Werdnig Hoffmann disease is the most malignant spinal muscular atrophy that develops from birth or in the first 1-1.5 years of a child’s life. It is characterized by increasing diffuse muscular atrophy, accompanied by sluggish paresis, progressing to complete plegia. As a rule, Werdnig Hoffmann disease is combined with bone deformities and congenital malformations. The diagnostic basis is anamnesis, neurological examination, electrophysiological and tomographic studies, DNA analysis and the study of the morphological structure of muscle tissue. The treatment is weakly effective, aimed at optimizing the trophic nervous and muscular tissues.
G12.0 Infantile spinal muscular atrophy, type I [Werdnig Hoffmann]
Werdnig Hoffmann disease is the most severe variant of all spinal muscular atrophy (SMA). Its prevalence is at the level of 1 case per 6-10 thousand newborns. The disease has several forms: congenital, intermediate (early childhood) and late. A number of specialists distinguish the latter form as an independent nosology — Kugelberg-Velander amyotrophy. The absence of etiotropic and pathogenetic treatment and early death put the supervision of patients with Werdnig Hoffmann disease among the most difficult tasks facing modern neurology and pediatrics.
Werdnig Hoffmann disease is a hereditary pathology encoded by a breakdown in the genetic apparatus at the level of the 5q13 locus of the 5th chromosome. The gene in which mutations occur is called the survival motor neuron gene (SMN) — the gene responsible for the survival of motor neurons. 95% of patients with Werdnig Hoffmann disease have a deletion of the telomeric copy of this gene. The severity of SMA directly correlates with the length of the deletion site and the concomitant presence of changes (recombination) in the H4F5, NAIP, GTF2H2 genes.
The carrier of the altered gene that causes the occurrence of the disease is every 50th person. But due to the autosomal recessive type of inheritance, pathology in a child manifests itself only when the corresponding genetic aberration is present in both the mother and the father. The probability of having a child with pathology in such a situation is 25%.
The result of the aberration of the SMN gene is the underdevelopment of motor neurons of the spinal cord, localized in its anterior horns. The consequence is insufficient innervation of the muscles, leading to their pronounced atrophy with loss of muscle strength and progressive extinction of the ability to perform active motor acts. The main danger is the weakness of the chest muscles, without the participation of which movements that ensure respiratory function are impossible. At the same time, the sensory sphere remains intact throughout the disease.
SMA I manifests clinically before the age of 6 months. Intrauterine may be manifested by sluggish movement of the fetus. Muscle hypotension is often noted from the first days of life and is accompanied by the extinction of deep reflexes. Children scream weakly, suck badly, can’t hold their heads. In some cases (with a later onset of symptoms), the child learns to hold his head and even sit, but against the background of the development of the disease, these skills quickly disappear. Early bulbar disorders, a decrease in the pharyngeal reflex, fascicular twitching of the tongue are characteristic.
This Werdnig Hoffmann disease is combined with oligophrenia and disorders of the formation of the osteoarticular apparatus: deformities of the chest (funnel-shaped and keeled chest), curvature of the spine (scoliosis), joint contractures. Many patients have other congenital anomalies: hemangiomas, hydrocephalus, clubfoot, hip dysplasia, cryptorchidism, etc.
The course of SMA I is the most malignant with rapidly increasing immobility and paresis of the respiratory muscles. The latter causes the development and progression of respiratory failure, which is the main cause of death. Due to the violation of swallowing, it is possible to throw food into the respiratory tract with the development of aspiration pneumonia, which can be a deadly complication of spinal amyotrophy.
Early childhood form
SMA II debuts after the age of 6 months. By this period, children have satisfactory physical and neuropsychic development, in accordance with age norms, acquire the skills to hold their heads, roll over, sit down, stand. But in the vast majority of clinical cases, children do not have time to learn to walk. Usually, this Werdnig Hoffmann disease manifests after a child has suffered a food toxicoinfection or other acute infectious disease.
In the initial period, peripheral paresis occurs in the lower extremities. Then they spread quickly enough to the upper limbs and the musculature of the trunk. Diffuse muscular hypotension develops, deep reflexes fade away. Tendon contractures, finger tremors, involuntary muscle contractions (fasciculations) are observed language. In the later stages, bulbar symptoms and progressive respiratory failure are added. The course is slower than that of the congenital form of Werdnig Hoffmann disease. Patients can live up to the age of 15.
SMA III is the most benign spinal amyotrophy of childhood. Manifests after 2 years, in some cases in the period from 15 to 30 years. There is no delay in mental development, patients are able to move independently for a long time. Some of them live to a very old age without losing the ability to self-serve.
Patients with spinal muscular atrophy type I are under the supervision of pediatric neurologists and neonatologists. Of great importance is the age of manifestation of the disease – Werdnig Hoffmann disease is characterized by development from birth to 6 months. In the anamnesis, there is often information about late and sluggish fetal movement during pregnancy.
When examining a child, attention is drawn to pronounced muscular hypotension, inability to sit or hold the head independently, a typical “frog pose” – shoulders raised, arms along the trunk, legs straightened and turned outward. Muscle twitching, weakening or absence of tendon reflexes, rough bone deformities (bell-shaped chest, X-shaped lower limbs) are noted. To confirm the diagnosis, the following additional studies are prescribed:
- Laboratory tests. In the blood test, a slight increase in the concentration of creatine phosphokinase is detected. In some patients, this indicator may be within normal values. The analysis of blood gases reveals a decrease in the partial pressure of oxygen (PaO2) and an increase in carbon dioxide (PaCO2).
- Spirometry. Due to the pronounced muscular weakness of the respiratory musculature, restrictive disorders in the form of a decrease in the vital capacity of the lungs are noted when measuring the function of external respiration.
- ENMG. When performing needle electroneuromyography, the following changes can be recorded – a sharp decrease in the rate of conduction and amplitude of evoked potentials, spontaneous bioelectric activity at rest (fasciculation, fibrillation).
- Histology. A pathomorphological examination of a muscle biopsy reveals a bundle atrophy of muscle fibers alternating with unchanged muscle tissue, hypertrophied myofibrils and connective tissue growths.
- DNA analysis. A verification test that allows you to reliably establish a diagnosis. The polymerase chain reaction method reveals a genetic mutation (deletion) of SMN1 exon 7.
Werdnig Hoffman disease should be differentiated from other genetically determined neuromuscular diseases that have the same rapidly progressing course. These include congenital structural myopathies, juvenile amyotrophic lateral sclerosis, Fukuyama syndrome.
To undergo treatment, all patients are subject to mandatory hospitalization in a hospital. In severe situations (for example, with severe hypoxemia due to weakness of the respiratory muscles), patients are transferred to the intensive care unit and connected to a ventilator. To date, there is no etiotropic therapy for Werdnig Hoffmann disease. All measures are symptomatic and palliative in nature. The following treatment methods are used:
- Provision of food. Since the swallowing process is difficult for many patients, special attention is paid to the issue of feeding. The consistency of the food should be semi–solid, the position of the child should be vertical. If necessary, a nasogastric probe is installed.
- Physical therapy. To improve metabolism in muscle tissues, electrophoresis sessions, electrostimulation with modulated current, mud applications are carried out. Physical therapy. In order to increase muscle tone, regular physical exercises are necessary – passive (performed by a specialist) with a gradual transition to active (performed by the patient himself).
- Orthopedic treatment. Orthopedic devices (corsets, orthoses, immobilizing splints) that fix various parts of the body are used to combat bone and joint deformities, as well as to prevent them.
- Respiratory support. An important place in the treatment is the elimination of oxygen deficiency. Depending on the severity of the patient’s condition, oxygen inhalation through a facial mask / nasal cannula or non-invasive ventilation of the lungs through portable ventilators are prescribed.
To achieve maximum effect, treatment should be comprehensive, carried out continuously and selected individually for a particular patient. Medications used to treat Werdnig Hoffmann disease are as follows:
- Metabolic agents. To improve metabolic processes in nerve cells and muscle tissue, coenzyme Q10, L-carnitine, and nootropics are prescribed. Also, high doses of B vitamins (B1, B6, B12) are used to stimulate the regeneration of nervous tissue.
- Valproates. Antiepileptic drugs from the group of valproic acid derivatives are able to increase the formation of motor neurone survival protein (SMN), which can subsequently improve the clinical course of the disease.
- PPIs and prokinetics. Proton pump inhibitors (pantoprazole) and drugs that accelerate the motility of the gastrointestinal tract (itoprid) help in the fight against gastroesophageal reflux, which often occurs in patients with AVG due to severe swallowing disorders.
- Mucolytics and expectorants. In order to combat such respiratory problems as weak coughing, accumulation of thick sputum in the respiratory tract, drugs that dilute sputum (acetylcysteine) and stimulate its expectoration (terpinghydrate) are used.
With the development of gross deformities of the chest and spine or extremely pronounced contractures of the joints, orthopedic operations are indicated. In bedridden patients suffering from constantly recurring pneumonia, a tracheostomy is performed. With gastroesophageal reflux resistant to drug treatment, laparoscopic Nissen fundoplication is resorted to.
Ongoing research is underway to find an effective drug for the treatment of spinal muscular atrophy. The most promising direction is considered to be gene therapy. Antisense oligonucleotides that correct defects in matrix RNA in the SMN2 gene (Spinraza) are already used in clinical practice.
At the end of 2019, the drug Zolgensma, which contains a functionally complete SMN1 gene, was registered and approved for clinical use. Delivery of this gene to nerve cells is carried out with the help of an adeno-associated virus that penetrates the blood-brain barrier. The use of Zolgensma leads to a significant increase in the production of SMN1 protein and an improvement in the condition of patients.
Werdnig Hoffmann congenital amyotrophy has an extremely unfavorable prognosis. When it manifests in the first days of a child’s life, his death usually occurs before the age of 6 months. At the beginning of the clinic after 3 months of life, death occurs on average by the age of 2 years, sometimes by 7-8 years. The early childhood form is characterized by a slower progression, children die at the age of 14-15 years.
The primary prevention of Werdnig Hoffmann disease is prenatal diagnosis. If SMN1 mutation is detected in chorionic villi or amniotic fluid biopsies, termination of pregnancy is indicated. Secondary prevention is reduced to the prevention of complications – aspiration pneumonia, joint contractures, lower respiratory tract infections.