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  • 1. Approach to Neurodegenerative Disease Dr Satish T S
  • 2.      Introduction Classification Approach Investigation Management
  • 3.   Neurodegenerative disorders of childhood encompass a large, heterogeneous group of diseases that result from specific genetic and biochemical defects, chronic viral infections, and varied unknown causes The hallmark of a neurodegenerative disease is regression and progressive deterioration of neurologic function with loss of speech, vision, hearing, or locomotion, often associated with seizures, feeding difficulties, and impairment of intellect
  • 4. Storage disorders         Lysosomal storage diseases Sphingolipidoses Mucopolysaccharidoses Mucolipidoses Neuronal ceroid lipofuscinoses Glycogenosis type II Leukodystrophies Peroxisomal disorders
  • 5. Cellular intoxication    Amino acidurias Organic acidurias Urea cycle disorders Energy deficiency    Glycogen storage disorders Fatty acid oxidation disorders Mitochondrial disorder
  • 6. History Till what age the child was normal Type of onset Any precipitating factor Course of illness ; Usually later the first signs appear, the slower the disease progresses Videotapes and photographs of the child’s appearance and performance at earlier ages should be reviewed
  • 7.  History of present illness:  Onset/Age of onset  Fits ,Clumsiness or difficulty in gait  Deterioration of HMF  Ataxia or imbalance  Headache,Blindness,Vomiting, deafness  Change in personality and behaviour  Deteriorance in school performance  Increased startle response or hyperacusis
  • 8. Below 2 years  Failure to thrive, seizures, and inability to sit and stand at 1 year and to speak in short sentences at 2 years. School-aged child  regresses in language skills and withdraws socially Older children and adolescents,    gait difficulties and loss of vision and intellectual facilities .
  • 9. prenatal and perinatal histories are important, as they help determine whether the disorder is congenital or whether it began at some later time.  development: feeding, sleep, motor milestones, expressive and receptive language, behavior, social attainment Family History and mode of inheritance previous affected siblings, even when the diagnosis seems to be unrelated such as neonatal sepsis, sudden infant death 
  • 10. Head circumference Macrocephaly   Alexander disease     Tay-Sachs disease Canavan disease Sandhoff’s disease Glutaricaciduria type I Microcephaly Neuronal ceroid lepofuscinises Krabbe s disease
  • 11.      GM1 gangliosidosis I-cell disease Zellweger syndrome Menke s disease Mucopolysaccharidoses
  • 12.      Biotinidase deficiency Cockayne’s syndrome Fucosidosis Menkes syndrome Mucopolysaccharidoses
  • 13.  Persistant large mongolian spot   GM1 Gangliosidosis Hunter disease Hurler disease Mannosidosis Nieman Pick  Hyperpigmentation  Adrenoleukodystrophy   
  • 14.  Angiokeratomas  Fabry s Fucosidosis Sialidosis ll Mucolipidosis l   
  • 15. Cornea       Hurler’s disease Mannosidosis Maroteaux-Lamy syndrome Morquio’s disease Mucolipidosis type IV Wilson disease
  • 16. Retinitis Pigmentosa      Cockayne’s syndrome Hallervorden-Spatz disease Kearns-Sayre syndrome Neuronal ceroid lipofuscinosis Zellweger syndrome
  • 17. Cherry-Red Macula     GM1 gangliosidosis Niemann-Pick disease, types A and B Tay-Sachs disease Sialidosis
  • 18. Cataract      Fabry’s disease Galactosemia Homocystinuria Lowe syndrome Myotonic dystrophy Optic Atrophy      Canavan disease Globoid cell leukodystrophy Metachromatic leukodystrophy Pelizaeus-Merzbacher disease GM2 Gangliosidosis juvenile type
  • 19. Nystagmus      Ataxia telangiectasia Gaucher’s disease, types 2 and 3 Kearns-Sayre syndrome Niemann-Pick disease type C Pelizaeus-Merzbacher disease Macular Degeneration Neuronal ceroid lipofuscinosis
  • 20. Exaggerated startle response   Tay Sachs disease Krabbe s disease Hearing Loss Mucopolysacchrodosis Adrenoleukodystrophy
  • 21.  Short stature   MPS Lesch Nyhan syndrome  Hernia  MPS GM1 gangiosidoses 
  • 22.            Farber’s disease Gaucher’s disease Glycogenosis type II GM1 gangliosidosis I-cell disease Mucopolysaccharidoses Niemann-Pick disease Oligosaccharidoses Pseudo-Hurler polydystrophy Wilson’s disease Wolman’s disease
  • 23.   Valve abnormalities in MPS Conduction abnormalties in Kearns Sayre Syndrome
  • 24.               Adrenoleukodystrophy and adrenomyeloneuropathy Arginase deficiency Canavan disease Gaucher’s disease type III Globoid cell leukodystrophy (late infantile form) Glutaricaciduria type I GM1 gangliosidosis (late infantile form) Hallervorden-Spatz disease Hereditary spastic paraparesis Juvenile GM2 gangliosidosis Menkes syndrome (kinky hair syndrome) Metachromatic leukodystrophy Niemann-Pick disease type C Pelizaeus-Merzbacher disease
  • 25.           Aromatic-L-amino-acid decarboxylase deficiency Ataxia telangiectasia Cockayne’s syndrome Hallervorden-Spatz disease Juvenile GM2 gangliosidosis Juvenile Huntington’s disease Lesch-Nyhan syndrome Machado-Joseph disease Neuroacanthosis Wilson’s disease
  • 26.           Abetalipoproteinemia Adrenoleukodystrophy Cockayne’s syndrome Congenital disorder of glycosylation Familial dysautonomia Friedreich’s ataxia (E1) Juvenile GM2 gangliosidosis Krabbe’s disease (late infantile form) Leigh syndrome Metachromatic leukodystrophy
  • 27.      Initial attainment of milestones and subsequent slowing of development Regression of previously acquired milestones Family history of similar disease Unusual body odors Movement disorder
  • 28.       Hydrocephalus Hypothyriodism Epileptic Encephalopathy Lead encepalopathy Depression Repeated trauma
  • 29. Grey matter White matter Dementia early Late Seizure Early and prominent late Psychological Symptoms May be present uncommon Disturbance of tone gait and Uncommon and late reflexes prominent Basal Ganglia absent present
  • 30. Peripheral Neuropathy Not seen Seen in some case Retinitis pigmentosa with consecutive optic atrophy May or may not absent Primary optic atrophy rare May be seen Electroretinogram May be abnormal normal Visual evoked response And BERA Usually normal abnormal
  • 31. Screen for remendiable process 1.Rule out hydrocephalus 2.Rule out Hypothyriodism 3.Rule out aminoacidoaminopathy or organic aciduria Visceromegaly
  • 32.  Visceromegaly yes Dysmorphic no yes no Abnormalities of skin or hair Urine screen for Hurler phenotype ? Reducing substance + + Galactosemia Bone marrow aspirate for gaucher cells - Gauchers disease Sandhoff disease and Nieman
  • 33. Hurler phenotype ? yes no Urine screen for MPS + Zellweger s syndrome Neonatal adrenoleukodystrophy _ Mucopolysaccharidosis Urine screen for oligosaccharides + - Manosidosis Fucosidosis Sialosidosis Mucolipidosis GM 1 Gangliosidosis 1
  • 34. Abnormalities of skin or hair no yes MRI reveling demyelination no yes ocular pathology yes no seizure Lesch nyhan Menky kinky hair disease Fabry disease Biotinidase deficiency Cockayne s syndrome sjogren –larson syndrome GM2 Ganglisidosis Huntington's disease and mitochodrial cytopathy
  • 35. MRI reveling demyelination Macrocephaly no microcephaly yes no Seizure yes Krabbe s disease SSPE Mitochondrial cytopathy yes Alexanders disease Canavan s disease HIV infection no Pelizeaus Menzbacher Metachromatic leukodystrophy Adrenoleukodystrophy
  • 36.  Complete Blood picture-pancytopenia, vacuolated lymphocytes,acanthocytes  ABGs-metabolic acidosis(organic acidopathies, urea cycle defects, mitochondrial encephalopathies)  Electrolytes for adrenal insufficiency(adrenoleukodystrophy)  Ammonia level,LFTs,RFTs
  • 37.  Gray matter disease Bone marrow for storage cells ; Niemann pick - vacuolated foam cells Gaucher disease- crumpled paper appearance Urine copper , serum ceruloplasmin Hair microscope – Menke kinky conjunctival , skin , rectal biopsy- NCL(fingerprint bodies) Enzyme analysis in leukocytes , skin fibroblast- Lysosomal storage disease Urine MPS and skeletal survey Serum and CSF lactate and pyruvate for mitochondrial disease CSF antimeasles antiibodies HIV Elisa
  • 38.  White matter disease Aryl sulfates assay –MLD VLCFA for Adrenoleukodystrophy N Acetyl aspartic acid – canavan s disease Galactocereamidase – Krabbe’s
  • 39.  Directed towards the treatment of the underlying disorder, other associated features and complications   Supportive :The treatable complications :  feeding difficulties, Gastoresophageal reflux  spasticity, drooling  skeletal deformities, and recurrent chest infections  epilepsy, sleep disorder, behavioral symptoms A multidisciplinary approach(pediatrics, neurology, genetics, orthopedics, physiotherapy, and occupational therapy.
  • 40. Neurodegenerative disorders Specific treatment modality Krabbe leukodystrophy Bone marrow transplantation Metachromatic leukodystrophy Bone marrow transplantation Adrenoleukodystrophy Lorenzo s oil ;Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrow transplantation Mucopolysaccharidosis Bone marrow transplantation, Enzyme replacement therapy Menkes kinky hair syndrome Copper Histidine
  • 41. Neurodegenerative Specific treatment modality disorders Mitochondrial encephalopathies Nicotinamide, riboflavin, dichloroacetate, L-carnitine, CoQ10 Wilson disease D- penicillamine, trietine, zinc acetate, liver transplantation Refsum disease Reduction of phytanic acid intake Lesch-Nyhan disease Allopurinol Fabry’s Disease Recombinant human α galactosidase A
  • 42.  A precise history confirms regression of developmental milestones, and the neurologic examination localizes the process within the nervous system.  Outcome of a neurodegenerative condition is usually fatal and available therapies are often limited in effect  It is important to make the correct diagnosis so that genetic counselling may be offered and prevention strategies can be implemented.
  • 43.  Onset of inherited disease can occur at any age  Bone marrow transplantation and other novel therapies may prevent the progression of disease in certain presymptomatic individuals
  • 44.     Nelson textbook of Pediatrics Fenichel Pediatric Neurology Approach to Neurodegenerative Disease IJP 1990 Veena Kalra Practical Pediatric Neurology