Approach to Neurodegenerative Disease

Dr Satish T S

Introduction Classification Approach Investigation Management

Overview

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

Storage disorders Lysosomal storage diseases Sphingolipidoses Mucopolysaccharidoses Mucolipidoses Neuronal ceroid lipofuscinoses Glycogenosis type II Leukodystrophies Peroxisomal disorders

Cellular intoxication Amino acidurias Organic acidurias Urea cycle disorders

Energy deficiency Glycogen storage disorders Fatty acid oxidation disorders Mitochondrial disorder

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

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

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 .

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

Physical examination

Head circumferenceMacrocephaly Alexander disease Tay-Sachs disease Canavan disease Sandhoff’s disease Glutaricaciduria type I

Microcephaly

Neuronal ceroid lepofuscinises

Krabbe s disease

GM1 gangliosidosis I-cell disease Zellweger syndrome Menke s disease Mucopolysaccharidoses

Facial dysmorphism

Biotinidase deficiency Cockayne’s syndrome Fucosidosis Menkes syndrome Mucopolysaccharidoses

Hair

Persistant large mongolian spot GM1 Gangliosidosis Hunter disease Hurler disease Mannosidosis Nieman Pick

Hyperpigmentation Adrenoleukodystrophy

Skin

Angiokeratomas Fabry s Fucosidosis Sialidosis ll Mucolipidosis l

Cornea Hurler’s disease Mannosidosis Maroteaux-Lamy syndrome Morquio’s disease Mucolipidosis type IV Wilson disease

Eyes

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

Ears

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

Hepatospleenomegaly

Valve abnormalities in MPS Conduction abnormalties in Kearns Sayre Syndrome

Cardiac dysfunction

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

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

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

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

Hydrocephalus Hypothyriodism Epileptic Encephalopathy Lead encepalopathy Depression Repeated trauma

Mimics

Second step is to decide wheather degeneration has predominantly involved the grey matter or white matter

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

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

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

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

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

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

White matter disease Aryl sulfates assay –MLD VLCFA for Adrenoleukodystrophy N Acetyl aspartic acid – canavan s disease Galactocereamidase – Krabbe’s

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.

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

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

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

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

References

Thank you