Neuro degenerative disorders
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pediatric neurodegenerative disorders a clinical approach
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Neuro degenerative disorders
- 1. NEURO DEGENERATIVE DISORDERS Dr. shahanaz Ahamed Paediatric Neurologist
- 2. 3 situations • Normal development & then regression • Delayed development & then regression • Episodic regression with stepwise deterioration
- 3. 2nd Question • Is there delay or is there definitely regression? • Is it a pseudoregression or True regression? • Is it a static disorder or progressive disorder?
- 4. 3rd question • If there is a true regression is it global Regression or Focal Regression? • Example- Global regression is seen in Lysosomal storage disorders while • Focal predominantly language-social regression is seen in ASD • Motor regression alone may be seen in Aquired LMN disorders like DMD • Motor regression may be the initial manifestation in LeukoDystrophies also.
- 5. Isolated regression • Language & social regression- Autistic spectrum disorders • Isolated language regression – – Landau kloeffner syndrome – Certain epilepsies – Stroke involving language area
- 6. Isolated motor regression • MYELOPATHIES – Compressive-Spinal cord tumours – Non compressive-Hereditary spastic paraparesis • Infections of anterior horn cells- polio, West nile • SIDP & MADSAM • Genetic Ataxias-eg Fredericks , ATelengiectasia • Early stage of Leukodystrophies • Muscular dystrophies eg DMD • Metabolic or endocrine myopathies eg GSD •
- 7. Global Regression- cerebrum involved • Grey matter • White matter • Basal Ganglia • Mitochondrial D • Peroxisomal D • PMEs- progressive myoclonic epilepsies • IEMs- inborn errors of metabolism
- 8. • Pecuiliarity of IEMs is that they are small molecule defects & may have different types of presentations like- – Episodic dysfunction/ acute encephalopathy • - Step pattern deterioration or – progressive deteriorartion – When we talk of NDD we are predominantly concerned with the large molecule group slow neurodegeneration like NCL,LKD etc
- 10. Storage disorders • Lysosomal storage diseases • Sphingolipidoses • Mucopolysaccharidoses • Mucolipidoses • Neuronal ceroid lipofuscinoses • Glycogenosis type II • Leukodystrophies • Peroxisomal disorders
- 11. Combined Grey + White- Rare • Usually this pattern is produced by • Mitochondrial • Leighs D • MELAS • MERRF • Peroxisomal disorders • Zell weger • Refsum disease • Adreno leukoDystrophy • Certain IEMs • Methyl malonic acidemia • Glutaric aciduria • Urea cycle disorders etc
- 12. GM - presentations • Seizures • Myoclonus • Dementia- intellect deterioration • Aphasias – language dysfunction • Academic deterioration • Psycho behavioural disturbances • Involuntary movements( Gm of BG) • Apraxia- loss of learned motor skills or daily living skills • Vision loss of retinal type • Hypotonia , ataxia along with these above • Spasticity & plantar abn are late if at all they occur.
- 13. WM- presentations • Initially there may be a normal motor development or a motor delay followed by regression • Motor Clumsiness, Recurrent falls & walking difficulty are usual • Examn shows Spasticity , Ataxia weakness ,UMN signs • Later Visual dysfunction & neuropathic involvement occur Hypotonic weakness with reduced reflexes • Seizures & intellect deterioration are very late if at all noticed • Visual dysfunction may be presenting feature in posteriorly beginning leukodystrophies like AdrenoleukoD
- 14. Grey matter White matter Dementia early Late Seizure Early and prominent late Psychological Symptoms May be present uncommon Disturbance of tone gait and reflexes Uncommon and late prominent Basal Ganglia present absent
- 15. 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
- 16. GM+ WM • Mitochondrial • Peroxisomal • Vascular/Vasculitic D • Infective – HIV, CJD, • Progressive hydrocephalus • Tumours esp multicentric
- 17. History
- 18. 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
- 19. 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
- 20. 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 • .
- 21. • 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 Formulate a Diagnostic/Differential D hypothesis with History itself & proceed to examn History - otherHistory - other
- 22. Examination • General Examination • Head to foot Examination • Anthropometry for FTT • Developmental assessment • Focussed Neurological examination tailored to age & condition of child • Other systems examination esp for organomegaly , cardiomegaly etc
- 23. • Pallor- Gaucher, niemann pick etc • Icterus- tyrosinemia , WilsonD • Lymphoedema- GM1 • HFE – Look for Microcephaly, Macrocephaly • Facial dysmorphism • Hair, Eye abn • Kyphoscoliosis & skeletal abn • Skin lesions
- 24. Macrocephaly • Alexander disease • Tay-Sachs disease • Canavan disease • Sandhoff’s disease • Glutaricaciduria type I Microcephaly Grey matter D Neuronal ceroid lipofuscinoses Krabbe s disease Rett syndrome
- 25. Hurler phenotype • Mucopolysaccharidoses • Oligosacharidoses • Mucolipidosis • GM1 gangliosidosis • I-cell disease • Doll like phenotype • Zellweger syndrome • Von giercke D • Menke s disease
- 28. • Biotinidase deficiency- alopecia • Cockayne’s syndrome • Fucosidosis • Menkes syndrome- kinky hair • Mucopolysaccharidoses-
- 31. • Persistant large mongolian spot • GM1 Gangliosidosis • Hunter disease • Hurler disease • Mannosidosis • Nieman Pick • Hyperpigmentation • Adrenoleukodystrophy
- 33. • Angiokeratomas • Fabry s • Fucosidosis • Sialidosis ll • Mucolipidosis l
- 35. Corneal opacity • Hurler’s disease • Mannosidosis • Maroteaux-Lamy syndrome • Morquio’s disease • Mucolipidosis type IV • Wilson disease
- 38. Retinitis Pigmentosa • Cockayne’s syndrome • Hallervorden-Spatz disease • Kearns-Sayre syndrome • Neuronal ceroid lipofuscinosis • Zellweger syndrome
- 39. Cherry-Red Macula • GM1 gangliosidosis • Niemann-Pick disease, types A and B • Tay-Sachs disease • Sialidosis
- 41. Cataract • Fabry’s disease • Galactosemia • Homocystinuria • Lowe syndrome • Myotonic dystrophy Optic Atrophy • Canavan disease • Globoid cell leukodystrophy • Metachromatic leukodystrophy • Pelizaeus-Merzbacher disease
- 42. 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
- 43. Exaggerated startle response • Tay Sachs disease • Krabbe s disease Hearing Loss Mucopolysacchrodosis Adrenoleukodystrophy
- 44. • Short stature • MPS • Lesch Nyhan syndrome • Hernia • MPS • GM1 gangiosidoses
- 47. • 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
- 49. • Valve abnormalities in MPS • Conduction abnormalties in Kearns Sayre Syndrome
- 50. • 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
- 51. • 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
- 52. • 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 •
- 53. • Hydrocephalus • Hypothyriodism • Epileptic Encephalopathy • Lead encepalopathy • Depression • Repeated trauma
- 55. • Visceromegaly yes no Dysmorphic Abnormalities of skin or hair no yes Urine screen for Hurler phenotype ? Reducing substance + - +
- 56. Hurler phenotype ? yes no Urine screen for MPS Zellweger s syndrome Neonatal adrenoleukodystrophy + _ Mucopolysaccharidosis Urine screen for oligosaccharides + - Manosidosis
- 57. Abnormalities of skin or hair no yes MRI reveling demyelination Menky kinky hair disease no yes Fabry disease Biotinidase deficiency ocular pathology Cockayne s syndrome yes no sjogren
- 58. MRI reveling demyelination Macrocephaly no yes microcephaly Alexanders disease yes no Canavan s disease HIV infection Seizure yes no
- 63. • 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
- 64. • 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
- 65. • White matter disease Aryl sulfates assay –MLD VLCFA for Adrenoleukodystrophy N Acetyl aspartic acid – canavan s disease Galactocereamidase – Krabbe’s
- 66. • 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.
- 67. Neurodegenerative disorders Specific treatment modality Krabbe leukodystrophyKrabbe leukodystrophy Bone marrow transplantation MetachromaticMetachromatic leukodystrophyleukodystrophy Bone marrow transplantation AdrenoleukodystrophyAdrenoleukodystrophy Lorenzo s oil ;Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrow transplantation MucopolysaccharidosisMucopolysaccharidosis Bone marrow transplantation, Enzyme replacement therapy
- 68. Neurodegenerative disorders Specific treatment modality MitochondrialMitochondrial encephalopathiesencephalopathies Nicotinamide, riboflavin, dichloroacetate, L-carnitine, CoQ10 Wilson diseaseWilson disease D- penicillamine, trietine, zinc acetate, liver transplantation Refsum diseaseRefsum disease Reduction of phytanic acid intake Lesch-Nyhan diseaseLesch-Nyhan disease Allopurinol Fabry’s DiseaseFabry’s Disease Recombinant human α galactosidase A
- 69. • 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
- 70. • 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
- 71. • Nelson textbook of Pediatrics • Fenichel Pediatric Neurology • Approach to Neurodegenerative Disease IJP 1990 • Veena Kalra Practical Pediatric Neurology