Motor Neuron Diseases - Recognising Early Symptoms Makes the Difference

05 Nov 2025 | Defining Med

Dr. Crystal Jing Jing Yeo
Consultant, Department of Neurology, National Neuroscience Institute

Motor Neuron Diseases

Motor neuron diseases are often difficult to diagnose as many of their associated symptoms can be vague and similar to those of other conditions. We share pointers on what to look out for and the pathway to shared care between primary care physicians and specialists.

INTRODUCTION

Motor neuron diseases (MND) encompass a spectrum of progressive neuro degenerative disorders that selectively affect motor neurons in the brain and spinal cord. The two principle forms seen in Singapore are:

Amyotrophic lateral sclerosis (ALS)
The most common MND in adults, characterised by relentless, asymmetric weakness due to combined upper motor neuron (UMN) and lower motor neuron (LMN) degeneration.
Spinal muscular atrophy (SMA)
A genetically determined LMN disease. Although classically a childhood disorder, milder forms (Types 2-4) survive into adolescence and adulthood or may first present in adult practice.

Early recognition in primary care allows timely referral for diagnosis, access to disease-modifying treatments and coordinated supportive care.

Upper and Lower Motor Neuron Involvement in Motor Neuron Diseases

The following case-based guide summarises the epidemiology, clinical features, diagnostic pathway, and management of adults with ALS and SMA for general practitioners (GPs).

EPIDEMIOLOGY IN SINGAPORE

ALS

There is a prevalence of approximately 2-3 cases per 100,000, with 30-50 new diagnoses each year. Details on the first Singapore ALS registry and prognostic factors are here.¹
Most patients present between ages 50-70; men are slightly more frequently affected.
Familial ALS accounts for ~5-10% of cases, most cases are sporadic.

SMA 2-4

SMA is caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. Incidence is 1/10,000.SMN2: A backup SMN2 gene produces 10% the protein that SMN1 produces, with more SMN2 copies causing milder SMA disease.

Type 1 accounts for the majority of infant deaths in untreated SMA. With new disease modifying drugs approved by HSA since 2021, those treated survive to childhood and longer. Types 2-4 predominate among adult survivors.

SMA Type 2: onset 6-18 months; many children survive into adulthood due to improved respiratory support and disease-modifying therapies.
SMA Type 3: onset after 18 months; patients remain ambulant into adolescence or adulthood but develop slowly progressive proximal weakness.
SMA Type 4: true adult-onset (after age 18);extremely rare and typically presents with mildsymmetric proximal weakness.

CASE VIGNETTES

Case 1
ALS
Mr Tan, a 58-year-old accountant, reported progressive difficulty buttoning his shirt and using chopsticks over six months. Examination revealed wasting and fasciculations of the right hand, brisk reflexes and subtle dysarthria. He had no pain or sensory loss.

Such asymmetric, painless weakness with combined UMN and LMN signs should raise suspicion for ALS.

Case 2
Adult with SMA
Ms Lee, a 34-year-old teacher, had a lifelong history of proximal leg weakness. She struggled with stairs, developed scoliosis and fatigue but remained ambulant. There were no UMN signs or sensory symptoms.

Genetic testing confirmed homozygous SMN1 deletion with four SMN2 copies (SMA Type 3). This case illustrates how SMA can present with slowly progressive, symmetric proximal weakness and scoliosis in adulthood.

CLINICAL FEATURES AND PROGRESSION

The following points distinguish ALS from adults with SMA:

Motor neuron involvement: ALS features degeneration of both upper and lower motor neurons, where as SMA involves lower motor neurons only.
Weakness pattern: ALS typically presents with asymmetric limb or bulbar onset that evolves rapidly over 2-5 years. SMA produces symmetric proximal weakness (hips/shoulders) that progresses slowly over decades.
Scoliosis is characteristic of SMA due to long-standing proximal weakness.
Cognitive changes (frontotemporal dementia) occur in ~15% of ALS patients but are not seen in SMA
Sensory symptoms are absent in both conditions.
Fasciculations and muscle wasting occur in both disorders.

Summary of Clinical Features

Table 1
Feature	Amyotrophic lateral sclerosis	Adults with spinal muscular atrophy
Onset	50-70s, rapid course (2-5 years)	Adolescence/adulthood, slow progression over decades
Weakness pattern	Asymmetric, mixed UMN + LMN	Symmetric, LMN only
Reflexes	Brisk, UMN signs present	Normal or hypoactive
Bulbar symptoms	Common (dysarthria, dysphagia)	Common (dysarthria, dysphagia)
Sensory/Pain	Absent; sensation preserved	Absent; sensation preserved
Cognition	~15% develop FTD	Preserved

Key Takeaway
Think of MND when progressive motor decline is painless and without sensory loss.

GP MANAGEMENT

General practitioners play a crucial role in recognising potential MND and arranging timely referral. Key steps include:

Identify red flags: Progressive, painless motor weakness without sensory loss; fasciculations; mixed UMN/LMN signs; bulbar symptoms; scoliosis or long-standing proximal weakness.
Exclude mimics: Order baseline tests (complete blood count, thyroid function, vitamin B12, creatine kinase, electrolytes) to rule out treatable causes (e.g., neuropathy, myopathy, endocrine disorders).
Provide early supportive care: Manage cramps, spasticity, nutrition and vaccination (influenza, pneumococcal). Address psychological distress and caregiver burden.
Refer to Neurologist: Early referral ensures access to diagnostic confirmation and disease-modifying therapies.

Indications for referral include progressive unexplained weakness, mixed UMN/LMN signs, bulbar symptoms, scoliosis or suspected genetic neuromuscular disease.

SPECIALIST DIAGNOSIS AND TREATMENT

At NNI Neurology, patients undergo specialised assessment:

ALS Diagnosis

SMA Diagnosis

ALS diagnosis relies on clinical evaluation supported by electromyography (EMG) and nerve conduction studies (NCS) demonstrating widespread denervation and exclusion of mimics.
A diagnosis of ALS is confirmed when progressive motor impairment is accompanied by UMN and LMN dysfunction in ≥1 region or LMN dysfunction in ≥2 regions with no alternative explanation (the Gold Coast criteria).
Disease-modifying treatments include riluzole (prolongs survival by 2-3 months) and edaravone (offers modest functional preservation) with ethical considerations.³
A multidisciplinary approach provides non invasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), speech and swallow therapy, mobility aids and palliative support.

SMA diagnosis is confirmed by genetictesting for homozygous SMN1 deletion and determination of SMN2 copy number. Electrophysiology shows chronic denervation with preserved sensory responses.
Disease-modifying therapies now available for adults include nusinersen (intrathecal antisense oligonucleotide) and risdiplam (oral SMN2 splicing modifier). In adults, these treatments stabilise or modestly improve motor function and fatigue. ^4,5
Supportive care includes physiotherapy, orthotic management of scoliosis, respiratory monitoring, nutritional optimisation, non invasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), speech and swallow therapy, mobility aids.

Summary of Diagnosis and Treatment for ALS and SMA

Table 2
Aspect	ALS	SMA
Diagnosis	Clinical evaluation supported by EMG and NCS showing widespread denervation and exclusion of mimics. Confirmed when progressive motor impairment is accompanied by UMN + LMN dysfunction in ≥1 region, or LMN dysfunction in ≥2 regions, with no alternative explanation (Gold Coast criteria).	Confirmed by genetic testing for homozygous SMN1 deletion and SMN2 copy number. Electrophysiology shows chronic denervation with preserved sensory responses.
Disease modifying treatments	Riluzole – prolongs survival by 2-3 months Edaravone – modest functional preservation Ethical considerations apply	Nusinersen – intrathecal antisense oligonucleotide that increases protein expression from SMN2 Risdiplam – oral SMN2 splicing modifier In adults, stabilises or modestly improves motor function and fatigue
Supportive care	Multidisciplinary care with: Physiotherapy Occupational therapy Respiratory monitoring Nutritional optimisation Non-invasive ventilation (NIV) PEG feeding Speech/swallow therapy Mobility aids Palliative support	Supportive care with: Physiotherapy Orthotic management of scoliosis Occupational therapy Respiratory monitoring Nutritional optimisation Non-invasive ventilation (NIV) PEG feeding Speech/swallow therapy Mobility aids

Key Takeaway
Both diseases have disease-modifying therapies with modest effects in adults; the mainstay of treatment is supportive care.

SHARED CARE AND FOLLOW-UP

After diagnosis, patients remain under shared care between specialists and GPs, with GPs carrying out the following functions:

Monitor comorbidities (e.g., hypertension, diabetes) and provide routine health maintenance and preventive care.
Track weight and respiratory status, refer promptly for nutritional support or respiratory assessment and NIV consideration if required.
Review and reconcile medications to avoid polypharmacy and drug interactions.
Administer vaccinations and screen for osteoporosis (particularly in immobile patients).
Provide ongoing psychological support and assist with advanced care planning and end-of-life discussions.
Close collaboration ensures timely adjustments to therapy and coordinated palliative care when needed.

DIAGNOSTIC PATHWAYS

Flow diagrams highlighting the diagnostic pathways for ALS and adults with SMA seen at NNI are included below. Arrows indicate the direction from initial GP suspicion through specialist evaluation to diagnosis and treatment.

ALS Diagnostic & Care Pathway (Singapore)	Adult SMA Diagnostic & Care Pathway (Singapore)
GP Encounter Progressive, painless weakness, no sensory loss Initial labs (TSH, B12, CK, electrolytes)	GP Encounter Slowly progressive proximal weakness Symmetric, scoliosis possible No sensory loss, painless
NNI Neurology Neurological assessment, EMG/NCS, brain and cervical MRI Rule out mimics	NNI Neurology Neurological assessment, EMG/NCS Refer for genetic testing (SMN1/SMN2)
Neuromuscular Specialist Confirm ALS suspicion Discuss treatment options	Neuromuscular Specialist Confirm adult SMA diagnosis Counsel on therapies
ALS Treatment Riluzole, Edaravone NIV, PEG, Speech/swallow therapy Mobility aids, palliative care, physical and occupational therapy, dietition	SMA Treatment Nusinsersen, Risdiplam (usually used due to oral administration and MAF listing), NIV, PEG Speech/swallow therapy, physical and occupational therapy, dietitian, mobility aids, genetic counselling
GP Shared Care Manage comorbidities, monitor weight, manage osteoporosis Vaccinations, psychosocial support Advance care planning	GP Shared Care Manage comorbidities, monitor weight, manage osteoporosis Vaccinations, psychosocial support Advance care planning

REFERENCES

1. Xu IQ, Guo L, Xu J, Setiawan S, Deng X, Lo YL, Chai JYH, Simmons Z, Ramasamy S, Crystal Jing Jing Yeo. Predictive analysis of amyotrophic lateral sclerosis progression and mortality in a clinic cohort from Singapore. Muscle & Nerve. 2025;72(1):71–81. doi:10.1002/mus.28416.
2. Crystal Jing Jing Yeo, Tizzano EFT, Darras BT. Challenges and opportunities in spinal muscular atrophy therapeutics. Lancet Neurology. 2024;23(2):205–218. doi:10.1016/S1474-4422(23)00419-2.
3. Crystal Jing Jing Yeo, Simmons Z. Discussing edaravone with the ALS patient: an ethical framework from a U.S. perspective. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 2018;19(3–4):167–172.
4. Crystal Jing Jing Yeo, Simeone SD, Townsend EL, Zhang RZ, Swoboda KJ. Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy.J Neuromuscul Dis. 2020;7(3):257-268. doi: 10.3233/JND-190453. PMID: 32333595..
5. Crystal Jing Jing Yeo (Guest). Podcast: Spinal Muscular Atrophy (SMA) and its Management. American Association of Neuromuscular & Electrodiagnostic Medicine

Dr Crystal Jing Jing Yeo is a neurologist who is US Board-Certified in Neurology, Neuromuscular Medicine, Electrodiagnostic Medicine and Neuromuscular Ultrasound. At NNI, she manages neuromuscular patients and performs EMG, nerve conductions, and ultrasound. She leads the Translational Neuromuscular Medicine Laboratory at A*STAR and collaborates internationally on advancing patient care.

GPs who would like more information, please contact Dr. Crystal Yeo at crystal.yeo.j.j@singhealth.com.sg

GPs Appointment Hotline:
6326 6060 (SGH Campus)
6330 6363 (TTSH Campus)