Dr.Sree Lekshmy.S, Dr.Sajitha Nair, Dr.Sindhu, Dr.Sreya Nair ,DrC Jayakumar
Two year old female second born, non consangenous pareatage presented with wet cough of 1week, high grade intermittent fever of 4days and breathing difficulty
Child was conscious, tachypneic intercostal and subcostal retractions but no desaturation.
Clinical examination revealed weak cough, bell shaped chest and paradoxical abdominal breathing pattern. Chest examination revealed bilateral crepitations. Nervous system examination revealed tongue fasciculations, generalised hypotonia, power- 3/5 on UL, 2/5 on LL (proximal muscles >distal), DTRs were absent, Plantar- flexor.
Labs showed
Tc- 17ku/ml,
N-67%, L-30%
CRP- 89mg/dl
Chest xray bilateral paracardiac infiltrates with segmental collapse of right upper lobe. Child was started on Inj Ceftriaxone.
Ba was observed to be floppy and had reduced spontaneous movements of limbs after birth. Cry was weak.
She attained social smile 6 weeks, but did not attain neck control.
At 5 months during an episode of lower respiratory infection, she was evaluated for hypotonia.
Differentials considered:
Congenital myopathies
Spinal muscular atrophy(SMA)
Cerebral palsy
Syndromes – Down syndrome, Prader-Willi syndrome
Metabolic disorders
Creatine kinase was normal. Nerve conduction study was also normal. MRI Brain done was normal. Genetic evaluation done revealed homozygous deletion of exons 7 and 8 in the SMN1 gene, which was suggestive of SMA Type 1.
She was started on Oral Risdiplam at 8 months of age.
After 1.5months of starting Risdiplam she had momentary NC on holding ba vertically, she could transfer objects, pincer grasp started appearing . After 3 months she had partial neck control, could raise arm above shoulders. At present Gross Motor: Neck control attained, sits without support, Fine Motor: reach out objects, transfer objects & hold objects, scribbles. Muscle tone, sound and cry is better.
Discussion:
Introduction: SMA is a degenerative disease of motor neurons that begins in fetal life and continues to be progressive in infancy and childhood.
The pathologic hallmark of SMA is the progressive denervation of muscle.
Incidence: is estimated to be 1 in 6,000-10,000 newborns.
Inheritance: Autosomal recessive (most common)
Pathology: caused a homozygous deletion in the survival motor neuron 1 (SMN1) gene on chromosome 5q13.
It appears to be a pathologic continuation of a process of programmed cell death (apoptosis) that is normal in embryonic life. If the process that arrests physiologic cell death fails to intervene a certain stage, neuronal death can continue in late fetal life and postnatally. The survivor motor neuron gene (SMN) arrests apoptosis of motor neuroblasts.
Classification: Types 0 congenital type 1 (most common)Werdnig Hoffmann disease 2Dubowitz disease 3 Kugelberg welander and 4Adult type
Clinically: Severe hypotonia, symmetrical generalised muscle weakness (LL>UL), tongue fasciculations, absent DTRs, weak cough, bell shaped chest, paradoxical abdominal breathing pattern, frog leg posture. Alert and bright expression, preserved cognitive functions.
Investigations:
i. Serum Creatine kinase (CK) – Normal, mildly elevated (up to 2- to 4-fold).
ii. Chest x-ray – Thin ribs (early onset disease).
iii. Electrocardiography (ECG) – Baseline tremor representing muscle fibrillations more prominent on lead II.
iv. Nerve conduction studies (NCS)- Normal, except for mild slowing in terminal stages of disease.
Diagnosis:
i. SMN 1 deletion/mutation and SMN2 copy number testing – Gold Standard – absence of SMN1 exon 7 confirms the diagnosis.
ii. Real-time PCR – give reliable SMN1 gene copy numbers.
iii. Multiplex ligation dependent probe amplification.
iv. Muscle Biopsy – used in patient with equivocal/negative genetic finding.
Management: Multidisciplinary and supportive approach
i. Gene therapy -Risdiplam, Zolgensma, Nusinersin.
ii. Genetic counselling
iii. Prenatal diagnosis- Offered to families with an index patient. Antenatal screening Chorionic villous sampling – b/w 10th and 12th week of gestation may serve for SMN1 deletion/mutation analysis.
Risdiplam: Action: SMN2 splicing modifier that binds two sites in SMN2 pre messenger RNA, there correcting splicing deficit of SMN2 leading to increased levels of full length SMN protein
FDA : pediatric & adult patients, Route : Oral
Dose: once a day after a meal using an oral syringe
2m – <2yrs: 0.2mg/kg OD
2yrs (