neuro degenerative disorders
TRANSCRIPT
NEURO DEGENERATIVE DISORDERS
Dr. shahanaz AhamedPaediatric Neurologist
3 situations
• Normal development & then regression• Delayed development & then regression• Episodic regression with stepwise
deterioration
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?
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.
Isolated regression
• Language & social regression- Autistic spectrum disorders
• Isolated language regression –– Landau kloeffner syndrome– Certain epilepsies– Stroke involving language area
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
•
Global Regression- cerebrum involved
• Grey matter• White matter• Basal Ganglia• Mitochondrial D• Peroxisomal D• PMEs- progressive myoclonic epilepsies• IEMs- inborn errors of metabolism
• 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
Storage disorders• Lysosomal storage diseases• Sphingolipidoses• Mucopolysaccharidoses• Mucolipidoses• Neuronal ceroid lipofuscinoses• Glycogenosis type II• Leukodystrophies• Peroxisomal disorders
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
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.
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
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
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
GM+ WM
• Mitochondrial • Peroxisomal• Vascular/Vasculitic D• Infective – HIV, CJD,• Progressive hydrocephalus• Tumours esp multicentric
History
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
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
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 sociallyOlder children and adolescents, • gait difficulties
• and loss of vision and intellectual facilities • .
• 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 deathFormulate a Diagnostic/Differential D hypothesis with
History itself & proceed to examn
History - otherHistory - other
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
• 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
Macrocephaly• Alexander disease• Tay-Sachs disease• Canavan disease• Sandhoff’s disease• Glutaricaciduria type I
MicrocephalyGrey matter DNeuronal ceroid
lipofuscinosesKrabbe s diseaseRett syndrome
Hurler phenotype• Mucopolysaccharidoses• Oligosacharidoses• Mucolipidosis• GM1 gangliosidosis• I-cell disease• Doll like phenotype• Zellweger syndrome• Von giercke D• Menke s disease
• Biotinidase deficiency- alopecia• Cockayne’s syndrome• Fucosidosis• Menkes syndrome- kinky hair• Mucopolysaccharidoses-
Kinky hairKinky hair
• Persistant large mongolian spot• GM1 Gangliosidosis• Hunter disease• Hurler disease• Mannosidosis• Nieman Pick
• Hyperpigmentation• Adrenoleukodystrophy
• Angiokeratomas• Fabry s• Fucosidosis• Sialidosis ll• Mucolipidosis l
Corneal opacity• Hurler’s disease • Mannosidosis • Maroteaux-Lamy syndrome • Morquio’s disease• Mucolipidosis type IV • Wilson disease
Retinitis Pigmentosa• Cockayne’s syndrome• Hallervorden-Spatz disease• Kearns-Sayre syndrome• Neuronal ceroid lipofuscinosis• Zellweger syndrome
Cherry-Red Macula• GM1 gangliosidosis• Niemann-Pick disease, types A and B• Tay-Sachs disease• Sialidosis
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
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
Exaggerated startle response• Tay Sachs disease• Krabbe s disease
Hearing Loss Mucopolysacchrodosis Adrenoleukodystrophy
• Short stature• MPS• Lesch Nyhan syndrome
• Hernia• MPS• GM1 gangiosidoses
• 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
• Valve abnormalities in MPS• Conduction abnormalties in Kearns Sayre
Syndrome
• 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
• 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
• 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
• Hydrocephalus• Hypothyriodism• Epileptic Encephalopathy• Lead encepalopathy• Depression• Repeated trauma
• Visceromegaly yes no
Dysmorphic Abnormalities of skin or hair no yes
Urine screen for Hurler phenotype ?Reducing substance+ - + Gauchers diseaseGalactosemia Bone marrow aspirate for gaucher cells - Sandhoff disease and Nieman
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
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
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
• 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
• 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
• White matter disease Aryl sulfates assay –MLD VLCFA for Adrenoleukodystrophy N Acetyl aspartic acid – canavan s disease Galactocereamidase – Krabbe’s
• 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.
Neurodegenerativedisorders
Specific treatment modality
Krabbe leukodystrophyKrabbe leukodystrophy Bone marrow transplantation
Metachromatic Metachromatic leukodystrophyleukodystrophy
Bone marrow transplantation
AdrenoleukodystrophyAdrenoleukodystrophy Lorenzo s oil ;Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrowtransplantation
MucopolysaccharidosisMucopolysaccharidosis Bone marrow transplantation,Enzyme replacement therapy
Menkes kinky hair Menkes kinky hair syndromesyndrome
Copper Histidine
Neurodegenerative
disorders
Specific treatment modality
Mitochondrial Mitochondrial
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
• 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.
• 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
• Nelson textbook of Pediatrics• Fenichel Pediatric Neurology• Approach to Neurodegenerative Disease
IJP 1990• Veena Kalra Practical Pediatric Neurology