Werdnig-hoffman disease

A group of inherited disorders characterized by degeneration of motor neurons

Spinal Muscular Atrophy (SMA)
MRI showing spinal cord atrophy in SMA
Synonyms	SMA, Werdnig–Hoffmann disease, Kugelberg–Welander disease
Pronounce	N/A
Field	Neurology, Genetics
Symptoms	Muscle weakness, hypotonia, respiratory failure, motor delay
Complications	N/A
Onset	Infancy to adulthood (depending on type)
Duration	N/A
Types	SMA Type I, II, III, IV
Causes	Autosomal recessive mutation in the SMN1 gene
Risks	N/A
Diagnosis	Genetic testing, electromyography, muscle biopsy
Differential diagnosis	N/A
Prevention	N/A
Treatment	Gene therapy, antisense oligonucleotide therapy, supportive care
Medication	N/A
Prognosis	Varies by type; improved with modern treatments
Frequency	1 in 6,000 to 10,000 live births
Deaths	N/A

Spinal muscular atrophy (SMA) is a group of inherited disorders characterized by the progressive loss of motor neurons in the spinal cord and lower brainstem. These motor neurons are essential for controlling skeletal muscle activity such as walking, swallowing, breathing, and speaking.

Other Names

• Werdnig–Hoffmann disease (SMA Type I)
• Kugelberg–Welander disease (SMA Type III)
• Proximal spinal muscular atrophy

Pathophysiology

SMA involves the degeneration of alpha motor neurons, which are nerve cells in the anterior horn of the spinal cord and brainstem responsible for voluntary muscle movement. As these neurons die, communication between the nervous system and muscles breaks down, leading to muscle atrophy and weakness.

The loss of motor neurons results in:

• Reduced muscle tone (hypotonia)
• Diminished or absent deep tendon reflexes
• Progressive paralysis of proximal muscles
• Respiratory and swallowing complications in severe cases

Cause

The majority of SMA cases are caused by mutations or deletions in the SMN1 (Survival Motor Neuron 1) gene located on chromosome 5q13. This gene encodes the SMN protein, which is crucial for the survival of motor neurons.

A nearly identical gene, SMN2, exists but primarily produces a truncated, nonfunctional version of the SMN protein. The number of copies of SMN2 influences the severity of the disease — more copies often result in milder phenotypes.

Types

SMA is classified into several types based on the age of onset and the highest motor milestone achieved:

Type I (Werdnig–Hoffmann disease)

• Onset: Before 6 months of age
• Severity: Most severe and common form
• Symptoms: Severe muscle weakness, contractures, absent reflexes, feeding difficulties, respiratory failure
• Prognosis: Without intervention, most children do not survive beyond 2 years

Type II

• Onset: Between 6–18 months
• Symptoms: Can sit unsupported but cannot stand or walk unaided; scoliosis, joint contractures, restrictive lung disease
• Prognosis: Reduced lifespan, but many live into adolescence or young adulthood

Type III (Kugelberg–Welander disease)

• Onset: After 18 months (may be diagnosed in childhood or adolescence)
• Symptoms: Can walk independently but may lose mobility over time; musculoskeletal deformities, frequent respiratory infections
• Prognosis: Normal life expectancy with care; may require mobility aids

Type IV

• Onset: Adulthood (usually after age 21)
• Symptoms: Mild to moderate muscle weakness, especially in the lower limbs, occasional tremors or fatigue
• Prognosis: Normal life expectancy with minimal impact on daily activities

Diagnosis

Diagnosis is typically confirmed by:

• Genetic testing to identify mutations or deletions in the SMN1 gene
• Electromyography (EMG) and nerve conduction studies to assess motor unit abnormalities
• Muscle biopsy (rarely used now)
• Newborn screening in some regions

Treatment

Although there is no cure, several disease-modifying therapies have significantly changed the prognosis for SMA:

FDA-approved therapies

• Nusinersen (Spinraza) – An antisense oligonucleotide that modifies SMN2 splicing to produce more functional SMN protein
• Onasemnogene abeparvovec (Zolgensma) – A one-time gene therapy that delivers a functional copy of the SMN1 gene via AAV vector
• Risdiplam (Evrysdi) – An oral medication that enhances SMN2 splicing

Supportive care

• Respiratory therapy, mechanical ventilation, and airway clearance techniques
• Nutritional support, including feeding tubes for those with swallowing difficulty
• Physical therapy to maintain mobility and prevent contractures
• Orthopedic surgery for scoliosis or joint issues

Prognosis

The prognosis of SMA has improved dramatically with early diagnosis and modern therapies. Outcomes depend on the type and severity:

• Type I: Historically fatal, but with early treatment, survival and motor function can significantly improve
• Type II & III: Many live into adulthood with appropriate care
• Type IV: Generally mild with normal life expectancy

Early initiation of treatment offers the best outcomes, particularly before the loss of motor neurons becomes irreversible.

Epidemiology

SMA affects approximately:

• 1 in 6,000 to 10,000 live births worldwide
• Carrier frequency is about 1 in 40–50 individuals

It is one of the most common genetic causes of infant mortality.

See Also

• Muscular dystrophy
• Motor neuron disease
• Amyotrophic lateral sclerosis
• Newborn screening
• Neuromuscular disorder
• Gene therapy
• Assistive technology

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External links

• Comprehensive information from the National Institute of health.
  

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NIH genetic and rare disease info

• NIH info on Werdnig-hoffman disease

Werdnig-hoffman disease is a rare disease.