Neuroacanthocytosis is a genetically determined degenerative brain lesion combined with a change in the shape of red blood cells (acanthocytosis). The clinic is dominated by extrapyramidal disorders of the motor sphere (hyperkinesis, Parkinsonism), mental, cognitive abnormalities, axonal polyneuropathy. Neuroacanthocytosis is diagnosed according to neurological, ophthalmological, neuropsychological, genetic examination when acanthocytes are detected in a blood test. Symptomatic treatment: neuroleptics, benzodiazepines, levodopa, psychotropic drugs.General information
Neuroacanthocytosis was first described in 1960 by the American physician I. Levin, then in 1968 by the English neurologist M. Critchley. In honor of the researchers, the disease was named Levin-Critchley syndrome. Subsequently, the genetic basis of the pathology was determined, but the etiopathogenetic mechanisms remain poorly understood. Neuroacanthocytosis is a rare disease, the prevalence is 1-5 cases per 1 million population. There are known variants of the disease in the age range from 8 to 62 years. Neuroacanthocytosis manifests most often in the period of 10-39 years. The incidence does not depend on gender, with the exception of forms with x-linked inheritance.
Causes
Levin-Critchley syndrome is a genetically determined multisystem disease with a predominant lesion of the subcortical ganglia of the brain and an anomaly of erythropoiesis. The defective gene is located at the 9q21 locus of the ninth chromosome. An autosomal recessive pathway of hereditary defect transmission is usually traced. Accordingly, neuroacanthocytosis is manifested due to the transmission of a pathological gene from both parents. The probability of having a sick child in a married couple of heterozygous carriers is 25%. In some patients, autosomal dominant, recessive X-linked inheritance was revealed, there are sporadic cases of the disease.
Pathogenesis
Pathogenetic mechanisms have not been sufficiently studied. The synthesis of abnormal chorein protein determined by a genetic defect was detected. Many researchers believe that this protein affects neurosynaptic transmission by participating in the functioning of ion channels of the cell membrane. Presumably, the cause of neuronal damage is excessive activation of the postsynaptic membrane. The processes mainly affect neurons of striar and pallidar structures. Morphologically, the decrease in the number of neurons, the reactive proliferation of glial elements (astrocytes) is determined. The changes extend to the reticular formation, the thalamus, less often — the cerebral cortex, do not affect the cerebellum, the Lewis body.
Symptoms
The core of the clinical picture of Levin-Critchley syndrome is a combination of hyperkinesis with mental disorders. Typical is the onset of symptoms in 2-4 decades of life. Gradually, there is a slight dyskinesia of the muscles of the orbital region, the face, which develops into orofacial hyperkinesis. Typical are stereotypical grimaces, smacking, chewing movements, licking, sticking out the tongue that appear against the will of the patient. Possible dental gnashing (bruxism), spasm of the masticatory muscles (trism). Dystonia of the tongue muscles leads to involuntary ejection of food placed in the mouth. In neurology, the symptom is called “food dystonia”.
A typical feature of hyperkinesis is autoaggression: patients bite the inner surface of the cheeks, bite the tongue and lips. Violent contractions of the muscles of the pharynx and larynx cause swallowing disorder (choking on food, difficulty swallowing even liquids), disorders of the articulatory apparatus with the development of dysarthria — unintelligible, intermittent speech. Subsequently, vocal tics appear, provoking involuntary pronunciation of individual sounds. Motor tics of the bulbar muscle group cause violent hiccups, grunting, snuffling.
Over time, hyperkinesis spreads to the muscles of the limbs, trunk, takes on the character of choreography. In the initial stage, patients are able to arbitrarily control violent motor acts, gradually the ability to control weakens. Neuroacanthocytosis is characterized by a combination of rapid uncoordinated sweeping movements of generalized choreic hyperkinesis with tics, dystonic phenomena. The latter arise as a result of tonic muscle contraction, manifested by the freezing of the patient in a pretentious pose. As the disease progresses, hyperkinetic syndrome is replaced by hypokinesia — Parkinsonism syndrome. Cases of early manifestation of Levin-Critchley syndrome are distinguished by the occurrence of bradykinesia and stiffness at the initial stage of clinical manifestations, their combination with tics, and the absence of chorea.
In parallel with hyperkinesis, neuropsychological disorders are increasing. Neurotic disorders are typical: obsessive-compulsive disorder, phobic syndrome. Affective disorders, elements of apraxia (violations of action planning), decreased memory, intellectual abilities are possible. 40% of patients with neuroacanthocytosis suffer from generalized epileptic paroxysms. Seizures make their debut in any period of the disease, sometimes precede the appearance of extrapyramidal disorders. In most cases, polyneuropathy is observed. Patients complain of numbness of the distal extremities. Distal flaccid paresis, hyporeflexia gradually develops.
Complications
Steadily progressing, neuroacanthocytosis leads to profound disability. Patients lose the ability of self-service, independent movement. The aggravation of cognitive deficits leads to dementia. Serious complications are associated with constant biting of the oral mucosa, causing its chronic injury. The resulting wounds bleed, their infection is possible with the occurrence of stomatitis, gingivitis, cheilitis. Swallowing disorder can be complicated by aspiration of food into the respiratory tract with the development of pneumonia. A number of patients have cardiomyopathy leading to heart failure.
Diagnostics
A hereditary history, a typical clinical picture with a combination of extrapyramidal symptoms (chorea, tics, parkinsonism), mental and cognitive disorders, signs of polyneuropathy allows to suspect neuroacanthocytosis. Of decisive importance is the detection of acanthocytes, which make up more than 15% of all red blood cells. The examination of the patient includes:
- Neurologist’s examination. Hyperkinesis or Parkinsonian syndrome (bradykinesia, stiffness, tremor), hypesthesia of the extremities according to the type of “gloves and socks”, muscular dystonia, distal paresis, decreased achilles, knee reflexes, neurological status data indicate damage to extrapyramidal structures combined with neurogenic amyotrophy.
- Ophthalmological examination. During ophthalmoscopy, an ophthalmologist reveals signs of retinitis pigmentosa, which often accompanies neurodystrophic processes. In half of the cases, neuroacanthocytosis occurs with retinitis pigmentosa.
- Neuropsychological testing. Performed by a neuropsychologist or psychiatrist. Allows you to conduct a comprehensive psychological examination, determine the state of the cognitive sphere.
- Laboratory tests. A clinical blood test should include microscopy of a blood smear, which detects acanthocytes – abnormal red blood cells with spike-like outgrowths. In the biochemical analysis of blood, there is an increase in the concentration of CPK, the level of lipoproteins corresponds to the norm.
- Electrophysiological studies. Electroneuromyography diagnoses axonal polyneuropathy. Electroencephalography reveals epileptiform brain activity.
- Neuroimaging. CT, MRI of the brain visualize nonspecific atrophic changes, most pronounced in the caudate nucleus, striatum. PET of the brain determines striatum hypometabolism, a decrease in the number of dopamine receptors.
- Genetic diagnostics. A geneticist is consulted with the compilation of a family tree to determine the hereditary nature of the disease, the type of inheritance. Karyotyping is possible in order to identify an abnormal gene.
Neuroacanthocytosis should be differentiated from Huntington’s chorea, Farah’s disease, minor chorea, Rett syndrome, dysmetabolic, drug-induced choreic hyperkinesis. Huntington’s chorea is characterized by the inability of patients to restrain hyperkinesis, lack of autoaggression. Farah’s disease is accompanied by the formation of foci of calcification in the brain, visualized using cerebral CT. A feature of minor chorea is the presence of rheumatic disease, positive rheumatoid blood tests. Rett syndrome manifests at an earlier age than neuroacanthocytosis.
Treatment
There is no specific therapy for Levin-Critchley syndrome. Symptomatic treatment is carried out. Hyperkinetic syndrome is stopped by neuroleptics (haloperidol). When hyperkinesis is combined with epileptic seizures, benzodiazepines (clonazepam) are prescribed. Parkinsonism is an indication for therapy with levodopa drugs, dopamine receptor agonists (piribedil). Mental disorders require the appointment of sleeping pills, sedative pharmaceuticals, neuroleptics, antidepressants.
Due to the progression of the disease, patients increasingly need outside care over time. Taking into account dysphagia, an important point is to ensure proper nutrition of patients. Special pads are used to protect the mucous membrane from biting. Oral cavity wounds are treated with antiseptics to prevent infection.
Prognosis and prevention
Neuroacanthocytosis is a steadily progressing pathology of the central nervous system, leading to the loss of the ability to move, communicate, and self—serve. Patients die from complications on average after 14 years from the time of the onset of clinical symptoms. Specific preventive measures have not been developed. Genetic counseling of couples planning pregnancy contributes to the prevention of the disease.