Werdnig-Hoffmann Disease

Etiology

Werdnig-Hoffmann disease is acquired in an autosomal recessive fashion. Abnormality is noted in the survival motor neuron (SMN) gene. 2 SMN genes have been identified. Both these genes are located on chromosome 5. SMN1 gene is located at locus 5q11-q13. SMN2 is located next to the SMN1 gene. SMN1 is believed to cause SMA, while SMN2 is believed to affect the severity of the disease; higher SMN2 copies result in a milder form of SMA. In addition, other genetic mutations have been identified to play a role in the severity of SMA. 1, and such identified mutation is the deletion of neuronal apoptosis inhibitory protein (NAIP) gene.[3][4]

Epidemiology

Werdnig-Hoffmann disease affects about one in every 10,000 live births.[5] It is the second most common autosomal recessive disorder. It can affect men and women equally. About 50% of individuals die before birth. Age at presentation is always prior to 6 months of age.

Pathophysiology

Werdnig-Hoffmann disease is a motor neuron disease in which there is anterior horn cell degeneration of the spinal cord. In utero, there is an excess of motor neuroblasts, with only half surviving until birth. After birth, the disease progresses with continued loss of motor neurons in the spinal cord and brainstem.[2]

History and Physical

The majority of infants present at birth with severe weakness and wasting of the limbs. These infants have difficulty with swallowing and respiratory muscles. Other brain stem muscles also become involved, including the bulbar muscles. The distinctive feature of Werdnig-Hoffmann disease is that these individuals do not have any evidence of cerebral or higher central nervous system dysfunction. They have normal intelligence and demonstrate a keen sense of learning. Hypotonia is a very profound and classical finding. Deep tendon reflexes are absent diffusely. Hypermobility of the joints is noted secondary to poor muscle tone. The twitching of muscles of the tongue (fasciculations) is noted. Tongue fasciculations are classical findings seen in motor neuron diseases and are also seen in other motor neuron diseases like amyotrophic lateral sclerosis, etc. The child does not gain head control and is unable to sit, stand, or walk. They often have difficulties with swallowing and breathing. They have a poor sucking reflex. They have a high risk of aspiration pneumonia due to weak bulbar muscles. For infants in whom the symptoms develop after birth, motor regression occurs, and there appears to be greater involvement of lower extremities than upper extremities. Muscles controlling extraocular movements are generally spared.[6][7]

Evaluation

The diagnosis of Werdnig-Hoffmann disease is made after a detailed clinical history and physical exam. A family history of the disease is highly suggestive of the disorder. Genetic tests are available prenatally and postnatally for a definitive diagnosis. Prenatally, chorionic villus sampling or amniocentesis can be done to obtain tissues for genetic testing.[8][9]

Molecular genetic testing is available and tests for the SMN gene. Werdnig-Hoffmann disease is caused by partial or complete loss of SMN gene. Electromyography (EMG) testing can be helpful in identifying myopathic potentials, but due to the widespread availability of genetic testing, it is no longer used in the diagnosis of this condition.

Treatment / Management

There is no cure for Werdnig-Hoffmann disease.

Nusinersen is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide, and FDA approved for the treatment of SMA in adult and pediatric patients. It is administered intrathecally. It increases exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) and assists in the production of full-length SMN protein.[10]

The treatment is supportive. Medications that are often used to improve symptoms include phenylbutyrate, valproic acid, albuterol, and hydroxyurea. Unfortunately, clinical trials have not shown any definite evidence that these medications prevent the progression of the disease. Treatment is directed towards symptom control. Symptomatic treatment is aimed at support with feeding, breathing, and motor weakness.[7]

Feeding difficulties: Children often have difficulty with feeding and can have nutritional deficiencies or aspiration pneumonia secondary to swallowing difficulty. Percutaneous endoscopic gastrostomy (PEG) tubes can help with nutritional supplementation.

Respiratory difficulties: Children may require non-invasive ventilator support initially as respiratory muscles are involved. As symptoms worsen, they may need tracheostomy and ventilator support.

Motor weakness: Physical and occupational therapy can help with muscle stretching, strengthening, and minimizing contractures. Surgical procedures to help with scoliosis and braces may be helpful.

Differential Diagnosis

• Prader-Willi syndrome: Hypotonia, short stature, mental retardation, developmental delay, cognitive delay, hypersomnia, multiple endocrine abnormalities, hypogonadism, temperature instability, and central adrenal insufficiency.[11]
• Congenital myasthenia gravis: caused by a mutation in an AChR subunit gene. It presents with fatigable weakness involving the ocular and cranial muscles.[12]
• Congenital myopathies: Slowly progressive muscle disease presenting with muscle weakness with hypotonia.[13] 
• Infantile Pompe disease: Muscle disease presenting with hypotonia, hearing problems, failure to thrive, and cardiac muscle involvement.[14]
• Congenital muscular dystrophy (CMD): Individuals present with hypotonia, contractures, delay of motor milestones. 
• Arthrogryposis multiplex congenita: Individuals develop multiple joint contractures. 
• Adrenoleukodystrophy: Individuals present with seizures, trouble swallowing, hearing loss, and cognitive impairment.

Prognosis

The prognosis for Werdnig Hoffmann disease is very poor. The disease presents before 6 months of age, and it is a progressive muscular disorder that often results in early death. Most patients die prematurely either in infancy or early childhood, often by 2 years of life. This is the most common genetic cause of infant mortality.[7]

Complications

• Orthopedic complications are common secondary to hypotonia, muscle weakness, and wasting. Scoliosis, joint contractures, ankylosis are seen often. Physical and occupational therapy, orthopedic surgery, and braces can help with the management of these symptoms.
• Aspiration pneumonia may occur secondary to bulbar weakness.
• Malnutrition is a common complication secondary to swallowing difficulty.