What Is Friedreich's Ataxia?

1. Friedrich's ataxia The disease mostly occurs at the age of 5 to 18 years, and a few can be as late as 30 years. Recessive heredity occurs earlier than dominant heredity. Siblings are of similar age. Men and women are roughly equal. Occult onset, the course of the disease is slowly progressive. The early manifestations are gait instability, staggering gait, standing body shaking, wide basal gait, closed eyes and difficult to establish signs, low muscle tone, and tendon reflexes disappear. With the progress of the disease, he has clumsy hands, intentional tremor, dysarthria, and slow and vague speech. In the later period, the deep sensation of the limbs disappeared, and the pathological reflex appeared due to the obvious damage of the pyramidal tract. Most have nystagmus and a few have atrophy of the optic nerve. Mild mental retardation may occur in the later stages.

Hereditary ataxia in children

Hereditary ataxia is a group of neurological degenerative diseases with familial tendencies that are mainly manifested by ataxia. Most causes are unknown. The disease mainly affects the spinal cord, cerebellum, and brain stem, so it is also called spinal-cerebellar-brain stem degeneration. Other parts such as the spinal nerve, cerebral nerve, basal ganglia, thalamus and cerebral cortex can be affected. It is also often accompanied by other system abnormalities, such as bones, eyeballs, heart, endocrine and skin. Due to the different degrees of focal degenerative damage, age of onset, and genetic methods, these diseases are clinically manifested in many types or syndromes, with at least 60 types. There are often cross symptoms between various types, and there is no ideal classification method yet. Hereditary ataxia includes different diseases with three common characteristics: ataxia, genetic basis, pathological changes in the cerebellum or its associated structures. In most cases, pathological changes extend beyond the cerebellum, especially the posterior column, pyramidal tract, pontine nucleus, and basal ganglia. These lesions have corresponding neurological signs. There may be a wide range of clinical and pathological features within a family; this heterogeneity makes classification difficult. In 1983 Harding proposed a draft classification based on age of onset, genetic pattern, and known special biochemical abnormalities. Harding's classification is widely used, especially the classification of autosomal dominant cerebellar ataxia (ADCA) and its three subtypes. In the past 10 years, the loci of autosomal dominant cerebellar ataxia subtypes have been located and classified into spinal cerebellar ataxia type 1, 2, 3, etc. (SCA 1, 2, 3, etc.).

Signs and symptoms of hereditary ataxia in children

1. Friedrich's ataxia The disease mostly occurs at the age of 5 to 18 years, and a few can be as late as 30 years. Recessive heredity occurs earlier than dominant heredity. Siblings are of similar age. Men and women are roughly equal. Occult onset, the course of the disease is slowly progressive. The early manifestations are gait instability, staggering gait, standing body shaking, wide basal gait, closed eyes and difficult to establish positive signs, muscle tension is low, and tendon reflexes disappear. With the progress of the disease, he has clumsy hands, intentional tremor, dysarthria, and slow and vague speech. In the later period, the deep sensation of the limbs disappeared, and the pathological reflex appeared due to the obvious damage of the pyramidal tract. Most have nystagmus and a few have atrophy of the optic nerve. Mild mental retardation may occur in the later stages.

Skeletal deformities are another feature of the disease, with arched feet, kyphosis or scoliosis being more common.

Chest X-rays often indicate an enlarged heart, and electrocardiograms and echocardiograms indicate cardiomyopathy, and heart failure and arrhythmias can occur. 20% of patients develop diabetes and need insulin therapy, and 40% to 50% of patients have impaired glucose tolerance. Diabetes is prone to occur in patients between 20 and 30 years of age, and its neurological complications can in turn aggravate the symptoms of the patients themselves.

Some patients may be accompanied by cataracts and blue sclera. Nerve conduction velocity measurement showed that the sensory action potential was significantly reduced or disappeared, and the motor nerve conduction velocity was only slightly reduced, which was consistent with the pathological characteristics of axonal neuropathy.

2. Ataxia telangiectasia is roughly equal in men and women or slightly more women than men. Onset in infants and young children, the first symptoms are cerebellar ataxia, intentional tremor, dysarthria, nystagmus and gait instability. With the progress of the disease, extrapyramidal symptoms and spinal symptoms may appear, including abnormal muscle tone, slow movements of hands and feet, lack of deep sensation, and positive pathological reflexes, etc. It may also be accompanied by lordosis or lateral processes of the spine, mental decline, and tendon remission Or disappear.

Capillary dilatation often occurs at the age of 4 to 6 years. It first appeared in the bulbar conjunctiva, and later appeared on the skin of the eyelids, cheeks, ears, upper part of the collarbone, flexion of the upper limbs, and so on. Skin and hair show premature changes. Female patients do not develop ovaries. Sick children often have recurrent respiratory infections. The thymus is not developed, and about half of them have malignant tumors.

3. Olive bridge cerebellar atrophy The ratio of male to female is about 2: 1, and the age of onset is from 2 months to 60 years, and onset is more than 30 years old. The onset is hidden, the lower limbs are often tired at the beginning of the disease, the gait is unstable, the movements of the hands are gradually inflexible, the fine movements are difficult to complete, with obvious speech disorders, intentional tremor and poor discrimination. Some patients have difficulty swallowing. This was followed by Parkinson's syndrome, which reduced muscle tone from stiffness to stiffness. In addition to the tremor of the head, limbs and trunk, repeated contractions of the levator levator (soft palate tremor) can be seen, with tremor of the tongue and facial muscle bundles in between. Some patients have ophthalmoplegia, optic nerve atrophy, nystagmus, and pigmented retinitis. In the later stage, there may be pyramidal tract damage, urinary incontinence and visual impairment. Due to the slow eye movement caused by rapid saccadesis, it has a gaze shape, and the eyeball can be almost fixed in the late stage.

Pediatric hereditary ataxia call medicine treatment

No specific treatment is available for most hereditary ataxias. Mainly to improve symptoms such as physical therapy, massage, physical therapy. Medical treatment cannot change the course of the disease, and it is desirable to find treatments that regulate oxidative stress or directly affect the expression of frataxin.

1. Drug treatment Any effect can only achieve moderate improvement.

(1) Vitamins: the repeated application of multiple vitamins, especially vitamin B12; vitamin E replacement can prevent and improve familial vitamin E deficiency.

(2) Oral salicylic acid lentil powder.

(3) Levodopa: In patients with SCA, especially MJD / SCA, levodopa can relieve tonicity or other Parkinson's symptoms.

(4) Baclofen or trizanidene: May be helpful for spasms.

(5) Acetazolamide: can control the onset of paroxysmal paroxysmal ataxia (EA 1 and EA 2).

(6) Sodium phenytoin: relieves muscle twitching of the face and hands of EA 1.

(7) Amantadine and Buspirone: can improve different types of cerebellar ataxia.

(8) Prevention and control of infection: In addition, active prevention and control of sinus, upper respiratory tract and lung infections. You can try drugs that improve the body's immune function, such as thymosin, transfer factor, globulin, etc., but there is no positive effect.

2. Physical therapy and orthopedics are mainly for ataxia.

3. Surgical treatment In Friedreich ataxia, orthopedic surgery can relieve foot deformities.

Based on the increased knowledge of the molecular mechanisms of hereditary ataxia, we expect to have new and specific treatments.

Pediatric hereditary ataxia diet health care

Pay attention to daily habits and usual eating habits.

Preventive care of hereditary ataxia in children

Patients and their families should be genetically counseled and genetically tested.

Pathological causes of hereditary ataxia in children

Friedreich ataxia (FRDA), described in 1863, is one of the most common early-onset autosomal recessive ataxias. The most basic clinical manifestations are adolescent onset (between adolescence and 25 years of age), progressive gait and limb ataxia, lack of tendon reflexes, and sacral reflex elongation. Other common features are dysarthria, cortical spinal tract awkwardness, loss of proprioceptive function in the legs, scoliosis, and heart disease. Friedreich's ataxia with a lack of tendon reflexes in the onset of the leg before the age of 25 years, should be associated with delayed Friedreich's ataxia and other early-onset cerebellar ataxias with lack of tendon reflexes. "The syndrome is different. With the Friedreich ataxia gene cloned, it has been identified that certain "Friedreich ataxia-like" syndromes are also the result of Friedreich ataxia gene mutations.

The clinically applied classifications are as follows:

1. Spinal cord types include: Friedreichs ataxia; hereditary spastic paraplegia; posterior column ataxia.

2. Spinal cerebellar types include: hereditary spastic ataxia; alipoproteinemia-free; ataxia telangiectasia (Louis-Bar syndrome); spinal pontine degeneration and so on.

3. Cerebellar types include: Olive bridge cerebellar atrophy; Cerebellum olive atrophy; Myoclonic cerebellar coordination disorder (Ramsay-Hunt syndrome); Machedo-Joseph disease (also known as Azorean disease); Hereditary ataxia -Cataract-dwarf-intelligence deficiency syndrome; Hartnup disease and so on.

Because this classification does not include etiology and pathogenesis, it overlaps with other classification methods. For example, -lipoproteinemia and Hartnup disease are congenital metabolic abnormalities, and ataxia capillary dilatation is in the category of neurocutaneous syndrome.

Diagnosis of hereditary ataxia in children

It needs to be distinguished from the following diseases: hereditary motor sensory neuropathy type is peroneal muscle atrophy; tumor of the posterior cranial fossa; Arnold-Chiari malformation; congenital metabolic abnormalities, such as alipoproteinemia, Refsum disease, Wilson disease Etc .; chronic liver disease; cystic fibrosis.

Ataxia telangiectasia is mainly distinguished from Friedreich's ataxia. The main point of identification is that the latter has skeletal deformities and cardiac changes, without capillary dilatation and premature senescence, and serum IgA and alpha-fetoprotein are normal.

Pediatric hereditary ataxia test method

Laboratory inspection:

1. Hematology examination Peripheral white blood cell count and neutrophil classification were significantly increased during infection.

Blood test

(1) Immunoglobulin abnormalities: 40% to 80% of children lack or decrease serum and secretory IgA and IgG, and increase IgM.

(2) Elevated alpha-fetoprotein: Abnormal sensitivity to ionizing radiation and -alpha-fetoprotein increased significantly.

(3) Cytogenetic abnormalities: chromosome examination revealed homologous chromosome 14 translocation [t (14q +; 14q-)].

3. Cerebrospinal fluid examination is normal.

Other auxiliary checks:

Includes characteristic electrocardiographic changes and echocardiographic evidence of ventricular hypertrophy or unusual asymmetric septal hypertrophy. Peripheral nerve conduction velocity is normal and sensory nerve action potential is missing or significantly decreased. The main points that distinguish Friedreich ataxia from Charcot-Marie-Tooth disease. Other common abnormalities are decreased amplitude of visual evoked potentials, decreased supraclavicular (somatosensory evoked potentials), or absence and delayed diffuse potentials in the sensory cortex. Brain CT scan and MRI examination showed cerebellar and brain stem atrophy. MRI often shows cervical spinal cord atrophy.

Complications of hereditary ataxia in children

Optic nerve atrophy, mental retardation, arched feet, kyphosis or scoliosis, cardiomyopathy, heart failure and arrhythmia, diabetes, cataract, blue sclera, repeated respiratory infections, and malignant tumors can occur. Olive bridge cerebellar atrophy can appear Parkinson's syndrome, difficulty in swallowing, late stage may have pyramidal tract damage, urinary incontinence and visual impairment.

Prognosis of hereditary ataxia in children

Friedreich ataxia is caused by the disruption of frataxin caused by GAA intron amplification, resulting in frataxin deficiency. As a consequence of amplification, one DNA strand has long purines and the other DNA strand has long pyrimidines; these nucleotide sequences with abnormal spiral structures can inhibit transcription. The more repeated the inhibition of frataxin transcription, the earlier the onset, and the more severe the symptoms.

The course of the disease progresses gradually; most patients cannot walk for 15 years after the onset of symptoms, although the rate of progression varies. The average age of death was 40 to 60 years, and most of them died of infection or heart disease. Medical treatment cannot change the course of the disease, and it is desirable to find treatments that regulate oxidative stress or directly affect the expression of frataxin.

Ataxia telangiectasia has a poor prognosis, most continue to progress, and can't walk around 10 years of age. Often died of lung infections and malignancies. The average course of disease is about 15 years.

Pathogenesis of hereditary ataxia in children

1. Friedreichs ataxia Friedreichs ataxia was first reported by Friedreich in 1863. It is a more in-depth type of hereditary ataxia. Most cases, especially typical cases, are autosomal recessive, and a few cases appear to be dominant or sporadic. The etiology of this disease is unknown and no specific biochemical abnormalities have been found. The lesions mainly involve the spinal posterior cerebellar and pyramidal tracts in the posterior and lateral cords of the spinal cord. The pathological changes were mainly nerve fiber demyelination and axon rupture, Clark column cells disappeared, and glial proliferation. The posterior root has similar lesions. Cerebellar damage is relatively minor or normal. Most cases are accompanied by diffuse degeneration of myocardial fibers and connective tissue hyperplasia.

2. Genetics The Friedreich ataxia gene (X25) is located on 9q of chromosome 9 and encodes a highly conserved protein, frataxin. More than 95% of Friedreich ataxia patients are homozygous for repeated amplification of the GAA triplet of the first intron of the X25 gene. A small number of Friedreich ataxia patients are heterozygotes with GAA intron amplification and truncating or missense mutations. Some, but not all patients, are heterozygous for atypical and mildly diseased complexes.

Normal chromosomes usually have fewer than 42 triplets, but diseased chromosomes have 66 to 1700 repeats. When passed from parent to child, the duplication of normal chromosomes is stable, but increased GAA repetitions show instability of meiosis, often contracting after parental transmission and amplification or contraction after parental transmission. The meiotic instability of repeat amplification varies in different tissues, including different brain regions.

The expression of Friedreich ataxia gene is tissue-specific, and it is highest in most affected parts of Friedreich ataxia, such as heart, liver, skeletal muscle and pancreas. In the central nervous system, the expression level of the spinal cord is the highest and the cerebellum is the lowest. frataxin is located in the inner mitochondria. The lack of yeast cells in the frataxin counterpart causes iron accumulation in mitochondria and increases sensitivity to oxidative stress. Defects in iron deposition and iron sulfatase are seen in the heart of Friedreich ataxia patients. The pathogenesis of Friedreich ataxia may be mitochondrial dysfunction and free radical toxicity.

3. Ataxia telangiectasia Ataxia telangiectasia, also known as Louis-Bar syndrome, is a primary immunodeficiency disease involving nerves, blood vessels, skin, endocrine, and reticuloendothelial system. It is also a chromosomal instability syndrome. The main pathological changes were diffuse cerebellar atrophy, thin spinal cord tract and spinal cerebellar tract demyelination. The thymus is significantly reduced or missing.

4. Olive bridge cerebellar atrophy Olive bridge cerebellar atrophy is autosomal dominant or sporadic. The lesions mainly involve the olive nucleus, pontine basal nucleus, and cerebellar hemisphere. The posterior spinal cord and cerebellar tract of the spinal cord can also be affected. Cells in the affected area were significantly reduced and myelin sheath was lost.