Is my child going backwards in development? An overview of Neuro-degenerative Disorders of Childhood.

Transcription

1 Is my child going backwards in development? An overview of Neuro-degenerative Disorders of Childhood. - By Dr.Ratnakar.P.Kini M.D. Pediatrician Objectives: The learner will be able to explain - What neuro degeneration disorders are? - How they manifest? - What are the different neuro degenerative disorders? - What are the investigations to be done? - What is the treatment protocol? Synopsis: Neurodegenerative disorders in children are terrifying for any family. Therefore, providers need to be able to recognize serious issues with children. Important factors include milestones, classifications, investigation and treatment will be reviewed. A brief description will be given regarding the different conditions. Classification, investigation and treatment can be the key with these disorders to either treat the disease or give the family some comfort in the final time with their child. Dr. Kini will help us look more closely at these and help us differentiate what some of the disorders are. This article is an overview of the neurodegenerative disorders of childhood. Neurodegenerative disorders of childhood are one of the least understood disorders in Pediatric Neurology. More research studies are being done utilizing the newer investigative methods. This article includes (in the following order) 4 Brief case scenarios Introduction of neurodegenerative disorders Developmental milestones Classification of Neurodegenerative disorders Investigations of neurodegenerative disorders Treatment 1

2 A brief description of the different neurodegenerative disorders A detailed case scenario to assess the learners Multiple choice questions to assess the readers with the keys at the end of the test Case Scenario 1: A 11 year old girl presented to the neurology department with complaints of involuntary movements. The girl was apparently normal before that. Her mother said that she could notice some changes in her behavior. She also said her school performance has gone down. Her elder sibling also had similar complaints. The examination of the eyes showed a golden brown ring in the cornea. Her urinary copper levels were elevated. The liver biopsy done showed increased copper content. What is your provisional diagnosis? Case Scenario 2: A 5 year old boy who was apparently normal till 2 years of age presented with increased clumsiness. He started staggering while walking. He also had roving movements of eyes, Examination revealed small tortuous blood vessels over the conjunctiva of eyes, forearm and over the bridge of the nose. His mother said he gets repeated infections especially of the sinuses. What is your provisional diagnosis? Case Scenario 3: A 9 year old boy presented to the neurology department with complaints of repetitive shock like contraction of the body. His mother said that the boy has started performing badly in school and his intellect and memory has come down a lot. When properly probed she revealed that he had measles at 3 years of age. What is your provisional diagnosis? Case Scenario 4: A one and half year old girl was brought to a physician with complaints of breathing difficulties. History revealed that the baby was normal till 1 year of age. From then the mother started noticing some changes in her. The baby who was uttering a few words stopped uttering. The baby stopped using her hands and there were involuntary movements. She started spending time alone and she stopped playing with other kids. On examination her head was less than normal size for that age. What is your provisional diagnosis? 2

3 Are you able to understand the different case scenarios given above? What do you think the scenarios are concerned with? Do they represent diverse diseases or any syndrome? How do you think you can proceed further in these cases? This article is going to give a comprehensive detail of all these scenarios. The different case scenarios given above represent Wilson Disease, Ataxia telengiectasia, Sub acute sclerosing Pan Encephalitis and Rett syndrome respectively. Yes we are going to look into the details of Neurodegenerative disorders of Childhood. What exactly are neuro degenerative disorders? They are diverse groups of disorders that results in progressive deterioration of the functions of the nervous system. They could result from any of the following causes. Genetic disorders Biochemical defects Chronic viral infections Toxins Idiopathic where the cause is unknown Though a few causes are mentioned, all of them are rare. Then the question which arises is how to diagnose if it is rare. Rare diseases are easy to diagnose provided you suspect the possibility of that particular disease. When to suspect that there is neurodegeration? A precise history will definitely give you the clue. There will be a decline in the neurological function and the disease keeps worsening as time goes on. But the single most important clue is- Regression of developmental mile stones. Regression of milestones when milestones are lost: From birth all babies develop according to a particular sequence. All the babies need not develop these milestones in a similar pace. For each milestone there is an age range. Normal babies attain specific milestones within this normal range- some attaining faster and some slower and yet both within this normal range. If they don t attain the milestone or attain it outside 3

4 the normal range, they are said to have developmental delay. Some of the developmental milestones and their normal range are given below. Developments 3 rd percentile (in months) 95 th percentile (in months) Social smile Eyes follow pencil Holds head steadily Turns from back to stomach Turns head towards sound of a bell or rattle Transfers object from hand to other Raises self to sitting position

5 Standing up by Furniture Fine prehension pellet Pat a cake Walks with help Throws ball Walks alone Say two words Walks backwards Walks upstairs with Help Points to parts of a Doll(3 parts) (Courtesy: Nair MKC et al, Indian Pediatrics 28: ) 5

6 The above table shows the 17 items used for assessing development by one of the simplest methods called the Trivandrum Development Screening Test. All the items are described at the 3 rd and the 95 th percentiles. The interval between these is two standard deviations which means, it includes 95% of the babies. So 95% of the babies develop these milestones in these ranges. For example, 95% of babies attain the milestone of holding the head steady between 1.1 and 3.8 months. If any of the babies does not develop the milestone even at the 95 percentile limit, then development delay is suspected. For example if a baby does not develop head control by 3.8 months, then development delay is suspected. Let s take the average ages of certain milestones to understand regression of milestones. Development Age (in months) Head Control 2.0 Transfers objects from hand to hand 5.5 Sits without support 6.0 Walks alone 12.0 Speaks 4-6 words 15.0 (Courtesy Nelson Textbook of Pediatrics -16 th edition) 6

7 To understand the regression of milestones, we can utilize the above table of milestones. Let us take an example of a 15 months old baby. At 15 months the baby would have reached the development of speaking 4-6 words. If the baby after attaining this milestone suddenly one day is not able to speak, it is termed as loss of a mile stone. If subsequently it stops walking, the baby is said have lost one more milestone of earlier age. So now at 15 months the baby is with milestones of a less than 1 year old baby. The baby is growing older as per age. But developmentally, the baby is going backwards. In the end the baby would have lost even head control which is one of the earliest milestones. This progressive loss of mile stones is called the Regression of milestones and it is the diagnostic feature of neuro degenerative disorders. How many types of neurodegenerative disorders are there? The list is a long one. The different disorders are categorized in a number of ways. Etiological Classification Pathological classification Genetic/ biochemical classification Clinical and age wise classification Etiological Classification Genetic / Biochemical defects. Chronic viral infections Toxins 7

8 Idiopathic Pathological Classification Gray matter disease White matter disease Basal Ganglia disease Spinocerebellar disease Peroxisomal disorders Mitochondrial disorders Genetic / Biochemical Classification Sphingolipidosis Neuronal Ceroid Lipofuscinosis Adrenoleukodystrophy Sialidosis 8

9 Clinical and Age wise Classification Children less than 2 years with liver enlargement Children less than 2 years without liver enlargement Children between 2-5 years Children between 5-15 years How to proceed? Science is developing in leaps and bounds. A couple of years ago when Pediatric Neurology was still in the infant stage, the children who were suspected to have neurodegeneration were subjected to invasive investigations like brain, skin, conjunctival and rectal biopsies. These primitive methods are gone now and modern sophisticated neuroimaging techniques and specific biochemical molecular diagnostic tests are being utilized for the diagnosis of neurodegenerative disorders. Some of the modern investigative methods in neurodegeneration are given below. 9

10 Given below are different investigations and their applications in Neurodegenerative disorders with an example for each investigation. Newer investigative methods: Investigations Application in Neurodegenerative Disorders Magnetic Resonance Imaging (MRI) MRI helps to locate the lesion and also helps in finding out whether it is a gray matter or a white matter disease ( MRI of normal brain) MRI detects of radio frequency signals produced by displaced radio waves in a magnetic field. It provides an anatomical view of the brain. delineates the gray and the white matter. MRI of brain affected by Multiple Sclerosis showing the characteristic white plaques. 10

11 Positron Emission Tomography (PET) The decreased functional activity of brain in Neurodegeneration can be detected. The disease progression can be assessed. The disease can diagnosed early in its course even before it manifests clinically. ( PET scan of normal brain) The image on the right shows decreased metabolic activities of brain (The above images show different areas of affected by neurodegenerative disorder brain functioning during different acts) ( Alzheimer s in this case) A scanner detects radioactive substance that is injected to produce an image of the brain. The radioactively -labeled substance used include oxygen, fluorine, carbon and nitrogen. When this substance gets into the bloodstream, it goes to areas of the brain that uses it. So, oxygen and glucose accumulate in brain areas that are 11

12 metabolically active. This method provides a functional view of the brain. Visual Evoked Responses (VER) The visual nerve pathways from the eyes to the occipital cortex (visual center) of the brain are evaluated by having the patient stare at a pattern a video screen. It helps to diagnose problems with the optic nerves that affect sight. Neurodegenerative disorders like Tay Sach disease, Krabbe disease, Pelizaeus Merzbacher disease and Neuronal ceroid lipofuscinocies show characteristic VER abnormalities. Auditory Brain stem Evoked Reponses (ABR) The ABR show abnormal wave patterns in neurodegenerative disorders It is used to evaluate the auditory (hearing) nerve pathways from the ears through the brainstem by placing electrodes on the scalp and ear lobes and giving stimulus like clicking with an ear phone. 12

13 Electroretinography (ERG) If there is demyelination there is decreased amplitudes of the waveforms. If there is optic atrophy there is absent waveforms. It measures the electrical response of the eye's light-sensitive cells (rods and cones). Electrodes are placed on the cornea and the skin near the eye. The hereditary and acquired disorders involving the retina can be evaluated with this test. Somatosensory Evoked Potential (SSEP The SSEP show abnormal wave forms in neurodegenerative disorders. It is performed by passing a small painless electric current to the skin over the nerves to arms and legs. It helps in assessing the nerve pathways to arms and legs from the brain and the spinal cord 13

14 Enzyme assays and cultures: Assays of the enzymes are done using white blood cells and cultured fibroblasts. By doing this one can know the blood levels of a particular enzyme- whether they are present, decreased or absent. The neurodegenerative disorders with enzyme deficiencies can be diagnosed using these assays. 14

15 Investigations Computed Tomography (CT) Application in Neurodegenerative Disorders The CT scan can be used to locate the lesion anatomically and to know any structural defect is present. CT scans use a series of X-ray beams passed through the head. It shows the structure of the brain. The above CT scan shows the white plaque of Multiple Sclerosis near the midline. Nerve Conduction Studies (NCS) The white matter diseases show prolonged latencies. Nerve conduction studies are performed by placing electrodes on the skin over particular nerves or a muscle that is strengthened by a nerve. Electrical stimulation is applied to activate the nerve. The test is not painful, only a tingling sensation is felt. NCS tests are used to evaluate conditions which produce numbness, tingling, pain, loss of sensation or other neurological diseases affecting the peripheral nervous system. 15

16 Electro-encephalogram (EEG) Some of the neurodegenerative disorders show characteristic findings in the EEG. For example in SSPE, EEG shows bursts of high voltage slow waves interspersed with a normal background. An EEG is performed by placing electrodes on the scalp to record the electrical activity of the brain. EEG is done to diagnose a number of conditions that include seizure disorders, neurodegenerative disorders, stroke and psychiatric illnesses. Retinal Fundoscopy Many neuro degenerative disorders show cheery red spot and optic atrophy. ( Cherry red spot seen in the macula) (Normal fundus of eye) ( Small pale disc Optic atrophy) 16

17 The retina is viewed through the dilated pupil with the help of an ophthalmoscope. The optic disc, macula and the retinal blood vessels are seen. Histopathological Examination (HPE) Biopsies of different affected parts are fixed on a slide and viewed through a microscope, sometimes using an electron microscope to get a magnified picture of the substance. This investigation was routinely used in the past for diagnosis. Now it has been replaced by the newer techniques. The characteristic feature of some of the disorders is described under respective sections. Biopsies of brain, skin, muscle and conjunctiva are usually utilized. 17

18 Regression of mile stones Suspect Neurodegeneration Do Imaging studies and evoked potential studies MRI PET scan CT scan Visual evoked Auditory Brain Responses Stem evoked Responses Categorize the disease in to gray matter, white matter, basal ganglia or spinocerebellar disease Do the relevant Biochemical molecular diagnostic test for specific diagnosis Flow chart for the work up of a case of Neurodegenerative Disorder. 18

19 Treatment: These vast groups of disorders don t have any cure. They progress relentlessly resulting in death. Then one may question the need for diagnosing and treating these babies. Any child with neurodegeneration needs to be investigated thoroughly and treated adequately for the following reasons. Whether the child is normal or not, his/her life is to be supported by the caretakers. A child affected by neurodegeneration may have various problems like feeding difficulties, blindness, convulsions and so on. These problems can be managed so that even though the disease progression cannot be stopped, the affected children can avoid miserable life. Appropriate investigations and proper diagnosis is essential for research purposes. These researches can one day find a solution for these diseases. Fluoxetine Hydrochloride which is an anti depressant is now found to slow down the progression of Huntington s chorea. The drug Phosphocysteamine is being studied for treatment of Infantile Neuronal Ceroid Lipofuscinosis. One website claims that Lorenzo oil is effective in ameliorating the maladies of adrenoleukodystrophy. The role of enzymes supplementation is also being studied. As many of the neurodegenerative disorders are inherited, a proper etiological diagnosis is essential for genetic counseling. This helps the parents in planning for the next baby. 19

20 The classifications of neurodegenerative disorders and a brief overview of some of the important disorders are given below. Etiological Classification Genetic / Biochemical defects. See separate classification given below Chronic viral infections Sub acute Sclerosing Pan Encephalitis Toxins Copper Wilson Disease Iron containing pigments- Hallervorden Spatz disease Idiopathic Multiple Sclerosis Rett Syndrome Alexander Disease Sub acute Sclerosing Pan Encephalitis -SSPE (Dawson s Encephalitis): It is a chronic infection of the brain caused by persistent measles virus infection. The virus could be a wild one causing measles or it could be following measles vaccination. Age of onset is 6 months to 30 years. It follows measles infection after 12 years and measles vaccination after 8 years The incidence is 1 in 1,000,000 cases of measles infection and 0.7 in 1,000,000 cases of measles vaccination There is destruction of the brain substance and the virus can be seen in electron microscopy of the brain The virus changes its genetic code to escape from the immune system and establish a chronic infection 20

21 The initial symptoms are personality changes and aggressive behavior The other manifestations are Myoclonic seizures Increased muscle tone Progressive bulbar palsy Decerebrate rigidity The following investigations help in diagnosing SSPE. CSF analysis Measles antibodies are detected EEG shows bursts of high voltage slow waves interspersed with a normal background which is very characteristic of this disease Brain biopsy shows the virus The disease has a progressive course and there is no treatment for it. Death usually occurs 1-2 years after the onset of the symptoms. Wilson disease: It is an autosomal recessive disorder affecting the copper metabolism. The defective gene is located at Chromosome 13q This results in defective excretion of copper in the bile. The disease is characterized by the involvement of two organs. Basal Ganglia of Brain Liver The liver symptoms occur during the first decade of life and the neurological symptoms during the second decade of life. Liver symptoms: The presentation may be Sub acute liver failure often mistaken to be due to hepatitis virus Cirrhosis of liver Neurological Symptoms The presentations may be Worsening of the school performance 21

22 Behavioral Changes Tremors Golden Brown colored Kayser Fleisher Rings in the Cornea of eyes ( See picture below) Other symptoms include Arthritis Hemolysis Endocrinopathies Renal Failure KF ring in the cornea The disease can be diagnosed by the following investigations. Serum copper Elevated Serum ceruloplasmin- Decreased Urine copper Increased Liver Biopsy increased copper content The affected patients are treated by Avoiding copper containing foods like nuts and chocolates Using drugs like D Penicillamine which helps in excretion of copper. Hallervorden Spatz Disease: It is a rare neurodegenerative disorder inherited as an autosomal recessive disorder. The defective gene is located at Chromosome 20p13. This results in deposition of iron containing pigments in the Basal ganglia. The manifestations include Increased muscle tone Dystonia Involuntary movements choreoathetosis Intellectual impairment 22

23 The MRI of brain shows lesions in the basal ganglia and the smear shows iron containing substances. There is no cure and the affected die during early childhood. Multiple Sclerosis: It is a neurodegenerative disorder characterized by multiple white lesions in the central nervous system. The myelin sheath which is a covering of the nerve fibers under go degeneration and form white plaques. Though a lot of research studies are being done on this disease it is still not known why this disease occurs. Multiple sclerosis is rare in Pediatric age group The initial presentation is usually weakness of one side of the body or staggering gait. The other manifestations include Head ache Pins and needles in hands and feet Blurred vision and sometimes sudden loss of vision due to optic atrophy (See fundoscopy picture in the investigation section) Bladder disturbances The investigations that are done to diagnose Multiple sclerosis are MRI The white plaques can be visualized (See MRI picture in the investigation section) Electroretinogram shows absent or diminished amplitude wave forms The disease process keeps waxing and waning. Complete recovery is possible. Drugs that can decrease disease activity include Corticosteroids Interferon β 1b given by sub cutaneous injection on alternate days Interferon β 1a given by intramuscular injection ever day Immunoglobulin 23

24 Pelizaeus Merzbacher Disease: It is a group of neurodegenerative disorders having in common the following two features. Abnormalities of myelin sheath of the nerves Nystagmus the involuntary roving of eyes. The Classic form of this disease is inherited as an X linked disorder which results in abnormalities of Proteolipid protein (PLP) gene. This gene is responsible for the formation of myelin which is the nerve sheath. The children affected by this disorder also manifest Delayed milestones Staggering gait Involuntary movements Increased muscle tone Loss of vision The affected children can be investigated with the following methods. MRI- shows decrease in the myelin formation ABR shows loss of waves III and IV SSEP- shows delayed latencies or absent cortical responses VEP shows prolonged latencies. There is no treatment for this group of diseases. The affected children usually succumb in the 2 nd or 3 rd decade. Alexander Disease: It is a rare neurodegenerative disorder characterized by progressive increase in the head size during the first year of life. The increase in the size is due to the deposition of substances whose nature is not known. The deposition mainly occurs around the blood vessels and below the covering membranes of the brain. This results in the degeneration of the white matter which is characteristically seen in the frontal lobe. The affected children clinically manifest Loss of intellect Increased muscle tone Convulsions MRI and CT scan show thinning of the white matter and histopathological examination of the brain biopsy shows the deposited substance. 24

25 There is no cure for this disease and the affected child succumbs by 5 years of age. Phenyketonuria: Phenylketonuria is a neurodegenerative disorder due to the deficiency of the enzyme Phenylalanine hydroxylase. This results in accumulation of Phenylalanine and its metabolites. These substances cause degeneration of brain. The baby is normal at birth. It has blonde hair and blue eyes. Slowly neurodegeneration sets in. It is estimated that a baby with Phenylketonuria lose 4 IQ points every month. The manifestations include Characteristic body odor described as mousy order Mental retardation Hyperactive purposeless movements Eczematoid skin rash The diagnosis is by the The characteristic mousy body odor Guthrie Test The treatment is mainly elimination of Phenylalanine from the diet at least up to 6 years of life. Pathological Classification Gray matter disease Nieman Pick Disease Gangliosidosis Neuronal Ceroid Lipofuscinosis MERRF White matter disease Pelizaeus Merzbacher Disease Adrenoleukodystrophy Metachromatic leukodystrophy Multiple sclerosis 25

26 Basal Ganglia disease Huntington Disease Wilson Disease Hallervorden Spatz Disease Spinocerebellar disease Friedreich Ataxia Ataxia telengiectasia Abetalipoproteinemia Peroxisomal disorders - Zellweger Syndrome - Neonatal Adrenoleukodystrophy - Classical Adrenoleukodystrophy Mitochondrial disorders Mitochondrial Encephalomyopathies Gray matter diseases: The neurons and associated cells in the brain and spinal cord form the Gray matter. In the brain gray matter mainly occupies the cortical region and in the spinal cord it occupies the H shaped region around the central canal. The disorders affecting predominantly gray matter have manifestations like Convulsions Intellectual impairment Visual impairment 26

27 White matter diseases: The nerve tracts arising from the brain and passing through the spinal cord and peripheral nerves form the White matter. The disorders affecting predominantly white matter have manifestations like Increased muscle tone Decreased muscle power Exaggerated tendon reflexes. Basal Ganglia Diseases: Basal Ganglia is the part of the brain found below the cortex. The disorders affecting predominantly the basal ganglia have manifestations like Increased muscle tone Involuntary movements Huntington Disease: Huntington Disease is a neurodegenerative disorder inherited as an autosomal dominant disorder. The defective gene is located at Chromosome 4p16.3. The characteristic features of this disease are Chorea Presenile dementia The disease is rare in pediatric age group which represents less than 1% of the cases. The symptoms in this age group include Dystonia Increased muscle tone Chorea Convulsions Mental retardation Cerebellar signs CT scan brain shows atrophy of Putamen and Caudate nucleus of the basal ganglia. MRI shows increased density of Putamen. There is no specific treatment of this disorder. 27

28 Spinocerebellar Diseases: The cerebellum occupies the hind part of the lower portion of the brain. The disorders mainly affecting the spine and the cerebellum have manifestations like Decreased muscle tone Inco-ordination Staggering gait- Ataxic gait Friedreich Ataxia: This is a neurodegenerative disorder inherited as an autosomal recessive disorder. The defective gene is located at Chromosome 9q13. Intelligence is normal in this group. The age of onset is around 10 years. The manifestations include Ataxia Slurring of speech Loss of position and vibration sense Arched feet pes cavus Hammer toes Kyphoscoliosis Cardiac failure due to hypertrophic cardiomyopathy it is the cause of the death. The VEP, ABR and SSEP are all abnormal in this disease. Abetalipoproteinemia (Bassen Kornzweig Disease): It is an autosomal recessive disorder characterized by Malabsorption of fat and fat soluble vitamins including Vitamin E. Spinocerebellar degeneration Pigmented retinopathy The hallmark of this disease is abnormal lipid and lipoprotein profile. The manifestations include Ataxia Retinitis pigmentosa Peripheral neuritis 28

29 Abnormal position and vibration sense Mental retardation. The important investigations include Peripheral smear shows acanthocytes (See below). Acanthocytes may be described as red cells with finger-like projections. These cells have a decreased survival time and may be observed in abetalipoproteinemia and liver disorders. Courtesy: anomalie-hematies.htm Serum levels of Vitamin E, cholesterol and triglycerides are decreased. Ataxia Telengiectasia: It is a neurodegenerative disorder inherited as an autosomal recessive disorder. The defective gene is located at Chromosome 11q22-q23. The disease is characterized by Ataxia Telengiectasia (Tortuous blood vessels) over the conjunctiva, nose ears and extremities The age of onset is 2 years. The other manifestations include Recurrent Sino pulmonary infections due to decreased immunity Increased susceptibility to tumors like leukemia, lymphoma and Hodgkin s Disease 29

30 Death usually is due to infections or spread of the tumor. Peroxisomal Disorders: These are disorders in which there is failure to form or maintain peroxisomes inside the cell. It may be also due to the absence of a single enzyme that is normally located in that organelle. Peroxisomes are organelles inside the cell containing many enzymes for metabolism. Zellweger Syndrome (Cerebro hepato renal syndrome- CHRS): Zellweger Syndrome is a rare neurodegenerative disorder which is inherited as an autosomal recessive disorder. It is due to the absence of migration of the nerve cells which usually occurs when the baby is in the womb. The affected babies have characteristic features which include Abnormal facies with features like Frontal bossing Flat occiput Abnormal external ears Roving movements of eyes High arched palate Excessive skin folds of the neck Decreased muscle tone Cataracts in both eyes Loss of vision due to optic atrophy Liver enlargement Jaundice in the newborn period The investigations which are useful include Retinal fundoscopy MRI ERG 30

31 Mitochondrial Disorders: These are disorders due to defective genes present in the mitochondria. The mitochondria are obtained from the mother at the time of fusion of the sperm with ovum. So all the mitochondrial disorders are inherited from the mother. Myoclonic Epilepsy and Ragged Red Fibers (MERRF): This very rare disorder is a mitochondrial disorder characterized by Progressive myoclonic epilepsy Myopathy Cerebellar degeneration Mitochondrial disorders are inherited from the mothers. There is a positive family history and the affected person is very short. The other manifestations include Loss of intellect Hearing loss Loss of vision due to optic atrophy Peripheral neuropathy Increased muscle tone Arched foot The diagnosis can be done with the following investigations. Blood biochemistry shows elevated lactate levels Muscle biopsy shows red ragged fibers MRI shows neuronal loss, gliosis and cerebellar degeneration Muscle biochemistry shows defective complexes As with most of the neurodegenerative disorders, there is no appropriate treatment for this disorder. Coenzyme Q10 was found to be effective in a mother and her daughter with this disorder. 31

32 Genetic / Biochemical Classification Neuronal Ceroid Lipofuscinosis Infantile Late Infantile Juvenile Adult onset Adrenoleukodystrophy Classical Adrenoleukodystrophy Adrenomyeloneuropathy Neonatal Adrenoleukodystrophy Sialidosis Sialidosis I Sialidosis II Sphingolipidosis Nieman Pick Disease Gaucher Disease GM1 Gangliosidosis GM2 Gangliosidosis Krabbe Disease Metachromatic Leukodystrophy 32

33 Neuronal Ceroid Lipofuscinosis (NCL): It is a group of inherited severe neurodegenerative disorders characterized by accumulation of auto fluorescent lipopigments in the lysosomes in the tissues of the central nervous system. The lipopigments which get accumulated are Ceroid Lipofuscin It is the most common of the neurodegenerative disorders in children and it is found in 1.2 babies per 100,000 live births. The manifestations of this disease are Regression of milestones Progressive loss of vision due to optic atrophy Convulsion including myoclonus Ataxia Decreased muscle tone The following investigations help in diagnosing NCL (also see the How to proceed section). MRI shows cortical atrophy Conjuctival/ skin biopsy shows curvilinear, finger print, granular osmopholic or mixed bodies depending on the type of NCL Visual evoked potentials are diminished and disappears with age Electroretinogram- shows waves of diminished amplitudes There are four major subtypes of NCL based on the age of onset and the type of deposit as detected by electron microscopy. All the types are inherited as autosomal recessive disorders except the adult onset type which is autosomal dominant. Infantile Late Infantile Juvenile 33

34 Adult onset Infantile NCL (Haltia Santavouri disease): It is the most severe form of NCL Convulsions in the first year is the presenting symptom It is due to the defective enzyme palmitoyl protein thioesterase(ppt) linked to chromosome 1p32 Granular deposits are seen in the biopsies Death usually occurs by the age of 10 Late Infantile NCL (Bielschowsky-Jansky disease): It is the most common form of NCL Age of onset is 2-4 years Convulsions is the presenting symptom It is due to the defective enzyme pepstatin-insensitive lysosomal protease linked to chromosome 11p15 Predominantly curvi linear deposits are seen in the biopsies Death usually occurs 10 years after the onset of the disease Juvenile NCL (Spielmeyer-Vogt-Sjogren-Batten disease, also called Batten disease): Age of onset is 4-10 years Progressive loss of vision is the presenting symptom Convulsions are milder It is due to a defective transmembrane protein of unclear function linked to chromosome 16p12 Finger print bodies are seen in the biopsies Adult onset NCL (Kuf s Disease): It is the rarest form Age of onset is 3 rd decade There is no vision loss The defective gene is yet to be found Predominantly granular deposits are seen in the biopsies 34

35 Adrenoleukodystrophy (ALD): It is an inherited disorder characterized by degeneration and hypo function of two organs. Central Nervous system Adrenal glands. It is transmitted as a X- linked disorder except the Infantile type which is inherited as an autosomal recessive type. The defect is in the oxidation of the very long chain fatty acid. The manifestations of ALD are CNS manifestations: It is due to the involvement of white matter Gait abnormalities Academic deterioration Behavioral changes Convulsions Paralysis of all four limbs Swallowing difficulties Visual, hearing and speech loss Mental retardation Adrenal Gland manifestations Increased pigmentation of skin Decreased blood sugar Decreased levels of the hormone cortisol. There are three types of ALD. Classical type Adrenomyeloneuropathy Neonatal type Classical Adrenoleukodystrophy: Age of onset is 5-15 years The incidence is 1 in 20,000 boys Academic deterioration, behavioral disturbances and gait abnormalities are the presenting features 35

36 cases CNS involvement is mainly white matter type Hypo functioning of adrenal glands seen in 50 % of the The abnormal gene is located at Xq28 The clinical course varies. But death occurs within 10 years after the onset of the disease Adrenomyeloneuropathy: Age of onset of neurological symptoms is 3 rd or 4 th decade Hypo functioning of adrenals present from early childhood CNS involvement is of white matter type and includes Progressive spastic paresis Urinary incontinence Impotence Neonatal ALD: Age of onset is first year of life In contrast to other types there is decreased muscle tone Convulsions occur early along with deterioration of vision Though adrenal glands are degenerated, adrenal function tests show normal results Sialidosis /Sialoduria: It is an inherited neurodegenerative disorder characterized by accumulation of sialic acid oligosaccharide complexes mainly in the nerve cells and also in other tissues. This complex is also excreted in the urine. It is due to the deficiency of the lysosomal enzyme Neuraminidase. The disorder is inherited as an autosomal recessive disorder. Patients affected with this disorder have survived beyond the 5 th decade. The common manifestations of this disorder are Cherry Red spot in the fundus of retina Myoclonus 36

37 There are no characteristic findings of this disease in Neuroimaging and electrophysiological studies. Diagnosis is mainly by clinical methods and enzyme assays. Enzyme assays show deficiency of the lysosomal enzyme Neuraminidase. Sialidosis II has a few additional findings which can be detected. X-ray lumbar spine- shows anterior beaking of the vertebra Peripheral smear shows lymphocytes with vacuoles in the cytoplasm Liver Biopsy shows vacuoles in the cytoplasm of Kupfer Cells Nerve Biopsy shows vacuoles in the cytoplasm of Schwann Cells There are two types of this disorder based on the clinical manifestation. Sialodosis I Sialodosis II Sialidosis I (CRSM Syndrome- Cherry Red Spot Myoclonus Syndrome): Age of onset is 2 nd decade Progressive loss of vision is the presenting symptom Myoclonus is triggered by voluntary movements, touch and sound and is not controlled by anti convulsants. Sialidosis II: There are two sub-types, Infantile and Juvenile, based on the age of onset There is multiorgan involvement unlike type I The additional features are Coarse Facies Corneal clouding Skeletal deformity 37

38 Sphingolipidosis: It is an inherited neurodegenerative disorder characterized by deposition normal lipid component of the cell wall inside the cell. This is due to absence of the enzymes which normally metabolize them.there are six types of sphingolipidosis. Nieman Pick Disease Gaucher Disease GM1 Gangliosidosis GM2 Gangliosidosis Krabbe Disease Metachromatic Leukodustrophy Nieman Pick Disease: It is a neurodegenerative disorder inherited as an autosomal recessive disorder. It is due to the deficiency of the enzyme sphingomyelinase. This results in defects in cholesterol metabolism. The defective gene is located at Chromosome 11 p15.1 p15.4. The disease is characterized by Neurodegeneration Enlargement of liver and spleen Failure to thrive Cherry red spot in the fundus of eye There are six types of Nieman Pick disease. Type A the most severe form Type B additionally have lung involvement Type C- Presents with jaundice in the newborn period Type D have delayed onset of neurological symptoms Type E and F milder forms There is no specific treatment for Nieman Pick disease. Liver transplantation, Bone marrow transplantation are tried, but without any success. 38

39 Gaucher Disease: It is the most common lysosomal storage disease characterized by Hematological problems Organomegaly Skeletal involvement It is inherited as autosomal recessive disorder. The disease is common in Ashkenazi Jews. The defective gene is located at Chromosome 1q21-q31 due to which there is a deficiency in the enzyme acid β glucosidase. Due to this there is accumulation of glycolipids in bones, liver and spleen resulting in the disease. The manifestations include Easy bruisability Anemia Bone pain Pathological fracture Splenomegaly There are three types. Type I adult, non neuronopathic form Type II infantile, acute neuronopathic form the most severe form Type III Juvenile, Norrbotten form The disease can be diagnosed by Histopathology of bone marrow shows cells with wrinkled paper appearance called Gaucher Cell. Roentgenogram of femur - shows Erlenmeyer flask deformity The treatment include Blood transfusion for anemia Analgesics for bone pain Bone marrow transplantation Enzyme replacement supplementing the enzyme acid β glucosidase 39

40 Gangliosidosis: Gangliosidosis is an inherited degenerative disorder characterized by accumulation gangliosides within the cell. Gangliosides are normal components of the membranes of the nerve cells and their synapses. There is a deficiency of the enzyme Hexosaminidase A and B. These enzymes normally cleave the gangliosides. Therefore their absence results in the accumulation of the gangliosides inside the cell resulting in these disorders. Gangliosidosis is divided into two types. These disorders are inherited as autonomic recessive disorders. The two types are GM1 Gangliosidosis GM2 Gangliosidosis GM1 Gangliosidosis: This type is due the deficiency of the enzyme β Galactosidase. It has three sub groups based on the age of onset Infantile type Juvenile type Adult type Infantile GM1 Gangliosidosis: The affected babies start manifesting in the newborn period with poor sucking and inadequate weight gain. The affected babies have facial features similar to Hurler s Syndrome like Prominent forehead Depressed bridge of nose Large tongue macroglossia Hypertrophied gums The other features include Enlargement of liver and spleen Convulsions Anterior beaking of the vertebrae which is a small projection in the body of the vertebra 40

41 Progressive loss of vision Deafness Paralysis of all four limbs Cherry red spot in fundus of eye The affected children usually die in the 2 nd year of life due to aspiration pneumonia. Juvenile Type GM1 Gangliosidosis: The age of onset is usually about 1 year of life. They present with Incoordination Weakness Staggering gait Regression of language Unlike the infantile type there is no enlargement of liver and spleen and also they don t have coarse facial features. The other features are Convulsions Increased muscle tone Loss of vision These children hardly survive beyond the first decade. Adult GM1 Gangliosidosis: It is a slowly progressive disease with the following manifestations. Increased muscle tone Staggering or ataxic gait Slurring of speech Gradual loss of cognitive function GM2 Gangliosidosis: It is a diverse group of disorders which are inherited as autosomal recessive disorders. The defect is in the HEXA gene. There are four subtypes in this group. Tay Sach Disease Sandhoff Disease Juvenile GM2 Gangliosidosis Adult GM2 Gangliosidosis 41

42 Tay Sach Disease: It is due the deficiency of the enzyme hexosaminidase A. This disorder is common in Ashkenazi Jews. The affected children appear normal till 6 months of age after which they lag behind in the developmental milestones. At around 1 year of age regression of milestones like standing, sitting and speaking are noted. The other features include Progressive increase in the size of the head- Macrocephaly Cherry red spot in the fundus of eye Increased muscle tone Convulsions Blindness Deafness The affected children hardly survive beyond 3 years of life and they succumb to aspiration pneumonia. Sandhoff Disease: This disease is similar to Tay Sach in all aspects. But it addition it also has enlargement of spleen. This disease is due to deficiencies of the enzymes Hexosaminidase A and B. Both Tay Sach and Sandhoff Disease have similar findings in the investigations. Visual evoked potential (VEP) are normal early in the course. But later they become abnormal or absent The auditory brain stem responses (ABR) show prolonged latencies Enzyme assays using white blood cells show deficiencies Juvenile GM2 Gangliosidosis: This occurs in midchildhood. Unlike the above mentioned groups there is no cherry red spot. The deficiency of the enzyme hexosaminidase is variable. The symptoms include 42

43 Clumsiness as the initial presentation Increased muscle tone Involuntary movements Loss of language Convulsions Loss of vision due to optic atrophy The affected children succumb to the disease around 15 years of life. Adult GM2 Gangliosidosis: In this type the vision and intellect are not impaired. The hexosaminidase levels are significantly reduced. The manifestations include Ataxic gait Increased muscle tone Atrophy of muscles Slurring of speech Abnormal posturing of the body dystonia Krabbe Disease: Krabbe disease is an autosomal recessive disorder characterized by the following features. Loss of myelin Deposition of globoid bodies in the white matter The defective gene is located in chromosome 14q24.3-q32.1 which results in the deficiency of the enzyme galactocerebroside β galactosidase. This results in excessive accumulation of galactocerebroside which destroys the myelin sheath and deposition of globoid bodies. The disease manifest very early in life with symptoms like Increased body temperature Excessive crying Vomiting Feeding problems Poor weight gain 43

44 The initial diagnosis is usually is infantile colic or milk allergy. Later they develop other symptoms which help in proper diagnosis. Convulsions Increased muscle tone Loss of vision due to optic atrophy Deafness CT scan shows symmetric enhanced densities in caudate nuclei and thalami. The affected children succumb before 2 years of age. Late onset Krabbe Disease: This disorder manifest during later part of childhood and it is most of the times confused with adrenoleukodystrophy.the patients present with Optic atrophy Increased muscle tone Gait disturbances The investigations show the following findings. There is segmental loss of myelin which can be made out by nerve conduction studies. Cerebrospinal fluid analysis shows elevated protein content. The VEP shows waves of decreased amplitude and later there is loss of waveforms. ABRs show only presence of wave I and II. CT and MRI show decrease in the white matter of cerebellum. Metachromatic Leukodystrophy: This disorder of the white matter is inherited as an autosomal recessive disorder. The defective gene is linked to chromosome 22q13-13q ter.this results in the deficiency of the enzyme Aryl sulphatase A. This enzyme is essential for the breakdown cerebroside in the nerve fibers. Deficiency of the enzyme leads to the deposition of cerebroside which causes destruction of the myelin sheath. There are six types of metachromatic leukodystrophy of which three are important. Late Infantile MLD 44

45 Juvenile MLD Adult MLD Late infantile MLD: The affected child is normal till 1 year of life. Then regression of motor milestones occurs. Initially the child develops gait disturbances followed by inability to walk, stand and later even unable to sit. Other symptoms include Regression of language milestones Loss of vision due to optic atrophy Feeding and swallowing problems The investigations which help in the diagnosis are CT and MRI show thinning of the cerebral and cerebellar white matter VEP ABR SSEP NCV The affected babies usually succumb to the disease by 5 years of age. Recent researches show that early treatment with bone marrow transplantation can cause an improvement. Juvenile MLD: This is very similar to the late infantile type except that the age of onset is around 10 years. The affect present with the symptoms of Deterioration in the school performance Alteration in the personality Later the disease progress to manifest symptoms like Staggering gait Urinary incontinence Slurring of speech Increased muscle tone Convulsions 45

46 The affected succumb to the disease before the end of the second decade. Adult MLD: The disease may manifest anytime between the 2 nd and 6 th decade of life. The manifestations include Memory disturbances Personality changes Psychiatric disturbances Increased muscle tone Loss of vision due to optic atrophy Convulsions During the terminal stages the patient will be totally bed ridden and unresponsive. Clinical and Age wise Classification Children less than 2 years with liver enlargement Mucopolysaccharadosis I and II Nieman Pick Disease Infantile Type Tay Sach Disease Zellweger Syndrome Gaucher Disease Type II Children less than 2 years without liver enlargement Krabbe Disease Rett Syndrome Menke s Disease Phenylketonuria Pelizaeus Merzbacher Disease 46

47 Children between 2-5 years Nieman Pick Disease Type III and IV Wilson Disease Gangliosidosis II MERRF Ataxia Telengiectasia Huntington Disease Hallervorden Spatz Disease Metachromatic Leukodystrophy Adrenoleukodystrophy Subacute Sclerosing Panencephalitis Children between 5-15 years Adrenoleukodystrophy Multiple Sclerosis Neuronal Ceroid Lipofuscinosis Juvenile and Ad Type Sialidosis II Mucopolysaccharidosis: It is a diverse group of metabolic disorders characterized by the accumulation of glycosaminoglycans which are also called mucopolysaccharides. All the disorders are inherited as autosomal recessive disorders except Type II which is inherited as X linked recessive disorder. The lysosomal enzymes which normally metabolize them are lacking and this leads to accumulation of the mucopolysaccharides in various organs of the body. There are about 9 types of mucopolysaccharidosis which share a lot of features like Chronic and Progressive course Abnormal facial features Multisystem involvement Skeletal deformities Organomegaly Vision and Hearing defects 47

48 Cardiac abnormalities Mental retardation. Mucopolysaccharidosis I and II are usually associated with regression of milestones. The type I has three subtypes. Hurler Syndrome the most severe form Hurler Scheie Syndrome Scheie Syndrome the mildest form Type I is to due the deficiency of the enzyme L iduronidase. Type II is also called Hunter Syndrome. It is due to the deficiency of the enzyme Iduronate sulphatase. Unlike type I it does not have corneal clouding and also its progression is slower. Rett Syndrome: The Rett Syndrome is a neurodegenerative disorder affecting only girls. The disease is lethal to male fetus and they don t survive till birth. The characteristic features which appear around three years of age are Repetitive hand wringing movements Loss of purposeful and spontaneous use of hands The manifestations of the disease are Regression of language and motor milestones Autism Staggering gait Progressive decrease in the size of the head due decrease in the brain substance Tremors of hands Sighing respirations with breathing stopping intermittently Feeding difficulties Convulsions The patient usually succumbs to rhythm disturbances of heart. Death usually occurs in the third decade after the disease process reaches a plateau. There is no cure for Rett Syndrome. Treatment is mainly supportive. 48

49 Menke s Disease (Kinky Hair Disease): Menke s Disease is a progressive neurodegenerative disorder which is inherited as an X linked recessive disorder. There is a defect in the absorption and transport of Copper across the cell membrane of the gut. The initial symptoms seen during the first few months of life are Decreased body temperature Decreased muscle tone Myoclonic seizures The affected babies have the following characteristic appearance Chubby, rosy cheeks Kinky,colorless, friable hair The other manifestations of the disease are Feeding difficulties Poor weight gain Mental retardation Loss of vision due to optic atrophy The disease can be diagnosed with the following investigations. CT and MRI show degenerative changes in the gray matter and cerebellum Serum biochemistry shows decreased levels of copper and ceruloplasmin Microscopy of Hair shows fractures along the hair shaft and twisted hair. Retinal fundoscopy shows the pale shrunken optic disc indicating optic atrophy Electroretinography shows absent or decreased amplitude waveforms The affected babies show improvement if treatment is started early. The treatment consists of supplementation of copper in the form of copper histidine. Untreated babies succumb to the disease by 3 years of age. 49