark of SMA is the progressive denervation of muscle. 

This is compensated for in part by reinnervation from an adjacent motor unit, but giant motor units are thus created, with subsequent atrophy of muscle fibers when the reinnervating motor neuron eventually becomes involved.

 What part of NS is affected in SMA? 

Anterior horn cells is Spinal cord &  motor nuclei in the lower brainstem

Cognition is unaffected.

On what basis the SMA are classified?

On the basis of age of onset, milestones achied and clinical course.

What is the most common type of SMA?

Type 1

Which is most severe form of SMA?

Type 1 and type 0

What is the function of SMN1 that is defective in SMA?

The SMN gene is responsible for stopping the programmed cell deathof neuroblasts and other neurons formed from neuroectoderm and lack of this function leads to iuninhibited death of motor neurons.

Which is most severe form of SMA?

SMA type 0 and type 1

Which is the least severe type of SMA?

Type 4 – adult onset type

What is the classical clinical feature of SMA?

Diffuse, symmetrical proximal muscle weakness which is greater in the lower limbs than the upper limbs with absent or markedly reduced tendon reflexes.

Frog leg position

Tongue fasciculations

Selective involvement of axial and intercostal muscles but sparing of diaphragm because of which they have a characteristic paradoxical abdominal breathing pattern

Inverted V shaped upper lip.

Bell shaped chest

What about the respiratory insufficiency in SMA cases?

SMA is associated with a restrictive, progressive respiratory insufficiency, particularly SMA type 0 and type 1 

What other congenital anomalies are a/w SMA?

Sleep disturbances

Congenital heart defects may be present with SMA type 0

While there have been occasional reports of heart rhythm abnormalities in SMA types 1, 2, and 3, these may be coincidental associations.

What is the prenatal form of SMA?

SMA type 0 where degeneration of motor neurons begin in midgestation period.

What are the features of SMA type 0?

Most severe form

Death by 6 months and usually by 1 month

Death occurs d/t respiratory insufficiency

What can be the maternal complains in case of SMA type 0?

Mother may recognize the decrease fetal movements.

What are the clinical features of SMA type 0?

Hypotonia

Severe weakness

Areflexia

Facial diplegia

CHD

Arthrogyropsis (multiple joint contractures

No milestones achieved

What is fetal hypokinesia deformation sequence?          

Infants with SMA of neonatal onset may present with signs of fetal hypokinesia deformation sequence, including polyhydramnios, intrauterine growth retardation, skeletal abnormalities with multiple articular contractures, and pulmonary hypoplasia.

How many copies of SMN2 do SMA0 have?    

Only one copy

What are the types of SMA1?

SMA1a - severe weakness from birth or the neonatal period; head
control is never achieved.

SMA 1b - presentation after the neonatal period, within the
first 2 mo; head control is never achieved.

SMA 1c - onset after the neonatal period but head control is achieved, and some of the infants may gain the ability to sit with support.

What are the features of SMA 1?

All the features of SMA described as above.

Respiratory failure, sucking & swallowing difficulties depends on type of SMA 1.

What is the other name for SMA1?

Werdnig Hoffmann Disease

What is the prognosis of SMA 1?

SMA 1a die within 6 months of age

SMA 1b & 1c die within 2 years if no respiratory support is provided

What is the facial feature like in SMA 1?

SMA type I have an alert and bright expression with preserved cognitive
functions. There is no involvement of the facial and extraocular muscles at presentation, although facial weakness does occur at later stages of the disease.

However, due to the involvement of bulbar there is difficulty is sucking, swallowing and there is pooling of secretion

How many copies of SMN2 is present in SMA1?          

2 or 3 copies

What anomalies are a/w SMA? 

Early-stage developmental congenital heart defects described in severe SMA patients, generally carrying one copy of SMN2, include atrial septal defects, a dilated right ventricle,ventricular septal defects, and hypoplastic left heart syndrome.

Autonomic nervous system, which may result in arrhythmia and sudden death.

Vasculopathy can be another rare presentation, and ulceration and necrosis of the fingers and toes have also been described in two severe type I SMA patients

What is the type 2 SMA?

Intermediate form of SMA

Aka Dubowitz disease

Onset of 6-18 months

How common is SMA type 2?

30% of cases

What is the prognosis of SMA 2?

>2 years and about 70 % survive to 25 years of age

What milestones are achieved in SMA 2?

Able to sit without support but never stands or walks

What are other features of SMA 2?

Scoliosis – d/t progressive muscle weakness

Late onset respiratory muscle weakness – leading to restrictive lung disease

Average or above average muscle weakness

A fine tremor like form of myoclonus aka minipolymyoclonus affecting distal limbs

How many copies of SMN2 are present in SMA 2?

3 copies in 80 % cases

What is type 3 SMA?

Juvenile form

Kugelberg-Welander disease

How common is SMA 3?

10% cases

Walker SMAs

When is the age of onset of SMA 3?

>18 MONTHS < 3 YEARS FOR 3A AND > 3 YEARS FOR 3B

Which muscle is particularly involved in type 3?

Shoulder girdle muscles

What milestones are achieved in SMA 3?

They are almost normal

Bulbar involvement Is rare

Respiratory involvement is rare

How about the muscles in SMA 3?

Instead of atrophy hypertrophy and often confused with muscular dystrophies

What about the prognosis of SMA3?

Most cases gradually develop inability to walk and become wheel chair bound

Almost normal life span

What about fasciculations in SMA 3?

Present

Best to observe in tongue

Can be present in biceps brachii and deltoid

Polyminimyoclonus may be present

What about type 4 SMA?

Onset in 2^nd or 3^rd decade of life

Mild weakness

Normal IQ

Often they have better IQ

What is the prognosis of Type 4 SMA?

Normal life span

But progressive deterioration of ambulation and the high risk of falling and fracturing long bones or the pelvis eventually require use of a wheelchair; an electric wheelchair often is needed because weakness of the upper extremities does not allow the patient to manually push the wheels.

Progressive scoliosis is another serious complication.

How do we diagnose SMA case?

Creatine kinase level may be normal but commonly mildly elevated (2-4 fold) but usually not more than 10 fold

CXR – thin ribs

What is the use of ECG in SMA cases? 

Electrocardiography (EKG) may serve as a simple and practical tool in patients with SMA to demonstrate a baseline tremor as an artefact representing muscle fibrillations more prominent on lead II.

Finding of Nerve conduction studies in SMN

Normal except for mild slowing in terminal stages of the disease and helps in distinguishing SMA from peripheral neuropathy.

What is electromyography finding in SMA?

EMG shows fibrillation potentials and other signs of the denervation of muscle. There is no need for a muscle biopsy, which demonstrates a neurogenic pattern with group atrophy in all forms of SMA.

How do we diagnose SMA?

Molecular genetic testing with targeted mutational analysis can confirm the diagnosis and SMN2 copy number testing.

Absence of SMN1 exon 7 confirms diagnosis

Real time PCR and Multiplex-ligation dependent probe amplification (MLPA) gives a quick and reliable results.

What is the sensitivity and specificity of genetic testing and how can we further improve?

95% sensitivity and 100 %  specificity

Semiquantitative assays improve the diagnostic sensitivity up to 98%.

What type of mutations are most often identified in SMA based on molecular testing?

What is the difference between SMN1 and SMN2 gene?

The critical difference between SMN1 and SMN2 is a cytosine (C) to thymine (T) transition in exon 7 of SMN2

 

Both SMN1 and SMN2 genes can produce the full-length SMN mRNA transcript required to make normal SMN protein, along with other more unstable transcripts. However, while the full-length transcript is the major product of SMN1, SMN2 produces smaller amounts of the full-length SMN mRNA transcript and hence smaller amounts of full-length (functional) SMN protein. 

Where are SMN protein encoded by SMN gene located?

It is localized in a bright dot like structure called gems (gemini of Cajal bodies) in the nucleus

What are the pathophysiological findings in case of SMA?

What determines the severity of disease?

As mentioned earlier SMN2 copy number – major protective modifier

Amount of functional SMN1 protein

Genetic modifiers like plastin 3 and neurocalcin.

Can we diagnose SMA prenatally?

Yes by CVS and amniocentesis

Newborn screening in SMA cases

Pre-symptomatic SMA can be diagnosed by NBS

DNA extracted from newborn blood spots is tested using real-time PCR.

Challenges in newborn screening include the inability to detect carriers of heterozygous deletions of SMN1, and SMN2 copy numbers.

How do we manage cases of SMA?

Management of complications –

Respiratory ailments

Nutritional

Orthopedic physiotherapy

Other organ involvement

Psychological

Specific agents for treatment

What are the specific agents for treatment of SMA?

Nusinersen – anti-sense oligonucleotide that modifies splicing of the SMN2 gene to increase production of normal, full-length survival motor neuron protein, which is deficient in SMA.

What is the dosing of nusinersen?

5ml = 12 mg given intrathecally  

Treatment is initiated with four loading doses; the first three loading doses are given at 14-day intervals, while the fourth loading dose is given 30 days after the third. Thereafter, a maintenance dose is given once every four months. The cost of each dose is listed as $125,000.

Which TRIALS led to the approval of nusinersen for treatment of SMA?

ENDEAR trial for < 6months old children

CHERISH trial for 2 to 12 years

After FDA approval, children enrolled in ENDEAR, CHERISH, and other nusinersen trials were eligible to participate in a phase 3 extension study named SHINE

US FDA and European medicines Agency has approved nusinersen for use.

What is the role of gene therapy in SMA patients?

Onasemnogene abeparvovec is a recombinant adeno-associated viral vector containing complementary DNA encoding for the normal SMN1 protein.

Approved for FDA for use in children < 2 yrs of age.

What is the dosing of gene therapy?

Single dose

Steroids started 1 day before the therapy

Montor for AST and ALT

What is the cost of Onasemnogene abeparvovec?

2,125,000 $

What is the role of oral olesoxime?

Phase 2 studies with oral olesoxime (TRO19622) in the SMA type II or nonambulant type III patient population showed stabilization or improvement compared with placebo. 

Although the primary endpoint was not met, olesoxime was safe and might be used in combination with other drugs targeting other mechanisms of the disease. 

What are the non-5q SMAs?

Inherited SMAs which are not caused due to SMN mutation/deletion in chromosome 5. Although very rare, non-5q SMA forms are clinically and genetically heterogeneous. 

SMA Jokela type

Fazio-Londe disease, bulbar palsy