Maladie de Werdnig-Hoffmann

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

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterised by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis¹.

Werdnig-Hoffmann disease is a form of SMA and is otherwise called SMA type 1 (SMA1). It presents 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.

Werdnig-Hoffmann disease describes a subset of SMA and is distinguished by:

• The age at presentation (before 6 months).

• Severity (death from respiratory failure, typically by the age of 2 years).

Patients with other forms of SMA - SMA type 2 (Dubowitz syndrome - SMA2) and SMA type 3 (Wohlfart-Kugelberg-Welander disease - SMA3) - have later onset of symptoms and a slower progression of muscle weakness and respiratory symptoms.

Épidémiologie¹

The estimated incidence of SMA is 1 in 6,000 to 1 in 10,000 live births and the carrier frequency of 1/40-1/60. Werdnig-Hoffmann disease (SMA1) is the most severe and common type of SMA and accounts for about 50% of patients diagnosed with SMA.

Étiologie²

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

Présentation¹

Classically, infants with SMA1 have onset of clinical signs before 6 months of age and never acquire the ability to sit unsupported.

All children with SMA1 show a combination of severe hypotonia and weakness, with sparing of the facial muscles, invariably associated with a typical respiratory pattern. The weakness is usually symmetrical and more proximal than distal, with lower limbs generally weaker than upper limbs. Deep tendon reflexes are absent or diminished but sensitivity is preserved.

In the most severe forms decreased intrauterine movements suggest prenatal onset of the disease and present with severe weakness and joint contractures at birth (this has been labeled SMN0).

Some of these children may also show congenital bone fractures and extremely thin ribs. The spared diaphragm, combined with weakened intercostal muscles, results in paradoxical breathing.

The involvement of bulbar motor neurons often give tongue fasciculation, poor suck and an increasing swallowing and feeding difficulty over time. Aspiration pneumonia is an important cause of morbidity and mortality.

There is some evidence that some cases with severe SMA1 (generally carrying one copy of SMN2) may have heart defects, mostly atrial and ventricular septal defects and a possible involvement of the autonomic system that may be responsible for arrhythmia and sudden death.

Within SMA1 at least three clinical subgroups can be defined according to the severity of clinical signs:

1. Severe weakness since birth/neonatal period - head control is never achieved.

2. Onset of weakness after the neonatal period but generally within two months - head control is never achieved.

3. Onset of weakness after the neonatal period but head control is achieved. Some of these children may be able to sit with support.

Diagnostic différentiel

Comprend :

• Sclérose latérale amyotrophique.

• Dystrophie myotonique congénitale.

• Congenital myopathies.

• Congenital and neonatal myasthenia gravis.

• Metabolic disorders.

• Arthrogryposis multiplex congenita.

Enquêtes

Il peut s'agir de

• Serum creatine kinase levels - they are usually normal but may be raised.

• Genetic studies.

• Electromyogram (EMG) - may be difficult to interpret in young infants - may see evidence of denervation and reinnervation with normal conduction velocities.

• Biopsie musculaire.

Diagnostic delay is common for children with spinal muscular atrophy⁴.

Universal prenatal screening for SMA is not cost-effective. However, SMA testing may be a cost-effective strategy for populations at high risk, such as those with a family history⁵.

Gestion

No specific therapy is yet available for the treatment of Werdnig-Hoffmann disease⁶. Treatment is not disease-modifying. Affected children should be under the care of a multidisciplinary team with expertise in the management of SMA1.

Non médicamenteux

• 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 ventilation⁷. Others occupy a middle position, suggesting measures such as the use of non-invasive ventilation⁸. The ethical dilemma in deciding what is in the child, the family and society's best interest is great⁹¹⁰. Families need to be involved in these decisions and helped to understand the long-term implications of ventilation³.

• 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 the parents.

Médicaments

Werdnig-Hoffmann disease is an orphan disease. However, molecular genetics offer potential targets for drug therapy and the hope of gene therapy. A clinical trial network is being established¹¹.

Complications

• Progressive kyphoscoliosis.

• Failure to thrive.

• Dysphagia and feeding difficulties.

• Constipation.

• Contractures articulaires.

• High frequency of pathological fractures and hypercalcaemia.

• Pneumonie.

• Insuffisance respiratoire.

Pronostic

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

• If no intervention is provided, children with Werdnig-Hoffmann disease generally do not survive beyond the first two years¹.

• 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 phenotypical variability is not understood³.

• Non-invasive respiratory support and prompt treatment of respiratory complications also appear to prolong survival but not to alter the disease course⁷.

La prévention

Parents may wish to have genetic counselling before considering any further pregnancies. Prenatal testing has been available since 1998 for families who have had an affected child².