Dr. A. Radha Rama Devi*
Consultant Geneticist at Center for DNA Finger Printing and Diagnostics, Hyderabad
Email : email@example.com *
Neuroregressive disorders are a diverse group of conditions that causes progressive neuronal cell death leading to neuroregression in the child. Neuroregression is defined as, "a previously healthy child begins to deteriorate, losing already attained skills with progressive loss of speech, hearing, vision and muscle strength for more than three months".
Neuroregression is defined as, "a previously healthy child begins to deteriorate, losing already attained skills with progressive loss of speech, hearing, vision and muscle strength for more than three months".
Dementia, the termed used for neurodevelopmental regression in children, is associated with loss of memory, ability to think, understand and recognize along with personality changes or distressing behaviour. The etiology of neuroregression is varied from genetic to non-genetic causes. This includes various metabolic disorders, infections, toxins, head injuries and stroke. The term pseudoregression is applied when loss of skills is temporary i.e. during some rare epileptic situations.
Neurodegeneration can involve both the grey and white matter of the brain and spinal cord. Grey matter is the processing center, while white matter represents networking between these centers. The axons or the myelinated nerve cell processes connecting grey matter of the brain, carry nerve impulses between neurons thus they represent information transmitters. Processing of the information is done in grey matter, which is mainly composed of nerve cells. Injury to grey matter is irreversible. The grey matter disease will have seizures as the common presentation associated with psychomotor retardation and extrapyramidal disturbances along with visual impairment.
White matter, which is mainly represented by myelinated axons also called diencephalons. The nuclei of the white matter relay sensory information from the rest of the body to the cerebral cortex and also regulate autonomic functions such as body temperature, heart rate and blood pressure. White matter disease is dominated by motor difficulties. White matter disease is a common feature of inherited metabolic disorders and present with chronic encephalopathy.
Clinical and objective assessment of a child with regression of milestones is multi-disciplinary involving neurology, neuropsychology, psychiatry and genetics. The etiology of neuroregression could be genetic, which are mostly neurometabolic disorders or non-genetic such as infections mostly viral or toxins due to heavy metal poisoning or brain injuries or cerebral stroke.
The etiology of neuroregression could be genetic, which are mostly neurometabolic disorders or non-genetic such as infections mostly viral or toxins due to heavy metal poisoning or brain injuries or cerebral stroke.
Leukodystrophies are inherited white matter diseases due to defects occurring in the myelin synthesis or its maintenance. The pediatric Leukodystrophies are subdivided into hypomyelinating disorders, dysmyelinating disorders; disorders relating to cystic degeneration of myelin and disorders secondary to axonal damage. The common leukodystrophies involve the brain, spinal cord and peripheral nerves. Classic dysmyelinating disorders are Adrenoleukodystrophy, Metachromatic Leukodystrophy, Krabbe's disease and neuroaxonal dystrophy.
The common leukodystrophies involve the brain, spinal cord and peripheral nerves.
The common leukodystrophies involve the brain, spinal cord and peripheral nerves.
Prototypic examples of these hypomyelinating disorders are Alexander's disease, spongiform diseases as Canavan disease, and vacuolating megalencephalic leukodystrophy with sub-cortical cysts and miscellaneous conditions include vanishing white matter disease, childhood ataxia and diffuse cerebral hypomyelination. An integrated approach including clinical description, neuroimaging and pathophysiological features along with metabolic and molecular studies help in identifying most of these disorders. The disorders are subdivided into those that affect the lipid metabolism of lysosomes and peroxisomes i.e., MLD, globoid cell leukodystrophy and Adrenoleukodystrophy and those that affect the structural proteins.
Adrenoleukodystrophy is a life-threatening disorder occurring in males affecting the white matter of the brain and adrenal gland. Very long chain fatty acids accumulate in the cells and tissues causing myelin sheath damage as well as dysfunction of the adrenal gland. X-linked form is the commonest, symptoms presenting during childhood or adulthood. Childhood form starts at 4-10 yrs of age with severe behavioral changes, scholastic failure followed by visual loss, speech defects, seizures, defects in movement and Adrenal failure leading to Addison's disease. Gonadotrophin deficiency leads to failure in pubertal development. Neonatal ALD is not X-lined, is associated with liver and adrenal dysfunction and is a severe disorder. A mild form is seen in women who are carriers for the ALD. Diagnosis is made by estimation of very long-chain fatty acids in plasma.
X-linked form is the commonest, symptoms presenting during childhood or adulthood.
|Alexander's disease |
Alexander's disease, the midbrain and cerebellum is affected. It is on the most common infantile form that the frontal cortex is involved. Mutations in the gene for Glial Fibrillary Acidic Protein (GFAP) that maps to Chr 17 q 21 are responsible for the diseases. Most of the mutations are heterozygous. Hence, the possibility of a dominant inheritance. Onset is anytime during infancy or adulthood, mostly between birth to 2 yrs. Progressive spasticity and cerebellar ataxia with seizures and megalencephaly are the presenting features. Children rarely survive beyond 5 yrs. Diagnosis is not possible within the child's lifetime unless genotype analysis is done. The post mortem examination of the brain shows the characteristic "Rosenthal fibres" found in relation to blood vessels.
Onset is anytime during infancy or adulthood, mostly between birth to 2 yrs. Progressive spasticity and cerebellar ataxia with seizures and megalencephaly are the presenting features.
Canavan disease is the most common degenerative disease in infancy in which the white matter degenerates into spongy tissue with fluid filled spaces. The deficiency of aspartoacylase is associated with accumulation of N-acetyl aspartate in the CSF, blood and urine. This is inherited recessively, presents with progressive megalencephaly.
Metachromatic leukodystrophy is due to deficiency of Aryl sulphatase A or Sphingolipid activator protein (Saponin-B), characterized by accumulation of lipid sulphatide in the myelin sheath, brain and peripheral nerve. Cognitive function is minimally affected initially followed by motor difficulties and dysarthria. Diagnosis is by estimating Aryl sulphatase A in leukocytes or fibroblasts. CSF protein concentration is grossly elevated.
|Children with paroxysomal disorders such as Zellweger syndrome are associated with dysmorphic features and severe psychomotor retardation, sensory neuronal deafness, peripheral neuropathy and hepatocellular degeneration. Diagnosed by demonstrating the elevated very long chain fatty acids, pipecolic acid and bile and derivatives.
|Mitochondrial disorders |
|Mitochondrial disorders are due to a defect in the oxidative phosphorylation in the inner mitochondrial membrane involving the respiratory chain which is encoded by two genomes, the mt DNA and nuclear DNA. Mitochondrial disorders are classified into three groups based on the genetic abnormality.
Multiple system involvement is typical of mitochondrial cytopathies. Symptoms vary depending on the organ affected and presentation varies from poor growth to visual / hearing problems, learning disabilities, seizures and dementia. Imaging studies show that the brain is small with spongy-form degenerative changes in the cerebrum with white matter attenuation. Measurement of plasma lactate and pyruvate levels and calculation of lactate/pyruvate ratio distinguishes pyruvate dehydrogenase deficiency where the ratio is normal from neonatal form of pyruvate carboxylase deficiency type-B and mitochondrial electron transport defects where the ratio is greater than 25. MERRF, MELAS, NARP, LHON, KSS are the most common mitochondrial disorders.
Rett syndrome is a progressive neurodegenerative disorder with signs of the disease present at birth, but not obvious. Disease becomes evident by two years of age presenting mostly in girls. The characteristic presentation is loss of purposeful hand movement with gait abnormalities followed by development of mental retardation with loss of speech. Onset of regression could sometimes sudden. A mutation in the MECP-2 gene on X-chromosome is responsible and the mutations can be detected in 80% of the girls with Rett syndrome. The remaining 20% of cases may be due to partial gene deletions or mutations in other parts of the gene. Rett syndrome is mostly sporadic. Mutations occurring during spermatogenesis can lead to Rett syndrome in boys, but they usually die after birth.
The characteristic presentation is loss of purposeful hand movement with gait abnormalities followed by development of mental retardation with loss of speech.
|Creatine deficiency syndromes|
|Patients with these disorders develop delay/regression/mental retardation along with severe defects in expression and repetitive speech. Symptoms or due to severe depletion of creatine/phosphocreatine in the brain. The Guanidino acetate methyltransferase (GAMT) deficiency causes accumulation of guanidine acetic acid in the brain and the body fluids causing intractable seizures and movement disorders. The other two disorders i.e., CrT1 defect and AGAT are recently described. GAMT and AGAT are recessive, and CrT1 is X-lined. Diagnosis is mainly by demonstrating the lack of creatine/phosphocreatine signal in the MR spectroscopy in all three diseases. In AGAT, guanidine acetic acid is decreased and creatine in the blood is normal. In CrT1 deficiency, blood and urine creatine is increased and guanidinoacetic acid is normal.
Diagnosis is mainly by demonstrating the lack of creatine/phosphocreatine signal in the MR spectroscopy in all three diseases.
|Non-genetic causes |
Non-genetic causes include toxic and infectious agents and hormonal imbalance like hypothyroidism, brain injuries and childhood stroke. Among the common infectious agents, HIV encephalitis involving the white matter is seen in 30% of patients with AIDS because of direct invasion of neurons by the neurotrophic retrovirus. HIV and Cytomegalovirus often co-exist.
Among the common infectious agents, HIV encephalitis involving the white matter is seen in 30% of patients with AIDS because of direct invasion of neurons by the neurotrophic retrovirus.
Acquired toxic metabolic disorders are commonly seen with cancer chemotherapy, as they are neurotoxic. Acute affects are seen during chemotherapy and delayed affects range from asymptomatic white matter hyperintensities to a severe necrotizing leukoencephalopathy and are mostly seen in CNS leukemias.
Medical specialist caring for families of children with dementia should be able to detect these conditions and provide proper guidance in terms of counseling. Without this knowledge and if families are told that forgetfulness or mood changes as bad behavior in the child, families will be put into great distress. Proper counseling helps in planning families with the available technologies and prenatal diagnosis.
|How to Cite URL :|
|Devi R R A D.. Available From : http://www.pediatriconcall.com/fordoctor/ Conference_abstracts/report.aspx?reportid=410|