neurodegenerative disorder
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Approach to Neurodegenerative Disease
Dr Satish T S
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Introduction Classification Approach Investigation Management
Overview
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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
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Storage disorders Lysosomal storage diseases Sphingolipidoses Mucopolysaccharidoses Mucolipidoses Neuronal ceroid lipofuscinoses Glycogenosis type II Leukodystrophies Peroxisomal disorders
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Cellular intoxication Amino acidurias Organic acidurias Urea cycle disorders
Energy deficiency Glycogen storage disorders Fatty acid oxidation disorders Mitochondrial disorder
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History Till what age the child was normal Type of onset Any precipitating factorCourse 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
Approach
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History 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
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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 .
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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
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Physical examination
Head circumferenceMacrocephaly Alexander disease Tay-Sachs disease Canavan disease Sandhoff’s disease Glutaricaciduria type I
Microcephaly
Neuronal ceroid lepofuscinises
Krabbe s disease
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GM1 gangliosidosis I-cell disease Zellweger syndrome Menke s disease Mucopolysaccharidoses
Facial dysmorphism
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Biotinidase deficiency Cockayne’s syndrome Fucosidosis Menkes syndrome Mucopolysaccharidoses
Hair
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Persistant large mongolian spot GM1 Gangliosidosis Hunter disease Hurler disease Mannosidosis Nieman Pick
Hyperpigmentation Adrenoleukodystrophy
Skin
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Angiokeratomas Fabry s Fucosidosis Sialidosis ll Mucolipidosis l
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Cornea Hurler’s disease Mannosidosis Maroteaux-Lamy syndrome Morquio’s disease Mucolipidosis type IV Wilson disease
Eyes
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Retinitis Pigmentosa Cockayne’s syndrome Hallervorden-Spatz disease Kearns-Sayre syndrome Neuronal ceroid lipofuscinosis Zellweger syndrome
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Cherry-Red Macula GM1 gangliosidosis Niemann-Pick disease, types A and B Tay-Sachs disease Sialidosis
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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
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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
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Exaggerated startle response Tay Sachs disease Krabbe s disease
Hearing Loss Mucopolysacchrodosis Adrenoleukodystrophy
Ears
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Short stature MPS Lesch Nyhan syndrome
Hernia MPS GM1 gangiosidoses
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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
Hepatospleenomegaly
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Valve abnormalities in MPS Conduction abnormalties in Kearns Sayre Syndrome
Cardiac dysfunction
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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
Degenerative Diseases with Spasticity and Pyramidal Signs
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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
Degenerative Diseases with Extrapyramidal Features
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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
Progressive neuropathy
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Initial attainment of milestones and subsequent slowing of development
Regression of previously acquired milestones Family history of similar disease Unusual body odors Movement disorder
First step is to decide if it is a Neurodegenerative Disorder
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Hydrocephalus Hypothyriodism Epileptic Encephalopathy Lead encepalopathy Depression Repeated trauma
Mimics
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Second step is to decide wheather degeneration has predominantly involved the grey matter or white matter
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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
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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
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Screen for remendiable process1.Rule out hydrocephalus
2.Rule out Hypothyriodism3.Rule out aminoacidoaminopathy or organic aciduria
Visceromegaly
Third step is to consider common D/D based on age of onset and cerrtain physical findings
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Visceromegaly yes no
Dysmorphic Abnormalities of skin or hair
no yes
Urine screen for Hurler phenotype ?
Reducing substance
+ - + Gauchers disease
Galactosemia Bone marrow aspirate
for gaucher cells - Sandhoff disease and Nieman
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Hurler phenotype ?
yes no
Urine screen for MPS Zellweger s syndrome
Neonatal adrenoleukodystrophy
+ _
Mucopolysaccharidosis Urine screen for oligosaccharides
+ -
Manosidosis Mucolipidosis
Fucosidosis GM 1 Gangliosidosis 1
Sialosidosis
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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 –larson syndrome
seizure
Lesch nyhan GM2 Ganglisidosis
Huntington's disease and mitochodrial cytopathy
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MRI reveling demyelination
Macrocephaly
no yes
microcephaly Alexanders disease
yes no Canavan s disease
HIV infection Seizure
yes no
Krabbe s disease Pelizeaus Menzbacher
SSPE Metachromatic leukodystrophy
Mitochondrial cytopathy Adrenoleukodystrophy
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Investigations 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
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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
Investigation
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White matter disease Aryl sulfates assay –MLD VLCFA for Adrenoleukodystrophy N Acetyl aspartic acid – canavan s disease Galactocereamidase – Krabbe’s
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Management
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.
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Specific treatment
Neurodegenerativedisorders
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 marrowtransplantation
Mucopolysaccharidosis Bone marrow transplantation,Enzyme replacement therapy
Menkes kinky hair syndrome Copper Histidine
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Neurodegenerative
disorders
Specific treatment modality
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
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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.
Take home message
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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
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Nelson textbook of Pediatrics Fenichel Pediatric Neurology Approach to Neurodegenerative Disease IJP 1990 Veena Kalra Practical Pediatric Neurology
References
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Thank you