Werdnig-Hoffman disease

Historical Perspective

This disease was first described by Werdnig in 1891 in two brothers at the age of 10 months who exhibited tremors and weakness in their proximal leg muscles. These two brothers died earlier and the autopsy results show the bilateral and symmetrical loss of anterior horn cells in the spinal cord . Subsequently between 1893 and 1900 Hoffman identified the same condition in seven additional patients of 3 different families these early observations include muscle weakness primarily in muscles close to the center of the body (Proximal extremities), muscle along the spine (axial muscle), and between the ribs (intercostals muscles) while the diaphragm remain less affected initially the disease has wide spectrum symptoms and short life duration. Hoffmann was the first one who introduce the term spinal muscular atrophy.

The Subtype of Type one Spinal Muscular Atrophy

Based on the onset age of the disease and severity of the disease this type 1 of SMA is divided into three subtypes.

Type 1A

This sub-type of SMA appears between birth and 15 days of life. Because of brain stem involvement and breathing difficulty, it causes problems in sucking and swallowing.

Type 1B

This sub-type appears before the age of 3 months. With motor impairment as a result infant is unable to control the head.

Type 1C

It appears between the ages of 3-6 months and infant of this stage can control their head to some extent.

Pathophysiology.

Werdnig-Hoffmann, also known as spinal muscular atrophy (SMA) type 1B and 1 C disease causes severe muscle weakness affecting the limbs and trunk of infants and preventing them from sitting up. This is a serious neuromuscular disorder condition that leads to the death of the alpha neuron in the spinal cord and brainstem, resulting in atrophy and muscular weakness, this condition of the disease causes respiratory distress due to the disappearance of tendon reflexes which can lead to death. This disease appears under the age of 6 months and through reparatory support, patients can survive on average 2 years and inhibit motor development. It is a progressive autosomal recessive disorder caused by the mutation of both alleles of gene SMN1 is the cause of the disease, SMN is an ubiquitarian protein necessary for the survival of the motor neurons (MNs). The mutation of both alleles located in chromosome 5 is responsible for the insufficient production of SMA protein as a result the death of the (MNs) occurs, and the severity of the disease varies in individuals. The discovery of SMN2 helps to clarify the reason for variability it is almost identical and located next to the SMN1 gene with the difference of 11 nucleotides and C6T change in exon 7. Because of this only 10% of SMN2 transcripts escape splicing and produce functional full-length mRNA and active protein which is insufficient for normal functioning. And the amount of SMN2 varies among individuals. Therefore SMA is less progressive in individuals with multiple copies of SMN2 because this gene is associated with the severity of the disease. Additionally, several proteins also play their role in reducing the disease severity.

Epidemiology and Demographics

The prevalence of werdnig is approximately one in every 10,000 live births.

Age

The age at the onset of the disease is always before 6 months.

Gender

werdnig Hoffman disease is not gender specific it affects both males and females equally.

Risk Factors

Numerous prognostic factors influence the course of the disease such as age, number of SMN2 copies, and thoracic circumferences.

Age

The early onset of the disease tends to be more severe, associated with the fast progression of the disease, and causes paralysis and early death.

SNM2 copies

The number of SMN2 copies does not predict the severity of the disease. However, one research report that the survival of the patient will be 8 months with the 2 genes of SMN2, and approximately 75% of the patients have two copies of the SMA gene at the earlier onset of the disease Thoracic circumference: The TC/HC (Thoracic Circumference on Head Circumference) ratio is the measure of chest size relative to head size this ratio is decreased in the case of Werdnig Hoffmann disease as they grow and a study reported that decreased ratio is associated with the poor outcome and died within 3 months of age. The causes of the death include acute pulmonary infection, airway obstruction, respiratory exhaustion, or sudden bradycardic arrest.

Diagnosis

Diagnosis of the disease is made based on the clinical history physical examination and family history, genetic testing is available for prenatal and postnatal diagnosis, EMG testing is used to identify the myopathic potentials.

Clinical sign

Cognitive development is normal in patients with werdnig disease however other Clinical signs are helpful for the diagnosis of the disease including.

• Weakness characterized by the hypotonia and absence of tendon reflex leads to poor head Reduced moment of hand, forearms, and feed-reduced
• Involuntary muscle finger muscle twitches
• Due to trunk hypotonia unable to sit
• Respiratory issues with the weakness of inter-costals muscle between ribs (bell-shaped chest deformity)
• Facial muscle weakness (loss of facial expression)
• Tongue fasciculations
• Congenital heart deficit
• Generalized paralysis and respiratory failure

Specific symptoms and complications caused by brain stem involvement

• Swallowing disorder
• Voice and speech issues
• Tongue and facial symptoms
• Vosomotor disturbance
• Severe bradycardia
• Fluctuation in blood pressure
• Marked vasomotor disorder
• Acute Gastric dilation
• Limited mouth opening
• Micro-retrognathia
• Hyper-ogival palate

Treatment

There are a few technical possibilities to maintain the life of an infant for a few times through respiratory support including ventilation and tracheotomy but this technique does not increase the life span of the individual. There to increase the life span and make the quality of life better some supportive or palliative cares are required.

Respiratory management

There are various ways to manage respiratory problems such as Physiotherapy helps to clean the respiratory tract and some patients require suction or aspiration system to make the respiratory tract mucous, oxygen therapy is given at a low rate to prevent hypoxemia, and respiratory infections are treated with antibiotics and vaccinations.

Nutritional and digestive management:

It is crucial to prevent swallowing problems to ensure enough nutrition intake .enteral nutrition intake is employed with the nasogastric feeding tube and sometimes gastrostomy tubes are utilized. At the time of the progression of the disease, infants are unable to sit and they lie down which helps them to improve the function of the diaphragm for pain management some medications are started at the age of 5.2 months including oral morphine, paracetamol, benzodiazepines, amitriptyline.

New therapies

Recently, there have been advancements in developing innovative treatments that aim to change the natural course of SMA. Three disease-modifying treatments for SMA are currently undergoing clinical trials. These treatments work by increasing the production of SMN protein in lower motor neurons through various mechanisms. These medications include Nusinersen, Risdiplam, and Onasemnogene abeparvovec.