Amaurotic idiocy is a concept that unites a group of genetically determined diseases caused by dysmetabolism of gangliosides with their accumulation in cerebral cells. The leading symptoms of pathology are a progressive decrease in intelligence and loss of vision. Diagnostic measures include neurological examination, ophthalmoscopy, brain MRI, genetic consultation, blood lipid composition study, histochemical analysis of a brain biopsy. Symptomatic treatment: anticonvulsants, psychotropic pharmaceuticals, transfusions of freshly frozen plasma.
Amaurotic idiocy was first described in 1881 by Warren Tay, an ophthalmologist from the United States who studied changes in the fundus of patients. In 1887, neurologist Bernard Sachs presented a detailed description of the clinical picture of the disease. Subsequently, he made a number of observations of similar cases and concluded that the family nature of the pathology. This is how the most famous amaurotic idiocy was discovered — Tay-Sachs disease. Then, researchers in the field of pediatrics and clinical neurology described other variants of the disease that have a later debut. The prevalence of pathology in the general population is 1 case per 500,000 population, among persons of Jewish nationality — per 6,000 population. There are no gender differences in morbidity.
The familial nature of the disease is caused by gene mutations inherited by an autosomal recessive mechanism with high penetrance of the defective gene. Amaurotic idiocy develops when inheriting a pathological gene from both parents. The probability of having a sick child in heterozygous carriers of the defect is 25%. The genetic substrate of Tay-Sachs disease, which is a variable mutation of the HEXA gene located on the 15th chromosome at the q23-q24 locus, has been most studied. This gene encodes an enzyme responsible for catabolic reactions with the cleavage of gangliosides. Enzyme deficiency leads to the accumulation of gangliosides in the ganglion cells of the brain and retina, which is accompanied by their degeneration.
Amaurotic idiocy occurs due to metabolic disorders with lipid deposition in cerebral and retinal cells, to a lesser extent in somatic organs (liver, spleen). With the Tay-Sachs idiocy, as a result of violations in the HEXA gene responsible for the synthesis of the lysosomal enzyme hexosaminidase A, GM2 gangliosides are not catabolized, their gradual accumulation occurs. Similar dysmetabolic shifts are accompanied by other forms of the disease. Various lipid inclusions accumulate in cerebral neurons and retinal cells. The infantile form is characterized by fine-grained inclusions containing cholesterol, with late childhood and juvenile variants of the disease, the accumulation product, along with lipids, has a large amount of protein, cholesterol is absent.
Macroscopically, amaurotic idiocy is manifested by an increase in brain volume, extensive atrophic changes in the occipital lobes, cerebellum, thinning of the visual tracts. The microscopic picture in the brain is represented by the swelling of ganglion cells and their processes, the filling of the intracellular space with lipid inclusions, the wrinkling of the nuclei, the disintegration of the tigroid substance. Similar changes are observed in retinal cells, most pronounced in the area of the macula.
Amaurotic idiocy includes several clinical variants that differ in the age of manifestation of symptoms, the nature of the course, and the life expectancy of patients. They are probably caused by various genetic defects, certain features of metabolic disorders. Clarification of the clinical form of pathology is necessary to understand the prognosis of the disease, the choice of optimal treatment tactics. In accordance with the clinical features , there are four main forms:
- Early childhood (infantile form of Tay-Sachs). The most studied variant of the disease. Manifestation in 4-6 months is characteristic. The course is rapidly progressive, the fatal outcome is observed up to 3 years of age.
- Late childhood (form of Yansky-Bilshovsky). The debut falls at the age of 3-4 years. The clinic is identical to the early childhood form, has a slightly delayed course. The duration of the disease is 4-6 years.
- Youth (Spielmeyer-Vogt form). It begins at 6-9 years of age and is characterized by a relatively slow progression of symptoms. Patients live up to 20 years.
- Late (Kufs form). Manifests in puberty or in old age. It has the most favorable slow flow. The fatal outcome occurs on average 10-15 years after the onset of symptoms.
In some cases, there is a congenital amaurotic idiocy, called the Norman-Wood form. Symptoms occur in the first weeks of a child’s life, the main manifestation is the cessation of neuropsychiatric development. Some authors propose to include the Norman-Wood variant in the classification as a separate nosology.
The basis of the clinical picture is progressive visual disorders, gradual loss of acquired intellectual abilities. Concomitant manifestations are deafness, convulsive syndrome, extrapyramidal disorders, cerebellar ataxia. The severity of symptoms depends on the form of the disease.
Early childhood amaurotic idiocy manifests a decrease in the child’s motor activity, loss of the ability to sit, hold the head. Subsequently, the extinction of motor and static functions continues until tetraparesis with complete immobility. In the initial period, hyperacusis is typical, expressed by the child’s flinching at sound irritation. Visual impairments lead to a lack of tracking of toys, fixing the gaze on shiny objects. In a short time, complete blindness (amaurosis) occurs. Seizures with a predominance of the tonic component are noted. Bulbar syndrome, vegetative disorders (hyperhidrosis, acrocyanosis, hypothermia, pulse lability) are possible. Muscular hypotension is detected, progressing in the terminal stage to decerebration rigidity.
The amaurotic idiocy of Yansky-Bilshovsky arises in the fourth year of life. At the initial stage, along with decreased vision and cognitive impairment, cerebellar disorders are noted: unsteadiness of gait, rough discoordination, nystagmus. Gradually, the patient loses the ability to walk, stand, sit. The intellectual sphere degrades to the level of idiocy, amaurosis develops. The youthful form is characterized by a milder course: intelligence rarely degrades to idiocy, visual dysfunction does not reach amaurosis, the motor sphere remains more intact. Typical extrapyramidal disorders (athetosis, chorea, tremor), cerebellar dysfunction. Possible deafness, the occurrence of epileptic seizures. In some cases, myxedematous obesity is detected.
Amaurotic idiocy of Kufs is extremely rare, occurs without pronounced motor, visual, intellectual disorders. Manifests personality changes, limited range of interests, reduced activity. Over time, there is an intellectual decline, rarely reaching the level of pronounced organic dementia. Various mental disorders are typical: hallucinations, delusions, catatonia, affective psychoses. Extrapyramidal, cerebellar symptoms, epileptic paroxysms, hearing loss are possible.
At the initial stages of the disease, motor and visual disturbances cause frequent traumatization of the child. A sharp decrease in motor activity provokes the development of congestive pneumonia. A complication of convulsive syndrome is an epileptic status. Dysphagia in bulbar syndrome is dangerous if liquid and food enter the respiratory tract with the occurrence of aspiration pneumonia. A number of complications are associated with the deposition of lipids in the internal organs. Fatty liver dystrophy leads to the development of liver failure, fatty deposits on the valves — to heart failure. Patients die from cardiac, respiratory, multiple organ failure, intercurrent infections.
The characteristic combination of a triad of symptoms (cognitive degradation, sharp deterioration of vision, motor disorders) suggests a clinical diagnosis. Difficulties arise when determining the late form. Confirmation of the diagnosis is possible after a number of studies:
- Study of neurological status. The results of the neurologist’s examination depend on the form and period of the disease, the age of the patient. There is a sharp discrepancy between intellectual development and age. Spastic paresis, cerebellar dysfunction, hyperkinesis, muscular dystonia, vegetative-trophic disorders are revealed.
- Consultation of an ophthalmologist. In infants, there is a lack of tracking reaction, in older patients, visometry confirms a sharp decrease in visual acuity. Ophthalmoscopy diagnoses bilateral optic nerve atrophy. A pathognomonic sign is the presence of a cherry spot in the macular zone. Late amaurotic idiocy is characterized by the absence of this symptom, a picture of retinitis pigmentosa on the fundus.
- Blood test. Vacuolized lymphocytes are found in the blood. When conducting a biochemical blood test, changes in the lipid profile (an increase in the level of phospholipids, cholesterol), an increased concentration of individual enzymes can be determined.
- Neuroimaging. MRI of the brain visualizes atrophy of cerebral tissues, more noticeable in the cerebellum, occipital region. The severity of atrophic changes is maximal with early onset, minimal with late form. Along with atrophy, thinning of the optic nerves is revealed.
- Cerebral biopsy. Histochemical and cytological examination of the material from atrophic sites makes it possible to reliably establish the diagnosis of “amaurotic idiocy” by the presence of characteristic intracellular lipid inclusions. By the color of the staining of inclusions, it is possible to judge the form of the disease.
- Genetic analysis. The consultation of a geneticist includes the collection of a family history and the compilation of a family tree. It makes it possible to confirm the family character, to clarify the type of inheritance of pathology.
Amaurotic idiocy is differentiated from other hereditary dysmetabolic and degenerative diseases with central nervous system damage. The early childhood variant must be distinguished from Niemann-Pick disease, which occurs with a pronounced lesion of somatic organs. The late form requires differentiation from a number of diseases with leading cerebellar and extrapyramidal symptoms (multiple sclerosis, Lafora’s disease, leukodystrophy).
Specific therapy has not been developed. Symptomatic supportive treatment is being carried out. In the presence of epileptic paroxysms, anticonvulsants are used, psychotropic drugs (sedatives, tranquilizers, neuroleptics) are used for mental disorders. Some clinicians indicate the effectiveness of plasma transfusion, blood products. Vitamin therapy and restorative measures are recommended. In the later stages, the patient needs careful care, prevention of infectious complications. Genetic engineering is a promising direction in the search for effective treatment methods, but significant results in this area have not yet been achieved.
Prognosis and prevention
Amaurotic idiocy ends in death. The life expectancy of patients depends on the age of the onset of pathological changes. The most unfavorable prognosis has an infantile form — patients die after 1.5-2 years. The slowest benign course is observed in the late variant. Preventive measures are aimed at excluding related marriages. Parents who have a sick child are advised to abandon further childbearing. In the case of pregnancy of a heterozygous couple, it is possible to study the concentration of hexosaminidase-A in the amniotic fluid. A significant decrease is an indication for termination of pregnancy.