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