Newborn Screening and Spinal Muscular Atrophy Nancy Kuntz, MD - - PowerPoint PPT Presentation

CME / CE

Newborn Screening and Spinal Muscular Atrophy

Nancy Kuntz, MD Professor of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine

Newborn Screening for SMA

• Recommended Uniform Screening Panel expanded to include SMA
• Advisory Committee to Secretary of Health and Human Services made

recommendation based on:

• Disorder which causes permanent damage or injury prior to onset of clinical

symptoms

• Disorder for which effective treatment has been developed
• Accurate, low cost screening methodology has been developed

The Genetics of SMA

Image courtesy Dr. Kuntz

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/.

SMA Type Onset Milestones achieved Natural history Number of SMN2 genes

0 (or IA) Prenatal None Death in weeks 1 IB < 3 months Poor or absent head control Death by 2nd or 3rd year 2 IC > 3 months Head control Plateau in first 2 years 3 2 > 6 months Able to sit unaided Survive to early adulthood 3 3A 18 – 36 months Able to walk unaided Early loss of ambulation 3 3B > 3 years Able to walk unaided Later loss of ambulation 3-4 4 10 – 20 years Able to walk unaided Ambulant 4

Historical SMA Classification

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/.

Role of SMN2 in Rescuing the SMA Phenotype

Figure courtesy Dr. Kuntz from Crawford TC et al. Annual Spinal Muscular Atrophy Conference. Jun 29 – Jul 2, 2017; Orlando. Image courtesy Dr. Kuntz.

‘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

Diagnostic Challenges

Lawton S et al. Eur J Hum Genet. 2015; 23: 575-580.

State by State

https://www.newsteps.org/resources/newborn-screening-status-all-disorders

SMA is currently screened in 12 states (as of Nov 2019)

• Georgia
• Indiana
• Kentucky
• Maryland
• Massachusetts
• Minnesota
• Missouri
• New York
• Pennsylvania
• Utah
• Vermont
• Wisconsin

SMA Newborn Screening: State by State

According to CureSMA (as of Sept 2019)

• 10 states are doing NBS
• 18 states are planning on

doing NBS for SMA

• 3 states are conducting a

pilot program

https://www.curesma.org/newborn-screening-for-sma/

• 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:

Why Does Diagnosis Take So Long?

Prior TW et al. GeneReviews (internet). Last updated November 14, 2019.; personal experience

Type 1 Type 2 Type 3

X-lined infantile SMA SMARD1 Prader-Willi Myotonic dystrophy I Congenital MD Zellweger spectrum Congenital myasthenic syndromes Pompe disease Botulism Guillain-Barre Hexosaminidase A deficiency Fazio-Londe syndrome Congenital muscular dystrophies Peripheral neuropathies Limb girdle muscular dystrophies Spinal and bulbar muscular atrophy Hirayama disease

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

Infantile Onset

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

• Children 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