The impact of viruses on the development of Miller Fisher syndrome. Miller Fisher syndrome (rare nerve disease). Miller Fisher syndrome - causes

Etiology and incidence of Miller-Dieker syndrome. Miller-Dieker syndrome (MDS, MIM No. 247200) is an extended deletion syndrome caused by a hemizygous deletion of 17p13.3; The mechanism underlying repeated deletions of the 17p13.3 region has not yet been explained, but perhaps (like other syndromes) it involves recombination between a low-copy-number repeated DNA sequence.

Miller-Dieker syndrome- a rare disease of uncertain occurrence in all populations.

Pathogenesis of Miller-Dieker syndrome

In the region Miller-Dieker syndrome deletions more than 50 genes are mapped to 17p13.3, but only the LIS1 gene (MIM #601545) is associated with a specific phenotypic characteristic of the syndrome; hemizygosity for LIS1 causes lissencephaly. LIS1 encodes the brain isoform of the noncatalytic beta subunit of platelet acetyl hydrolase activating factor (PAFAH). PAFAH is an inhibitor of neuronal migration and also binds and stabilizes microfibrils. Preliminary observations indicate that PAFAH may play a role in microfibril reorganization required for neuronal migration.

Still isolated LIS1 haploinsufficiency does not cause other dysmorphic features characteristic of Miller-Dieker syndrome. Mutations in the LIS1 gene cause isolated lissencephaly (MIM #607432), i.e. lissencephaly without other dysmorphia. Since all patients with Miller-Dieker syndrome have dysmorphic facial features, this dysmorphism must be caused by haploinsufficiency of one or more other genes in the deletion.

Phenotype and development of Miller-Dieker syndrome

Symptoms Miller-Dieker syndrome includes brain dysgenesis, muscle hypotonia, developmental delay and facial dysmorphia. Cerebral dysgenesis is characterized by lissencephaly type I (complete agyria) or type II (widespread agyria with multiple sulci at the frontal or occipital pole), a cerebral cortex with four instead of six layers, gray matter heterotopia, and thinning white matter. Some patients also have cardiac malformations and omphaloceles.

Children with Miller-Dieker syndrome they eat and grow poorly. The ability to smile, brief eye contact, and nonspecific motor responses are the only abilities acquired by most patients. Except mental retardation, those affected usually suffer from opisthotonus, spasticity and seizures. Almost all of them die by 2 years of age.

Features of phenotypic manifestations of Miller-Dieker syndrome:
Age of onset: prenatal
Type I or II
Facial dysmorphia
Severe general mental impairment
Convulsions
Early death

Treatment of Miller-Dieker syndrome

Facial features of patients and detection on MRI Lissencephaly often suggests a diagnosis of Miller-Dieker syndrome. However, to confirm the diagnosis, the 17p13.3 deletion must be detected by chromosomal analysis or FISH with a LIS1-specific probe. Approximately 60% of patients have a visible deletion of the critical region of Miller-Dieker syndrome.

Miller-Dieker syndrome incurable; therefore, help is aimed at correcting symptoms and palliative care. Almost all children require medication to treat seizures. Most patients are fed through a nasogastric or gastrostomy tube due to feeding problems and repeated aspirations.

Risks of inheriting Miller-Dieker syndrome

80% of patients have a new microdeletion of 17p13.3, and 20% inherit the deletion from one of the parents carrying a balanced chromosomal rearrangement. Because of the frequency with which fission is inherited from a parent with a balanced translocation, karyotype analysis and FISH for LIS1 should be performed on both parents. A parent with a balanced translocation involving 17p13.3 has approximately a one in four chance of having an abnormal live birth (with Miller-Dieker syndrome or dupl7p duplication) and approximately a one in five chance of having a miscarriage. In contrast, if a patient has Miller-Dieker syndrome as a result of a new deletion, the parents are at low risk for recurrence of the syndrome in subsequent children.

Although the brain malformation of Miller-Dieker syndrome is caused by incomplete migration of neurons into the cerebral cortex during 3–4 months of gestation, lissencephaly is not detected on fetal MRI or ultrasonography until late in pregnancy. For prenatal diagnosis of Miller-Dieker syndrome, detection of the 17p13.3 deletion in chorionic villi or fetal amniocytes is necessary.

Example of Miller-Dieker syndrome. B.B., a boy 5 days old, born at the 38th week of gestation, was transferred to the ward intensive care neonatal units due to severe hypotension and feeding difficulties. The child was born from an uncomplicated pregnancy; Fetal ultrasound at 14 weeks of gestation and maternal serum screening at 16 weeks of gestation were normal. The boy was born from spontaneous vaginal birth; the Apgar score was 8 points at the 1st minute and 9 points at the 5th minute of life.

In the family child's genetic history, neurological or congenital diseases are missing. Clinical examination revealed muscular hypotonia and mildly dysmorphic facial features, including narrowing of the bitemporal distance, a depressed bridge of the nose, a small nose with everted nostrils, and micrognathia. The rest of the examination data is normal. His serum electrolytes, metabolic screening, and congenital infections were all within normal limits. Ultrasound scanning brain showed hypoplasia corpus callosum, slight expansion of the ventricles of the brain and a smoothed cortex.

After an additional meeting, the group geneticists recommended chromosomal analysis, fluorescence analysis (FISH) of the LIS1 gene (located in the 17p13.3 region) and brain MRI. MRI showed cortical thickening, complete agyria, numerous cerebral heterotopias, hypoplasia of the corpus callosum, and a normal cerebellum and brainstem. Chromosome analysis with G-staining was normal (46,XY), but FISH showed a deletion of LIS1 in one of chromosomes 17. Based on these results, the geneticist explained to the parents that the child had Miller-Diecker syndrome. Parents refused therapeutic measures, except those necessary for the comfort of the child, and he died at 2 months of age.

Miller syndrome is a rare genetic disorder that is characterized by cranial malformations that occur along with abnormalities of the arms and/or legs. Craniofacial abnormalities include: underdevelopment of the cheekbones (hypoplasia zygomatic bone), an abnormally small lower jaw (micrognathia), a cleft palate, small, protruding, “cup ears,” and/or colobomas. Limb abnormalities may include: incomplete development, syndactyly and/or absence of certain fingers and/or toes, improper development, fusion of the forearm bones (radiulnar synostosis). Miller syndrome is an inherited, autosomal recessive disorder that is caused by mutations in the DHODH gene.

Miller syndrome was first described in medical literature between 1969 and 1979 in several independent reports. This disorder has been given several names by several of the doctors who first discovered the disorder, including Miller, Wiedemann, and Genet.

Miller syndrome. Epidemiology

Miller syndrome is a rare disorder, with an estimated prevalence of approximately 1 in 1 million births. Because a proportion of cases may remain undiagnosed or misdiagnosed, the true incidence in the general population is difficult to estimate. In total, fewer than 75 cases have been described in the medical literature. Male faces and female develop this syndrome in equal proportions.

• Nager syndrome - rare hereditary disease, which is characterized by cranial malformations that are similar to those that develop in Miller syndrome, and patients often have malformations of the arms and/or legs.
• Treacher Collins syndrome is a rare genetic disorder characterized by distinctive abnormalities of the head and face resulting from underdevelopment (hypoplasia) of certain facial structures, including the jaw, cheekbones, and nearby structures. In addition to various facial abnormalities, patients may have malformations of the outer ear, middle ear structures, and eyes.

Miller syndrome. Causes

Miller syndrome is caused by mutations in the dihydroorotate dehydrogenase (DHODH) gene. The researchers determined that the DHODH gene is located on the long arm (q) of chromosome 16 at locus 16q22.2. This gene encodes the enzyme dihydroorotate dehydrogenase. Mutations in this gene lead to the development of deficiency or functional deficiency of dihydroorotate dehydrogenase. This enzyme plays important role in the production (biosynthesis) of pyrimidine, which is found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and in other complexes of the body.

Miller syndrome. Photo

Miller syndrome. Symptoms and manifestations

Most disorders are noticeable already at birth. Common craniofacial abnormalities include: underdeveloped cheekbones (zygomatic hypoplasia), abnormally small lower jaw (micrognathia), cleft palate, choanal atresia, small, prominent, “cup ears,” and/or colobomas. Additional craniofacial manifestations may include: wide nasal bridge, oblique palpebral fissures, partial or complete absence lower eyelashes and ectropion.

Micrognathia and choanal atresia may contribute to breathing difficulties and/or feeding difficulties. Some patients may develop hearing loss due to abnormalities in inner ear. Hearing loss can cause speech problems to develop if left untreated.

Patients also have various abnormalities of the hands and feet, including absent or abnormal fifth or fourth fingers and toes. In some cases, the ulna or fibula may also have abnormalities. Most children with this syndrome may have radioulnar synostosis. This can lead to shortening of the forearm. Additional manifestations include: fusion of fingers or toes, underdevelopment of the thumbs.

In some cases, babies may have growth deficiency after birth (postpartum growth deficiency), sunken breastbones, rib defects, and extra nipples. Children have an increased risk of hip dislocation, and very few of them may be born with a dislocation.

Some children also have kidney problems, gastrointestinal or cardiac abnormalities. Renal abnormalities may involve backflow of urine from Bladder into the kidneys (reflux). Gastrointestinal disorders may include abnormal bowel positioning and narrowing of the opening connecting the stomach and duodenum(pyloric stenosis). Heart defects may include a ventricular septal defect.

Miller syndrome. Diagnostics

Diagnosis of Miller syndrome is based on careful clinical assessment, a detailed examination of the patient's medical history and identification of characteristic physical manifestations. Many of the associated abnormalities are present at birth. X-rays can confirm the presence and/or extent of some observed craniofacial abnormalities. And molecular genetic testing can accurately confirm the diagnosis of Miller syndrome.

Miller syndrome. Treatment

Treatment for Miller syndrome is aimed at specific symptoms and manifestations. Some children will have a small hole made in their throat through which a small tube can be passed (to help with breathing). Also, a small hole may be required in the stomach, through which a tube will also be passed, but for feeding.

Once the patient's condition is stabilized, surgeons can begin correcting abnormalities of the jaws, limbs and eyes. Surgery and speech therapy are always necessary when correcting cleft palates or cleft lips. Congenital defects hearts also often require surgical intervention. If you have hearing loss, you may need hearing aid, in some cases. Other healing techniques will already depend on the presence of other anomalies.

Guillain-Barré syndrome is an autoimmune disease that primarily affects muscle movement and can manifest itself in many ways.

In this article we will analyze symptoms, causes and treatment of Miller Fisher syndrome, one of the most common forms of this disorder.

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What is Miller Fisher syndrome?

Miller Fisher syndrome is a disease that affects the nervous system, causing symptoms related to muscle motor and coordination. In some cases, this can cause changes in other physiological systems.

This is one of possible manifestations Guillain-Barré syndrome, a series of diseases resulting from infections that in turn cause inadequate functioning immune system..

Miller Fisher syndrome usually has good prognosis: subject to proper treatment symptoms disappear completely. However, this is not always the case, and if the damage to the nervous system is significant, some effects may remain.

About twice more cases Miller Fisher syndrome is detected in women than in men, and the prevalence is higher in the spring than in the rest of the year. Average age The onset of the disease is slightly above 40 years of age.

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Guillain-Barre syndrome

Guillain-Barré syndrome is an autoimmune disorder; This means that it consists of a malfunction of the immune system, resulting in an “attack” on the body's healthy cells. In this case, the lesions occur in the peripheral nervous system, primarily affecting the muscles of the limbs, and sometimes leading to complete paralysis..

In the most severe cases, this disease causes death as a result of disruption of the cardiac and respiratory systems. This is usually caused viral infections, although the mechanisms by which this is produced are not precisely known.

Differential diagnosis between Miller Fisher syndrome and other variants of Guillain-Barré syndrome is based on the presence characteristic features and symptoms. Let's see what features of the subtype interest us.

Symptoms and main signs

There are three main features that characterize Miller Fisher syndrome compared to other forms of Guillain-Barré syndrome: ataxia, areflexia and ophthalmoplegia. These changes usually appear between 5 and 10 days after contracting a viral infection.

Ophthalmoplegia and ataxia are usually the first signs of the disease. The first consists of muscle paralysis eyeball, while Ataxia is defined as loss of motor coordination. On the other hand, areflexia, which occurs in third place and mainly in the limbs, is the absence of reflex movements.

Another characteristic feature This variant of Guillain-Barré syndrome is a lesion cranial nerves, which is associated with a deficiency of nerve conduction.

In some cases there are other changes associated with the same injuries, mainly generalized muscle weakness and respiratory failure , which can lead to death if the symptoms are very intense. However, these problems are more common in other forms of Guillain-Barré syndrome.

Causes of this disease

Although Miller Fisher syndrome is usually associated with infections caused by viruses (and to a lesser extent also bacteria), the truth is that it has not been proven that they are the only possible reason this disease...

Signs and symptoms associated with destruction of the myelin sheath of peripheral nerves immune system. Myelin is a lipid substance that lines the axons of some neurons, allowing for efficient transmission of nerve impulses and increasing their speed.

However, changes have also been found in the central nervous system, especially in the posterior part spinal cord and in the brain stem.

On the other hand it was found anti-ganglioside immunoglobulin antibody GBQ1b most people diagnosed with Miller Fisher syndrome. This antibody appears to be particularly associated with the presence of ophthalmoplegia.

Treatment and management

Like other variants of Guillain-Barré syndrome, Miller Fisher disease is treated with two procedures: plasmapheresis, which involves removing antibodies from the blood by filtration and intravenous administration of immunoglobulins.

Both techniques are very effective in neutralizing the effects of pathological antibodies and reducing inflammation, which also damages the nervous system, but their combination does not increase the likelihood of success of the intervention. however, administration of immunoglobulins carries less risk.

Most people begin to recover after two weeks and one month of treatment if it is applied early. After six months, symptoms and signs are usually nil or very rare, although complications can sometimes occur and there is a 3% risk of them reappearing once they disappear.

One of the varieties of the rare Guillain-Barré syndrome, which is a branch of a clear picture of the processes occurring in the body of a sick person, is Miller-Fisher syndrome. It is characterized by a triad of symptoms that appear identically in all patients.

Definition

Guillain-Barre syndrome is quite rare. IN medical practice its indicators are 1-2 people per hundred thousand population. It appears more often in men and has two peaks of activity:

• young age - 20-24 years;
• elderly - 70-74 years.

It is well known to neurologists and has a number of characteristic features, confirmed by passing tests cerebrospinal fluid. In addition to the classical movement of this disease, there is Fisher Miller syndrome, described by this American neurologist back in 1956.

Symptoms

The disease is extremely rare and is an acute inflammatory autoimmune disease that affects the myelin nerve sheaths. At the beginning and at further development Miller-Fisher syndrome always manifests itself in the same way and consists of next row its characteristic symptoms:

• areflexia - there is a sharp decline, and subsequently a complete absence of limb reflexes;
• ataxia - cerebellar disorders;
• ophthalmoplegia - paralysis of the muscles of the eye, often external, and in complex cases, internal;
• tarapesis and paralysis of the respiratory muscles - develop in severe, advanced cases.

With the correct identification of symptoms and timely initiation of treatment, the disease is benign, does not cause complications and often ends in spontaneous recovery.

Causes

If you consult a doctor in a timely manner, Miller-Fisher syndrome can be cured within a few weeks or months. How long do they live with similar disease, it is not clear exactly, just as the reasons for its appearance are not clear. But for most people with this diagnosis, experts promise the most favorable prognosis. Complete restoration of all functions in the body with proper and appropriate treatment takes a maximum of ten weeks. And only a small number of patients with advanced cases require a number of additional medical measures.

Some medical professionals say that routine vaccination is often the cause of the development of this pathology. In a number of cases, it was detected after severely viral diseases, sometimes symptoms appeared after long-term treatment row complex infections. There are also known family cases of the development of the disease, suggesting genetic predisposition organism to this pathology.

Clinical indicators

The leading complaints that the patient provides are primarily expressed in the following aspects:

• weakness, loss of strength, lack of energy, possible dizziness;
• difficulties with chewing, and a little later with speech;
• difficulties in walking and self-care;
• frequent numbness of the hands and feet, wave-like pain in the limbs.

It is descending paralysis - a disturbance in the movement of the eyes, and then other limbs (the feeling of the presence of gloves on the hands) that Miller-Fisher syndrome manifests. The symptoms are very similar to Hein-Barre syndrome, but in this type of pathology there is paralysis of an ascending nature - from the lower part of the body to the upper.

In addition to weak coordination and complete loss of reflexes, the patient may also exhibit a number of secondary symptoms that contribute to a more accurate diagnosis.

• The temperature sensitivity of the skin is noticeably lower.
• The patient is practically insensitive to pain.
• Swallowing saliva becomes difficult.
• Speech is intermittent, words are difficult to pronounce.
• There is no gag reflex.
• Complaints about bladder problems.

Some symptoms, such as muscle weakness and difficulty speaking, may occur completely spontaneously. They clearly indicate a serious complication of the situation and require immediate consultation with a specialist.

Diagnostics

To accurately identify Miller-Fisher syndrome, a number of necessary studies are required.

1. A mandatory visit to a neurologist who conducts an examination and reveals everything possible violations neurological nature.
2. Shown spinal tap. In most cases, it reveals high protein levels characteristic of this disease.
3. PCR analysis allows you to determine the possible pathogen. This could be the herpes virus, Epstein-Barr virus, cytomegalovirus and others.
4. Often the specialist additionally prescribes computed tomography, which helps to identify possible concomitant neurological pathologies.
5. A mandatory blood test is taken to show the presence of antiganglioside antibodies. This is a clear indicator of presence inflammatory process, a positive result of this analysis becomes an accurate confirmation of the diagnosis.

Miller-Fisher syndrome requires comprehensive and maximum accurate diagnosis, electroneuromyography is used, a differential analysis that compares symptoms with a number of similar diseases.

Therapy

Treatment of this disease includes a set of measures aimed at suppressing immune reaction and purification of blood from antibodies. Proper supportive and symptomatic therapy allows for short time completely eliminate Miller-Fisher syndrome. Treatment under the guidance of an experienced specialist leads to the most positive results and full recovery. In extremely rare cases (only three percent of the total), relapses are possible, requiring an additional course of complex therapy.

1. Assessment in progress respiratory system, in cases where it is difficult for the patient to move independently, a hospital with constant medical supervision is assigned.
2. During the first five days (not late two weeks after the first detection of symptoms) plasmapheresis and immunoglobulin are prescribed.
3. For prevention possible thrombosis veins use anticoagulants.
4. Requires constant monitoring blood pressure, since it sharp changes can lead to serious complications.
5. Additionally, classes are conducted with a speech therapist.

2 years ago

A person often becomes a victim of various diseases or pathological conditions posing a threat to both health and life. Among them are a number of autoimmune diseases, a feature of which is a disruption of the immune system, as a result of which the body’s own cells are attacked.

One of the rare inflammatory autoimmune diseases is Miller-Fisher syndrome. The disease is characterized by damage to the protective membrane nerve fibers, ensuring normal transmission of nerve impulses (myelin sheath).
This is rare in some reference books. autoimmune disease It is not considered an independent disease, but a type of another syndrome - Guillain-Barre. Miller Fisher syndrome was first described in the mid-twentieth century by one of the Canadian neurologists, Miller Fisher. The symptomatic picture characteristic of the syndrome includes a triad of signs: the development of paralysis of the eye muscles responsible for motor function eyeball, cerebellar dysfunction and lack of tendon reflexes in the patient's limbs.

Symptoms of the syndrome

In addition to the characteristic triad of signs, symptoms such as difficulty swallowing, lack of ability to speak clearly, and lack of a gag reflex against the background of developing paralysis will help determine the development of Miller Fisher syndrome in a patient. There is also a decrease or absence of reaction to pain and temperature stimuli and disruption of the patient’s urinary system. In some cases, disturbances in the respiratory system may suddenly appear, leading to difficulty breathing.

A distinctive feature of Miller Fisher syndrome from other similar autoimmune diseases is the development of descending paralysis: from the eyes to the limbs. First, the patient complains of double images of the surrounding world, lack of clarity of vision, and inability to raise the eyelid. After some time, the complaints are supplemented by a feeling of numbness in the hands and feet, and a lack of sensitivity in them.

Causes of Miller Fisher syndrome

According to preliminary data, scientists considered this rare autoimmune disease to be independent, whose development does not require a prior violation of the patient’s health condition. However, a little later, a pattern was noticed: most often, recorded cases of the development of Miller Fisher syndrome were preceded by infections of various natures suffered by the patient (bacterial, viral or fungal) or immediately before the development of symptoms of the syndrome, the patient was given some kind of vaccine.

In Japan, cases of Miller Fisher syndrome have been reported in families, affecting all members. This suggests that hereditary predisposition also refers to the causes of this rare autoimmune disease.

Treatment methods

Timely detection of the development of the syndrome and adequately selected curative therapy allow you to see in 2 – 4 weeks obvious signs improving the patient's condition. If you follow the course of treatment full recovery the body occurs within 6 months. Relapses are not excluded, but occur extremely rarely.

Usually in medical complex for Miller Fisher syndrome, a course of immunoglobulin is included to bind and neutralize pathological antibodies, several sessions of blood plasma purification (plasmopheresis course), and in some cases corticosteroids are used. It is advisable to start receiving treatment no later than 2 weeks after the onset of the disease, this will increase the chances of successful treatment.