Diagnosing Spinal Muscular Atrophy Nancy Kuntz, MD Professor of - PowerPoint PPT Presentation

CME / CE Diagnosing Spinal Muscular Atrophy Nancy Kuntz, MD Professor of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine

What is SMA? Spinal Muscular Atrophy • A progressive genetic neurodegenerative disorder • Mutations in SMN1 gene lead to reduced SMN protein • Reduced SMN protein levels results in a plethora of cellular events that can lead to neuronal degeneration • Primarily affecting lower motor neuron Shorrock HK et al. Drugs. 2018; 78: 293-305. Bharucha-Goebel D, Kaufmann P. Curr Neurol Neurosci Rep. 29017;17:91

SMN Has Multiple Functions Within the Cell • SMN is involved in RNA Splicing – SMN is part of a large multi-protein complex involved in many cellular processes. It’s best characterized role in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and pre-RNA splicing • SMN may have neuron- specific functions – Axonal transport of proteins and mRNA? Carrel et al 2006 Zhang et al. 2003 Carrel et al. J Neurosci. 2006; 26: 11014-11022. Zhang et al. J Neurosci. 2003; 23: 6627-6637. Licensed under: https://creativecommons.org/licenses/by-nc-nd/3.0/.

The Genetics of SMA • Multiple genetic and infectious illnesses affect motor neurons • Most common form of Spinal Muscular Atrophy caused by SMN1 gene mutation on chromosome 5 • Autosomal recessive inheritance Peeters K et al. Brain. 2014; 137: 2879-2896. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

The Genetics of SMA Image courtesy Dr. Kuntz in cooperation with SMA UK

The Genetics of SMA • SMN1 gene mutation leads to SMA • Inverse relationship between clinical severity and SMN2 copy count • Each copy of SMN2 gene present transcribes small amount of functional SMN protein Talbot et al. Gene Ther. 2017; 24: 529-533. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Historical SMA Classification Milestones Natural Number of SMA Type Onset achieved history SMN2 genes 0 (or IA) Prenatal None Death in weeks 1 Death by 2 nd or 3 rd IB < 3 months Poor or absent head control 2 year Plateau in first 2 IC > 3 months Head control 3 years Survive to early 2 > 6 months Able to sit unaided 3 adulthood Early loss of 3A 18 – 36 months Able to walk unaided 3 ambulation Later loss of 3B > 3 years Able to walk unaided 3-4 ambulation 4 10 – 20 years Able to walk unaided Ambulant 4 Adapted from Talbot et al. Gene Ther. 2017; 24: 529-533. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Age (months) Adapted from Lin et al. Ped Neurol. 2015; 53: 293-300. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Diagnostic Challenges ‘You couldn’t put your finger on it but you knew that there was something.’ • Grandmother of girl, SMA Type 2 ‘I said nothing’s wrong with my child, you go into denial saying ‘nup, nothing’s wrong, nothing’s wrong.’ • Mother of girl, SMA Type 2 ‘I took her to about a dozen different doctors and they kept saying different things: ‘she’ll be fine, she’s just a late developer’ or ‘she has an immature nervous system’ which they were accounting for the tremor.’ • Mother of girl, SMA Type 2 ‘I went to a doctor when my child was around 14 months of age stating my child is not walking and we have been doing therapy since 10 months of age. The doctor dismissed it and said his child didn’t walk ‘til they were two.’ • Mother of boy, SMA Type 2 Lawton S et al. Eur J Hum Genet. 2015; 23: 575-580.

Why Does Diagnosis Take So Long? • Newborn screening not commonly used (see Module 3 in this curriculum for more information) • Multiple clinicians involved with limited SMA experience • Disorders to consider in a differential diagnosis are: Type 1 Type 2 Type 3 X-linked infantile SMA Guillain-Barre Limb girdle muscular dystrophies SMARD1 Hexosaminidase A deficiency Spinal and bulbar muscular atrophy Prader-Willi Fazio-Londe syndrome Hirayama disease Myotonic dystrophy I Congenital muscular dystrophies Congenital MD Peripheral neuropathies Zellweger spectrum Congenital myasthenic syndromes Pompe disease Botulism Prior TW et al. GeneReviews (internet). Last updated November 14, 2019 .; personal experience

SMA Early Symptoms Infantile Onset SMA Type 1 • Symptoms of SMA type I include hypotonia (reduced muscle tone), diminished limb movements, lack of tendon reflexes, fasciculations, swallowing and feeding difficulties, and impaired breathing • These children also develop scoliosis (curvature of the spine) or other skeletal abnormalities as they get older. Without any treatment, affected children never sit or stand and the vast majority usually die of respiratory failure before the age of 2 years National Institute of Neurological Disorders and Stroke: Spinal Muscular Atrophy Fact Sheet.

SMA Early Symptoms Late Infantile Onset SMA Type 2 They are able to sit without support but are unable to stand or walk unaided • Some may lose the ability to stay seated independently over time without • treatment They may have respiratory difficulties including hypoventilation in sleep • Flu like symptoms can delay diagnosis • The progression of disease is variable without treatment • National Institute of Neurological Disorders and Stroke: Spinal Muscular Atrophy Fact Sheet.

SMA Early Symptoms Juvenile Onset SMA Type 3 • Flu like symptoms can also delay diagnosis • They first show difficulty walking and running, climbing steps, or rising from a chair • The proximal leg muscles are most often affected first, with a tremor seen in the hands • Red flag – teenager can no longer do an activity they previously could do • Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints — caused by abnormal muscle tone and weakness, which prevents the joints from moving freely National Institute of Neurological Disorders and Stroke: Spinal Muscular Atrophy Fact Sheet.

SMA Diagnosis Prior TW et al. GeneReviews (internet). Last updated November 14, 2019 . Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Summary • SMA is a genetic neurodegenerative disorder • Mostly affects lower motor neurons • Cognition is not affected • Due to mutations in SMN1 gene • Clinical severity largely dependent on number of SMN2 copies • Severity and age of onset comprise a spectrum • Newborn screening advised but currently limited to a few states • Delays in diagnosis can lead to irreversible loss of motor neurons and motor function • Treatments are now available and FDA approved