Pediatric hereditary ataxia

Introduction to pediatric hereditary ataxia Hereditary ataxia is a group of neurodegenerative diseases characterized by ataxia as the main manifestation and familial tendency. Most causes are unknown. The lesion mainly involves the spinal cord, cerebellum and brain stem, so it is also called spinal cord-cerebellar-brain stem degeneration. Other parts such as the spinal nerve, cranial nerve, basal ganglia, thalamus and cerebral cortex can be involved, often accompanied by other systemic abnormalities such as bones, eyeballs, heart, endocrine and skin. Due to various degrees of focal degeneration damage, age of onset and genetic pattern, these diseases are clinically manifested in many types or syndromes, at least 60 types, and there are often cross-symptoms between various types. There is no ideal classification method so far. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: optic atrophy, mental retardation, cardiomyopathy, arrhythmia, cataract

Pediatric hereditary ataxia

(1) Causes of the disease

The Friedreich Ataxia (FRDA) described in 1863 is one of the most common early-onset autosomal recessive ataxia, with the most basic clinical manifestations of adolescent onset (between puberty and 25 years of age), progressive gait and Limb ataxia, loss of tendon reflexes, tendon reflexes, other common features are dysarthria, cortical spinal cord awkwardness, loss of sensory function in the leg, scoliosis and heart disease, legs that started before 25 years old The Friedreich ataxia, which is deficient in the sacral reflex, is distinguished from the delayed Friedreich ataxia and other "Friedreich ataxia-like" syndromes such as early-onset cerebellar ataxia with loss of tendon reflexes. As the Friedreich ataxia gene is cloned, certain "Friedreich ataxia-like" syndromes have been identified and are the result of mutations in the Friedreich ataxia gene.

The clinically applied classifications are as follows:

1. Spinal cord type includes:

1 Friedrichich ataxia.

2 hereditary spastic paraplegia.

3 post-column ataxia and so on.

2. Spinal cerebellum type includes:

1 hereditary spastic ataxia.

2 no beta lipoproteinemia.

3 ataxia telangiectasia (Louis-Bar syndrome); 4 spinal pons degeneration.

3. The cerebellum type includes:

1 Olive bridge cerebellar atrophy.

2 cerebellum olives shrink.

3 myoclonic cerebellar coordination disorder (Ramsay-Hunt syndrome).

4Machedo-Joseph disease (also known as Azorean disease).

5 hereditary ataxia - cataract - dwarf - mental retardation syndrome.

6Hartnup disease and so on.

Because the classification does not include the etiology and pathogenesis, and overlap with other classification methods, such as no beta lipoproteinemia and Hartnup disease are congenital metabolic abnormalities, ataxia telangiectasia is also a category of neurocutaneous syndrome.

(two) pathogenesis

1. Friedrichich ataxia: Friedrichich ataxia was first reported by Friedreich in 1863. It is a more in-depth study of hereditary ataxia, and most cases, especially typical cases, are common. Chromosomal recessive inheritance, a few cases seem to be dominant heredity, or sporadic, the etiology of this disease is still unclear, and no specific biochemical abnormalities have been found. The lesions mainly involve the spinal cord cerebellum and the posterior spinal cord. The pyramidal tract, the anterior cerebellar sinus lesions are mild, the pathological changes are mainly demyelination of the nerve fibers and axonal rupture, the disappearance of Clark column cells, gliosis, and similar lesions in the posterior root. The cerebellar damage is relatively mild 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 at 9q on chromosome 9, encoding a highly conserved protein, frataxin, and more than 95% of Friedreich's ataxia patients are the first intron of the X25 gene. A homozygous repeat of the GAA triplet, a small number of Friedreich ataxia patients are heterozygous for GAA intron amplification and truncating or missense mutations, some but not all patients are atypical Compound heterozygotes with mild lesions.

Normal chromosomes are generally less than 42 triplet repeats, but the chromosomes of the lesion have 66 to 1700 repeats. When AA repeats show the instability of meiosis, it is often amplified after the father passes the contraction and after the mother transmits or Contraction, meiosis instability of repeat sub-amplification varies in different tissues including different brain regions.

The expression of the Friedreich Ataxia gene is tissue-specific, with the highest expression in most affected sites in Friedreich ataxia, such as heart, liver, skeletal muscle and pancreas. In the central nervous system, the expression level of the spinal cord is highest and the cerebellum is the lowest. Frataxin is located in the mitochondrial inner membrane. The lack of yeast cells in the frataxin counterpart increases iron accumulation in mitochondria and increases sensitivity to oxidative stress. Iron deposits and iron thiolase defects are seen in the heart of Friedreich's ataxia patients, Friedreich The pathogenesis of 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 the nerves, blood vessels, skin, endocrine, reticuloendothelial system, etc. A chromosomal instability syndrome, the main pathological changes are diffuse cerebellar cortical atrophy, thin bundle of spinal cord and demyelination of the spinal cerebellar tract, and the thymus is significantly reduced or absent.

4. Olive bridge cerebellar atrophy: The atrophy of the cerebellum of the olive bridge is autosomal dominant or sporadic. The lesion mainly involves the olive nucleus, the basal ganglia of the pons and the cerebellar hemisphere. The spinal cord and the spinal cord cerebellum can also be affected. The cells in the affected area are significantly reduced. , myelin is lost.

Pediatric hereditary ataxia prevention

Genetic counseling should be performed on patients and their families and genetic testing should be performed.

Pediatric hereditary ataxia complications Complications optic atrophy, mental retardation, cardiomyopathy, arrhythmia, cataract

There may be optic atrophy, mental retardation, arched foot, kyphosis or scoliosis, cardiomyopathy, heart failure and arrhythmia, diabetes, cataract, blue sclera, repeated respiratory infections, malignant tumors, olive bridge cerebellar atrophy There may be Parkinson's syndrome, dysphagia, late pyramidal damage, urinary incontinence and visual impairment.

Pediatric hereditary ataxia symptoms common symptoms closed eyes difficult to sign gait instability arrhythmia cerebellar ataxia heart enlargement serum alpha-fetoprotein elevation dysarthria ataxia dysplasia

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 are beyond the cerebellum, especially the posterior column, pyramidal tract, pons nucleus, and basal ganglia, all of which 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, hereditary patterns, and known specific biochemical abnormalities. The classification of Harding is widely used, especially the classification of autosomal dominant cerebellar ataxia (ADCA) and its three subtypes. The site of the autosomal dominant cerebellar ataxia subtype has been located in the past 10 years. Divided into spinal cerebellar ataxia type 1, 2, 3, etc. (SCA1, 2, 3, etc.).

1. Friedrich Ataxia

The disease is mostly in the 5 to 18 years old, a few can be late to 30 years old, the latent inheritance is earlier than the dominant inheritance, the age of the siblings is similar, the men and women are roughly equal, the insidious onset, the course of the disease is slow Sexual development, early manifestations of gait instability, gait paralysis, body shaking when standing, wide base gait, closed eyes difficult to sign positive, low muscle tone, sputum reflex disappeared, hands clumsy as the disease progressed, intentional tremor , dysarthria, slow and vague speech, deep limbs disappeared in the late stage, pathological reflexes due to obvious damage to the pyramidal tract, most of them have nystagmus, a few have optic atrophy, and mild mental retardation can occur in the late stage.

Skeletal malformation is another feature of this disease. Arched feet, kyphosis or scoliosis are especially common.

Chest X-ray films often suggest heart enlargement, electrocardiogram and echocardiography suggest cardiomyopathy, heart failure and arrhythmia can occur, 20% of patients develop diabetes and require insulin therapy, 40% to 50% of patients with impaired glucose tolerance, diabetes is prone to occur In patients 20 to 30 years of age, neurological complications can in turn aggravate the patient's own symptoms.

Some patients may be associated with cataract, blue sclera, etc. The measurement of nerve conduction velocity shows that the sensory action potential is significantly reduced or disappeared, and the motor nerve conduction velocity is only slightly slowed, which is consistent with the lesion characteristics of axonal neuropathy.

2. Ataxia telangiectasia

Men and women are roughly equal or slightly more than male. Infants and young children are onset. The first symptoms are cerebellar ataxia, intentional tremor, dysarthria, nystagmus and gait instability. Extrapyramidal symptoms may occur as the disease progresses. And spinal cord symptoms, manifested as abnormal muscle tone, hand and foot Xu movement, deep sensory loss, pathological reflex positive, etc., may also be associated with lordosis or lateral process, mental gradual decline, tendon reflexes weakened or disappeared.

Capillary vasodilation often occurs in 4 to 6 years old, first seen in the bulbar conjunctiva, and later in the eyelids, cheeks, auricles, the upper part of the neck clavicle, the flexor of the upper limbs, etc., the skin and hair are premature, female The patient's ovary is not developed. The sick child often has repeated 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. The age of onset is 2 months to 60 years old. It is more than 30 years old. The onset is concealed. The lower limbs are often tired and gait is unstable. The hands are not flexible. Completion, with obvious speech impairment, intentional tremor and poor distance, some patients have difficulty swallowing, followed by Parkinson's syndrome, muscle tension changes from reduction to stiffness, except for head, limb and trunk tremors, visible Repeated contraction of the levator muscle (soft tremor), lingual and facial muscle tremor, some patients have ophthalmoplegia, optic atrophy, nystagmus, retinitis pigmentosa, late pyramidal damage, urinary incontinence And visual impairment, due to rapid saccade movement caused by slow eye movements, gaze-like, the eye can be almost fixed in the late stage.

Pediatric hereditary ataxia

First, laboratory inspection

1. Blood examination: Peripheral blood white blood cell count and neutrophil classification were significantly increased at the time of infection.

2, blood test:

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

(2) Alpha-fetoprotein elevation: abnormal sensitivity to ionizing radiation and a significant increase in alpha-fetoprotein.

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

Second, auxiliary inspection

Includes echocardiographic evidence of characteristic ECG changes and ventricular hypertrophy or uncommon asymmetry interval hypertrophy. Normal peripheral nerve conduction velocity and loss or significant decrease in sensory nerve action potential are the distinguishing points between Friedreich ataxia and Charcot-Marie-Tooth disease. Other common abnormalities are a decrease in the amplitude of the visual evoked potential, a decrease in the supraclavicular (somatosensory evoked potential), or a lack of latent diffusive potential in the sensory cortex.

Brain CT scan and MRI examination showed atrophy of the cerebellum and brainstem. MRI often shows cervical spinal atrophy.

Diagnosis and diagnosis of pediatric hereditary ataxia

diagnosis

The diagnosis of this disease is mainly based on typical clinical manifestations and positive family history, which is helpful for the diagnosis of this disease. The diagnosis points of this disease are: 1 Slow progressive progressive ataxia in adolescence. 2 dysarthria. 3 reflex disappeared and late onset paraplegia. 4 skeletal deformities. 5 Deep feeling weakened or disappeared. 6 abnormal heart. 7 positive family history.

The diagnosis of ataxia telangiectasia is based on typical clinical manifestations. For example, infants with ataxia with IgA deficiency can be diagnosed before telangiectasia occurs. Elevated serum alpha-fetoprotein is another important factor. Diagnose based on.

Differential diagnosis

1 hereditary motor neuropathy type I is iliac muscle atrophy.

2 posterior fossa tumors.

3Arnold-Chiari malformation.

4 congenital metabolic abnormalities, such as no beta lipoproteinemia, Refsum disease, Wilson disease and so on.

5 chronic liver disease.

6 cystic fibrosis and so on.

Ataxia telangiectasia is mainly identified with Friedreich's ataxia. The main point of differentiation is that the latter has skeletal malformations and cardiac changes, without telangiectasia and premature aging, and serum IgA and alpha-fetoprotein are normal.

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