This document discusses non-5q spinal muscular atrophy (SMA). It begins by describing the upper motor neuron (UMN) and lower motor neuron (LMN) pathways. The majority of SMA cases are caused by mutations on chromosome 5q, but 4% are non-5q SMA. Non-5q SMA is clinically and genetically heterogeneous. Several causal genes have been identified for different subtypes. The document then describes the clinical features and inheritance patterns of several rare non-5q SMA subtypes. Advanced genetic testing techniques like next-generation sequencing have helped identify more causal genes but also increased heterogeneity. Management involves symptom management while future challenges include determining pathogenicity of variants and developing accurate models.

1. NON 5q SMA
Dr Ravi goyal
SR neurology
GMC kota

2.  The UMN is a motor neuron, the cell body lies
within the motor cortex of the cerebrum, and the
axon forms the corticobulbar and corticospinal
tracts.
 The LMN lying in the brainstem motor nuclei and
the anterior horns of the spinal cord, directly
innervate skeletal muscles.
 The UMNs are rostral to the LMNs and exert direct
or indirect supranuclear control over the LMNs .

3.  The SMA are a group of disorders caused by
degeneration of anterior horn cells and in some
subtypes, of bulbar motor neuron.
 Majority (96%) related with mutation in 5q
chromosome – 5q SMA
 Another (4%) –Non 5q SMA

4.  Almost all cases are genetically determined, with
most being autosomal recessive due to
homozygous deletions of the survival motor
neuron (SMN) gene on chromosome 5q13.

7.  begins within the first few months of life.
 never able to sit without support.
 Symptoms include severe hypotonia, a weak cry and
respiratory distress.
 posture - characteristic “frog-leg” position.
 Death from respiratory failure, pneumonia, and
malnutrition usually occurs before age 2 years.

8.  usually begin between the ages of 6 and18 months.
 Delayed motor milestones are often the first clue.
 A fine hand tremor due to minipolymyoclonus suggests
diagnosis.
 It is quantitatively much milder, and progression is slower.
 Contractures of the hips and knees, clubfoot deformities,
severe scoliosis, and dislocation of the hips.
 survive into the third or fourth decade of adulthood.

9.  The onset is typically after 18 months of age (usually
between 5 and 15 yr years) and presents with difficulty in
walking .
 The disorder has an appearance not unlike a limb-girdle
muscular dystrophy With waddling gait.
 The clinical course of SMA 3 is slow progressive limb-
girdle weakness, with long periods of stability that last
for years.

10.  The characteristic clinical presentation is a slowly progressive
limb-girdle weakness leading to difficulty in walking, climbing
stairs, and rising from a chair or the floor.
 Fasciculations are an important finding and occur in 75% of
patients.
 Quadriceps muscle weakness is often a prominent feature.
 Bulbar signs, bony deformities such as scoliosis and respiratory
weakness are rare.
 Many cases have a distribution of weakness reminiscent of the
limb-girdle muscular dystrophies, leading to the older term,
pseudomyopathic SMA .

11.  very rare entity.
 clinically and genetically heterogeneous.
 Classified on the basis of -
 1. distribution of muscle weakness
(proximal, distal or bulbar)
 2. inheritance pattern (autosomal dominant,
autosomal recessive or X-linked)

12. Axon : Transport – DCTN1 ,BICD2
Chaperons –heat shock protein –HSPB1 ,HSPB3 , HSPB8
DNA/RNA – Processing - IGHMBP2
tRNA synthetase –GARS
Endoplasmic Reticulum - BSCL2
Membrane and synapse function –
neurotransmitter processing and synthesis –SLC5A7
ION flux –TRPV4
Signal transduction – NFKB1 –PLEKHG5

13.  The clinical hallmark is symmetrical muscle
weakness more for proximal than distal limb
muscles.
 Affecting the legs more than the arm.
 The clinical course ranges from static to rapidly
progressive, leading to respiratory distress
requiring mechanical Ventilation.

14.  Deep tendon reflexes can vary from absent to
brisk, depending on form, age at onset and
duration of he disease.
 In most cases intellect is preserved.
 It may be Early onset
Late onset

15.  Congenital to childhood onset
 May be AD , AR or XR
 Additional features, such as arthrogryposis,
myoclonic epilepsy, sensorineural deafness, or
pontocerebellar hypoplasia may be there .

17.  It is a rare disorder, with a variable onset age (from infancy
to early in the third decade).
 Encompassing sensorineural deafness, bulbar palsy and
respiratory compromise, often causing death.
 Type 1 is an AR condition caused by mutations in solute
carrier family 52, riboflavin transporter, member 3
(SLC52A3) implicated in dietary uptake of riboflavin.
 Type 2 is also AR condition related to mutations in
another riboflavin transporter gene, SLC52A2 function
 in riboflavin uptake from blood to target cells.

18.  Fazio-Londe syndrome is considered the same
disease entity as Brown-Vialetto-Van Laere
syndrome but it does not involve hearing loss.
 Type 1 have decreased plasma levels of riboflavin
and its coenzyme forms so oral supplementation
of riboflavin provides a life-saving treatment .
 Although patients with type 2 do not show reduced
plasma riboflavin, but they are also responsive to
high-dose oral riboflavin treatment.

24.  AR (SMARD1 /HMN6 /DSMA1)
 Gene mutation - IGHMBP2 (transcription factor)
 Age- congenital to 2 year (3 to 6 month of life).
 Presented with hypotonia distal>proximal weakness
 diaphagramatic paralysis (ventilator dependent)
cardiomyopathy and lactic acidosis .

25.  AR (DSMA4)
 Gene – PLEKHG (Pleckstrin homology domain
protein family G member 5
 Nuclear factor Kb activator
 Age 2-11 year
 Only LMN features

26.  GARS mutation (glyceyl tRNA synthetase)
 Age 17 yrs with rare UMN sign
 Distal SMA with UL predominance,type 5B
 BSCL2 (Seipin ) mutation
 Age 15 years
 UMN sign with Hyperhydrosis (40%)
Both have slow progression

27.  Allelic phenotype of BSCL2 gene mutation (11q12.3)
 AD
 Spastic paraparesis
 Amyotrophy of hands and feet
 Asmpytomatic 4% cases

28.  Brown –Viaietto-Van Laare syndrome
Type 1
Type 2
 Fazio Londe syndrome

29.  sporadic AD or AR progressive facial and bulbar
palsy of late childhood.
 Eventual develop respiratory failure in the second
decade of life.
 Llittle or no evidence of involvement of other motor
neurons and with normal extraocular motility.
 differential diagnosis includes a structural brainstem
lesion, myasthenia gravis, and the Miller-Fisher
variant of GBS.

30.  Molecular genetic tests :-
 Next Generation sequencing technology –
 Allow us to sequence DNA and RNA much more quickly
and cheaply than older ones with high speed.
 Include prepration of DNA , amplification by PCR and
array sequenceing .
 Electromyography to record the electrical activity From
the brain and spinal cord to a peripheral nerve root in
Arms and legs .

31. • Nerve conduction velocity studies -
• Measure electrical energy by Assessing the nerve’s
ability to send a signal.
• Muscle biopsy used to diagnose Neuromuscular
disorders and may also reveal if a person is a carrier
of a defective gene that could be passed to children.
• Serum CPK level

32.  No drug is available for curing non 5q SMA till now,
 Except Brown –Viaietto-Van Laare syndrome
(ribflavin is effective)
 Treatment consists of managing the symptoms
 and preventing complications .
 Muscle relaxants such as baclofen, tizanidine, and
the benzodiazepines may reduce spasticity.

33.  Antisense oligonucleotide increases exon 7
inclusion in SMN 2 mRNA
 FDA approved in 2016
 Intra thecal adminstration
 Dose - 12mg (5ml)

34.  4 loading doses 2 wk apart and 4th 30 days after
3rd dose, maintenance dose every 4 month
 Mc s/e respiratory infection and constipation.
 only for 5q SMA
 Very costly US$125,000 per injection

35.  It is an adeno-associated virus vector-based gene therapy .
 Indicated for the treatment of SMA less than 2 years of age with bi-
allelic mutations in the survival motor neuron 1 (SMN1) gene
 It address the genetic root cause of SMA by replacing defective SMN1
gene.
 Administration - a single, one-time intravenous (IV) infusion per year.
 Data from the Phase 3 STR1VE trial show prolonged event-free survival,
increases in motor function and significant milestone achievement in
patients with SMA Type 1, consistent with the Phase 1 START trial .

36.  FDA approved at 24 may 2019
 The most commonly adverse reactions (incidence >=5%)
elevated aminotransferases and vomiting.
 Administer systemic corticosteroid to all patients before
and after Zolgensma infusion. Continue to monitor liver
function for at least 3 months after on .
 Total cost $2.1 million or $425,000 a year spread out
over five years.
 the world’s most expensive drug.

37.  Occupational and physiotherapy improves
 Posture
 Prevent joint immobility
 Slow muscle weakness and atrophy.
Stretching and strengthening exercise reduces
 Spasticity
 Increase range of motion and
 Keeps circulation flowing.

38.  Some individual requires additional therapy for
 Speech, Chewing and swallowing difficulties.
 Assistive devices such as
 Supports or braces,
 Orthotics,
 Speech synthesizers and
 Wheelchairs may improve the quality of life with SMA.

39.  Non-5q SMA has long represented a challenge for
clinicians and scientists due to its enormous
variability, both clinically and genetically.
 The advances in next generation sequencing have
elucidated the causal genes for many SMA types,
 yet this only further complicates matters by revealing
overlaps with several other neuromuscular disorders.

40.  The major challenge for the future will be
determining the pathogenicity of the causal
mutation among a multitude of genetic
alterations.
 To this end, platforms for sharing of next
generation sequencing data should be developed
to increase the chances of finding a second hit,
 Accurate and predictive models of SMA should
be created by screening of potential mutations
and for the identification of drug hits.

41.  Pestronk A. Hereditary motor syndromes. Available at:
 http://neuromuscular.wustl.edu/synmot.html. Accessed
February 11, 2011.
 Harms MB, Allred P, Gardner R Jr, et al. Dominant spinal
muscular atrophy with lower extremity predominance:
linkage to 14q32. Neurology 2010;75:539 –546.
 Jokela M, Penttilä S, Huovinen S, et al. Late-onset lower
 motor neuronopathy: a new autosomal dominant
disorder.
 Neurology 2011;77:334 –340 Basil T. Darras
 Non-5q spinal muscular atrophies: The alphanumeric
soup thickens

42. THANK YOU