Werdnig-Hoffman Disease

Synonyms: spinal muscular atrophy type 1, SMA type 1, infantile spinal muscular atrophy.

Werdnig-Hoffman disease is a rare form of spinal muscular atrophy presenting in infants. It is an autosomal recessive condition characterised by the degeneration of anterior horn cells, leading to profound symmetrical weakness and wasting of voluntary muscle . It is the second most common lethal autosomal recessive disease of white populations after cystic fibrosis.

Werdnig-Hoffman describes a sub-set of spinal muscular atrophy (SMA) and is distinguished by:

• The age at presentation (before 6 months).
• Severity (death from respiratory failure, typically by the age of 2).

Patients with other forms of SMA (SMA II or Dubowitz disease and SMA III or Wohlfart-Kugelberg-Welander disease) have later onset of symptoms and a slower progression of muscle weakness and respiratory symptoms.

• Werdnig-Hoffman disease is the most common cause of genetically determined neonatal death.
• It has an incidence in the order of 1:25,000 live births in the UK.
• It has a carrier frequency of 1 in 60-80 in the UK.
• More common in boys despite the autosomal recessive inheritance. This appears to be accounted for by cases of sporadic mutation.

The survival motor neuron 1 (SMN1) gene is missing in 93% of all SMA patients² and in 50% of cases there will also be absence of both homologues of the neighbouring gene - neuronal apoptosis inhibitory protein (NAIP).³

During pregnancy:

• Reduced fetal movements during last trimester in 30%

At birth:

• Floppy baby (60%)
• Prolonged cyanosis

Postnatally:

• Severe weakness
• Respiratory difficulties
• Difficulty in sucking and/or swallowing
• Tongue fasciculations
• Poor head control
• Facial weakness
• Absent reflexes
• Congenital joint contractures
• Lack of normal motor movements

Includes:

• Amyotrophic lateral sclerosis
• Congenital myotonic dystrophy
• Congenital myopathies
• Congenital and neonatal myasthenia gravis
• Metabolic disorders
• Arthrogryposis multiplex congenita

May include:

• Serum creatine kinase levels- usually normal but may be raised
• Genetic studies
• EMG - may be difficult to interpret in young infants - may see evidence of denervation and reinnervation with normal conduction velocities
• Muscle biopsy

No specific therapy is yet available for the treatment of Werdnig-Hoffman disease. Treatment is not disease modifying. Affected children should be under the care of a multi-disciplinary team with expertise in the management of type I SMA.

Non-drug

• Support for the family throughout the lifetime of the child and beyond. Contact with other affected families can be helpful. Children's hospices can offer friendship and respite for affected families.
• The child may benefit from physiotherapy and respiratory support for the relief of symptoms. How aggressive respiratory management should be is controversial: opinion and practice vary from offering no respiratory support to the use of tracheostomy and long-term invasive ventilation.⁵ Others occupy a middle position, suggesting measures such as the use of non-invasive ventilation.⁶ The ethical dilemma in deciding what is in the child, the family and society's best interest is great.^7,8 Families need to be involved in these decisions and helped to understand the long-term implications of ventilation.²
• Only motor function is affected in these children. Sensation and intellect are normal so encouraging physical contact and interaction is important, for the well being of the child and parents.

Drug

Werdnig-Hoffman disease is an orphan disease. However, molecular genetics offers potential targets for drug therapy and the hope of gene therapy. A clinical trial network is being established.⁹

• Progressive kyphoscoliosis
• Failure to thrive
• Dysphagia and feeding difficulties
• Constipation
• Joint contractures
• High frequency of pathological fractures and hypercalcaemia
• Pneumonia
• Respiratory failure

The outlook for children with Werdnig-Hoffman disease is very poor:

• Median survival is 7 months and 95% of children with the disease have died by 18 months old.⁴
• Prognosticating for individual children is difficult however - several studies have cited individual cases where children have had onset of symptoms before the age of 6 months and not developed respiratory failure for years. The genetic basis of this phenotypic variability is not understood.²
• Non-invasive respiratory support and prompt treatment of respiratory complications also appear to prolong survival but not alter disease course.⁵

Parents may wish to have genetic counselling before considering any further pregnancies. Pre-natal testing has been available since 1998 for families who have had an affected child.¹