Dr. Amit VatkarMBBS, DCH, DNB Pediatrics

Fellow in Pediatric Neurology, MumbaiTrained in Neurophysiology & Epilepsy, USA

Contact No. : +91-8767844488Email: vatkaramit@yahoo.com

An approach to a child with Neuro-

Degenerative disorders

WHAT ARE THEY?

A group of inherited metabolic disorders.

Rare and untreatable - Mostly

Familial - Diagnosis is important for genetic

counselling.

Classification is difficult.

Difficult to remember all.

THE FIRST STEP

Differentiate fixed lesions from progressive

ones.

Earlier - Slowing in the rate of acquisition of

New Skills.

Later - Actual loss of acquired skills.

Rule out other disease processes like Infection,

Neoplasm, Hydrocephalus etc.,

• Regression: when child loses previously acquired

skills and milestones

• A progressive deterioration of neurological functions

with loss of speech,vision,hearing or locomotion ,often

associated with seizure, feeding and intellectual

impairment

• Neuroregressive /neurodegenerative disorders are a

group of heterogeneous diseases which results from

specific genetic, biochemical defect, chronic viral

infection, toxic substances

• Involves both the gray matter and white matter

• Dementia, used for neurodevelopmental regression in

children, is associated with loss of memory, ability to

think, understand and recognize along with

personality changes or distressing behaviour

Gray matter & White matter

Striations seen in white mater

White matter

Contains mostly myelinated axons

Appears pinkish white to the naked eye (myelin is

composed largely of lipid tissue veined with capillaries)

A 20 year-old male has a 176,000 km of myelinated axons

in his brain while that of a female is 149,000 km

connect various grey matter areas (the locations of nerve

cell bodies) of the brain to each other, and carry nerve

impulses between neuron

Gray matter

Major component of the CNS having a grey –brown

color(due to capillary blood vessels & neurinal cell bodies)

Consists of

neuronal cell bodies( in contrast to white matter)

neuropil (dendrites and both unmyelinated axons and

myelinated axons)

glial cells (astroglia and oligodendrocytes) & capillaries.

• The grey matter includes regions of the brain involved

in

– muscle control,

– sensory perception such as seeing and hearing,

memory, emotions, and speech.

Gray matter Disease White matter Disease

Processing center Represents networking

between these centers

Primarily involve neurons±

histologic evidence of

abnormal metabolic products--

> neuronal death and

secondary axon degeneration

Myelin is disrupted either

destruction of normal myelin

or biochemically abnormal

myelin production

Differentiatingfeatures

White matterdisorders

Gray matterdisorders

Age of onset Usually late(childhood) Usually early(infancy)

Head size May have megaenchepaly

Usually microcepaly

Seizures Late , rare Early, severe

Cognitive functions Initially normal Progressive dementia

Peripheral neuropathy

Early demyelination Late, axonal loss

Spasticity Early, severe Later, progressive

Reflexes Absent(neuropathy) or exaggerated(long tracts)

Normal or exaggerated

Differentiatingfeatures

White matterdisorders

Gray matterdisorders

Cerebellar signs Early,prominent late

Fundal examination May show optic atrophy

Retinal degeneration

EEG Diffuse delta slowing Epileptic form discharges

EMG Slowed nerve conduction velocity

Usually normal

Evoked potentials(VEP, ABR)

Prolonged or absent Usually normal

ERG Normal Abnormal

EEG=electroencephalogram, EMG= electomyography , VEP=visualevoked potential, ABR= auditory brain stem response,ERG= electroretinogram

Approach thru clinical findings

Abnormalities outside CNS

Chronic encephalopathy

•Seizures•Vision problems•dementia

yes

•Developmental regression•Seizures•Hard neurological signs

no

Signs of white matter disease

•Homocystinuria•Menkes•Fucosidosis•Galactosidodid•Prolidase defect

Mitochondrial myopathies

Muscle

GM1Sialidosis IIGaucher’sNiemann pick’sMPS-I, II, III, IVZellweger

hepatosplenomegaly

•Skin•connective tissue

Signs of grey matter disease

•NCL•GM2•Biotinidase def•Leigh’s disease•Alpers disease

•MLD•Krabbe•ALD•GM2•GM1•Organic acidurias•Aminoacidurias•Canavan

•Motor difficulties•Disorders of tone

Classification

• Gray matter: fits, decrease HMF

– EEG: early abnormality

– MRI Brain: cortical atrophy

• White matter: blindness ,Gait disturbances ,Motor signs-Spasticity ,optic atrophy

,ataxia , pappiledema

– EEG: late abnormality

– MRI Brain: Demyelination

– Nerve conductance + Evoke potentials• Basal Ganglia :Dystonia,Involantary movements• Spinocerebellar degeneration: Ataxia

Classification of neurodegenerative brain disease

Inherited Acquired

Focal manifestations

Both

White matter

Gray matter Metabolic

Infections

Acquired causes

• Infections

SSPE

Progressive Rubella

Syndrome

Chronic HIV

• Metabolic

Chronic lead poisoning

Hypothyroidism

Vit B12 & E deficiency

Drugs (anticonvulsant)

Inherited causes

• Gray matter involvement: seizure, dementia, visual loss, intellectual

impairment. Spike & sharp waves in EEG

• A. Gray matter involvement with visceromegaly

– GM1 Gangliosides-Infantile , generalized , juvenile

– Sandholf disease (GM2)

– Niemann pick Disease( Sphingolipid storage disease)

– Sialidosis

– MPS

– Gaucher disease( Sphingolipid storage disease)

SCHEMATIC FOR INHERITED METABOLIC DISORDERS OF INFANCY

Dysmorphic Features

Urine Berry Spot Test

Negative Positive

Mucopoly saccharidoses Oligosaccharidoses

Mental Retardation Urinary Sialic Acid Excretion

No Yes Increased Normal

SCHIE

Morquio

Maroteux -Lamy

Hurler

Hurler Schie

Hunter

San Filippo

B-Glucuronidase

Mucosulfatidosis

Mucolipidoses I

Mucolipidoses II

Mucolipidoses III

GM1 Gangliosidosis

Fucosidosis

Mannosidosis

Aspartyl-Glucosaminuria

Mucolipidosis (IV)

• B. Gray matter diseases involvement without

visceromegaly

– Tay Sach disease (GM2)

– Rett Syndrome

– Neuronal curoid lipofuscinosis

– Menke’s kinky hair disease

White matter involvement

• Spasticity , optic atrophy, ataxia ,peripheral neuropathy .Seizure

, dementia are the late manifestations. Slow waves in EEG

• A. Leukodystrophies

– Metachromatic leukodystrophy

– Krabbe disease

– Adrenoleukodystrophy

– Alexander disease , Cannavan disease,P.Merzbacker disease

• B. Acquired causes/ Demyelinating

– Multiple sclerosis

– Schilder’s disease

– Devic disease

• Basal Ganglia

– Wilson's disease

– Dystonia muscular Deformans

– Huntington’s Disease

• Spinocerebellar

– Friedrich’s Ataxia

– Ataxia Telangiectasia

Krabbe disease(Globoid Cell Leukodystrophy)

• AR

• Galactocerebroside-B-galactosidase

• Myelin loss & presence of globoid bodies in white matter

• Symptom appear by 6 months

– Irritability Vomiting

– Bouts of hyperpyrexia Alteration in body tone

– Convulsions UMN signs with absent jerks

Krabbe disease

• Investigations

– Leukocyte & Skin fibroblast enzyme level

– CSF: Elevated protein

– NCV: Markedly delayed

– Prenatal diagnosis: by assays in chorionic villi or

amniotic fluid cell culture

Metachromatic leukodystrophy

• AR

• Arylsulfatase A deficiency

• Onset in late infancy

– Hypotonia

– Absent deep tendon reflexes

– Optic atrophy

– Decorticate posture

Juvenile MLD

• Onset at 5-10 yr

– Deterioration in school performance

– Alteration in personality

– Incontinence

– Incoordination,Dysarthria

– Spasticity

– Generalized tonic clonic seizures

Gaucher disease

• Commonest

• Galactocerebrocidase deficiency

• Infantile form (neuropathic)

– Nuchal rigidity & opisthotonus

• Juvenile form (non-neuropathic)

• Diagnosis

– Bone marrow examination

– WBCs or fibroblast cultures & enzyme level

Niemann pick disease

• Accumulation of sphingomyelin

• Onset 1st yr

• Mental retardation,Hepatosplenomegaly,Cherry red

spot

• Diagnosis

– Foam cells in bone marrow

– WBCs or fibroblast cultures & enzyme level

Neuronal ceroid lipofuscinosis

• AR

• Storage of auto fluorescent hydrophobic material in

lysosomes of neurons & other tissue

• 3 subtypes

– Infantile

– Late infantile

– Juvenile

Neuronal ceroid lipofuscinosis

• S/S

– Myoclonic epilepsy

– Visual symptoms

– Cerebellar ataxia

– Dementia

– Pigmentary abnormalities in retina

• Max .age 10 yr

Neuronal ceroid lipofuscinosis

• Investigation

• Skin biopsy:

– Ultra structural abnormalities

• Cortical biopsy:

– Distended neurons

– Staining for ceroid & lipofuscinosis

Leucodystrophy

• Inherited white matter disease

• Defect in myelin synthesis

• involve the brain, spinal cord and peripheral nervesinvolve the brain, spinal cord and peripheral nerves. .

• Classic dysmyelinating disorders are

Adrenoleukodystrophy, Metachromatic Leucodystrophy,

Krabbe's disease and neuroaxonal dystrophy

Adrenoleucodystrophy

• Life-threatening disorder

• Occurring in males affecting the white matter &

adrenal gland.

• Very long chain fatty acids accumulate in the cells &

tissues causing myelin sheath damage as well as

dysfunction of the adrenal gland.

• X-linked form is the commonest

• Neonatal ALD is not X-lined, is associated

with liver and adrenal dysfunction and is a

severe disorder

• Diagnosis is made by estimation of very

long-chain fatty acids in plasma

Metachromatic leukodystrophy

• Deficiency of Aryl sulphatase A or Sphingolipid activator

protein (Saponin-B)= accumulation of lipid sulphatide in

the myelin sheath, brain and peripheral nerve.

• Cognitive function is minimally affected initially followed

by motor difficulties and dysarthria.

• Diagnosis is by estimating Aryl sulphatase A in leukocytes

or fibroblasts. CSF protein concentration is grossly

elevated

Peroxysomal disorders

• Children with peroxysomal disorders - Zellweger

syndrome :dysmorphic features &severe psychomotor

retardation, sensory neuronal deafness, peripheral

neuropathy & hepatocellular degeneration.

• Diagnosed by demonstrating the elevated very long

chain fatty acids, pipecolic acid and bile and

derivatives.

Mitochondrial disorders

• A defect in the oxidative phosphorylation in

the inner mitochondrial membrane

involving the respiratory chain which is

encoded by two genomes, the mt DNA and

nuclear DNA

Rett syndrome

• Onset in 1st yr

• Females affected only

– Regression of language & motor milestones

– Repetitive hand wringing movements

– Loss of purposeful & spontaneous movements

– Gen. tonic clonic seizures

– Max. age 2-3 yr

Creatin deficiency syndromes

• Patients with these disorders develop delay /

regression /mental retardation along with severe

defects in expression and repetitive speech.

• Symptoms are due to severe depletion of

creatine/phosphocreatine in the brain.

Sialidosis

• AR

• Lysosomal Neuraminidase deficiency

• Accumulation of sialic acid-oligosaccharide complex

• Type 1: late onset

• Type 2

– Infantile

– Juvenile

Sialidosis

• Intractable Myoclonic seizures

• Cherry red spots

• Somatic involvement

– Coarse facial features

– Corneal clouding

– Dystonia multiplex

Mucopolysaccharidosis

• Absence of variety of lysosomal hydrolases

• Degradation of MPs defective

• Abnormally large amount excreted in urine

Mucopolysaccharidosis

• Coarse facial features , Dwarfism , Kyphoscoliosis

• Hepatosplenomegaly , Cardiovascular abnormalities

• Neurologic abnormalities

– Type I Hurler syndrome

– Type II Hunter syndrome

– Type III Sanfilippo

– Type VII

Friedreich ataxia

• AR• Early teenage

– Ataxia– Dysarthria– Pes cavus– Decreased proprioception, vibration– Absent reflexes with upgoing plantars– Nystagmus– Hypertrophic cardiomyopathy

Lesch Nyhan syndrome

• X-linked recessive

• Deficiency of hypoxanthine guanine

phosphoribosyl transferase

• Formation of excess of uric acid

• Normal until late in 1st yr

Lesch Nyhan syndrome

• S/S

– Psychomotor retardation

– Chorioethetosis

– Spasticity

– Severe self mutilation

– Gouty arthritis

– Renal calculi

Wilson’s disease

• AR

• Degenerative disease of basal ganglia

• Inborn error of copper metabolism

– Academic deterioration

– Behavioral changes , Dysarthria ,Dysphasia

– Drooling, Dystonia

• K F rings

Subacute Sclerosing Panencephalitis

• Progressive slow viral infection of CNS by measles virus

– Personality changes

– Aggressive behavior

– Myoclonic seizures

• Investigation

– Anti measles Ab in CSF

– EEG

An approach to a child with regression of

milestones

History

History of present illness:Onset/Age of onsetFits ,Clumsiness or difficulty in gaitDeterioration of HMFAtaxia or imbalanceHeadache,Blindness,Vomiting, deafnessChange in personality and behaviourDeteriorance in school performanceIncreased startle response or hyperacusis

• Birth history:

– Term/preterm

– Postnatal complications

• Meningitis

• Head trauma

• kernicterus

• Developmental history:– Detailed development history- decide whether there is

delayed development milestones or regression of milestones

• Family history:H/o of consanguinity

Family history of neurological disorder

Early or unexplained death

Nature of the neurological manifestations should be clarified

• Classically , the loss of previously acquired

milestones(regression) marks the onset of

most Neurodegenerative brain disease with

subsequent progressive neurological

deterioration

Clinical examination

General physical examination

Dysmorphism: Zellweger syndrome, Neonatal adrenal

leukodystrophy, coarse facial features(MPS)

OFC –microcepaly (gray matter disease)

Megaenchepaly – certain white mater

disorder(Cannavan & Alexander)

Jaundice

Enlarged tongue

Skin & hair ( Hartnup Diseases-pellagra like skin rash, Menkes

disease-kinky hair)

Examination of the spine- for associated complications

(scoliosis)

Contractures of joints

Systemic examination:

Hepatosplenomegaly

Chest deformity

Cardiomyopathy

Neurological manifestation

Age group

Early infantile Late infantile Juvenile

Psychomotor Regression/ Dementia Deteriorating scholastic performance

GM 1 gangliosidosis GM 2 gangliosidosis Menke's diseaseNiemann-Pick disease type A I-cell disease

Niemann-Pick disease type C Neuronal ceroid lipofuscinosis Rett syndrome

Sanfilippo disease Late onset MLDJuvenile Krabbe disease Juvenile GM 1 and GM 2 gangliosidosis Niemann-Pick disease type C Gaucher type III

Extrapyramidal symptoms Choreoathetosis Dystonia

Lesch-Nyhan syndrome Pelizaeus-Merzbacher disease Glutaric aciduria type I

Ataxia telangiectasia Wilson disease Hallervorden-Spatz disease Huntington disease Neuronal ceroid lipofuscinosis

Speech disturbances

  Rett Syndrome  ALD

Psychosis

 

GM 2 gangliosidosis Wilson disease Sanfilippo disease Niemann-Pick disease type CNeuronal ceroid lipofuscinosis Hallervorden-Spatz Huntington chorea

Neurological examination

• Higher mental function, signs of raised ICP• Speech, memory• Cranial nerves• Gait• Motor system:

– Tone-hypo/ hypertonia,Deep tendon reflexes– Motor spasticity

• Sensory loss /neuropathy• Abnormal /involuntary movements

Eye examination

• Optic atrophy(white matter- due to demyelination)

• Retinal degeneration(gray matter)- as the retinal

receptors are neuronal cells): Cherry red spot,

retinitis pigmentosa

• Cataracts

• Telengiectasias

• K.F ring

DECIDE

• REGRESSION AND NOT DELAYREGRESSION AND NOT DELAY

• AGE ABOVE 2 YEARS OR LESS THAN 2 YEARSAGE ABOVE 2 YEARS OR LESS THAN 2 YEARS

• VISCEROMEGALYVISCEROMEGALY

• NEUROPATHYNEUROPATHY

• GRAY OR WHITE MATTER DISEASEGRAY OR WHITE MATTER DISEASE

Investigations- to identify the underlying diagnosis & examining the associated complications

• Complete Blood picture-pancytopenia, vacuolated

lymphocytes,acanthocytes

• ABGs-metabolic acidosis(organic acidopathies, urea cycle

defects, mitochondrial encephalopathies)

• S/E (Anion gap), for adrenal

insufficiency(adrenoleukodystrophy)

• Ammonia level,LFTs,RFTs

• Special tests:

– Lactate & pyruvate levels, Lysosomal enzyme level

– WBCs, Fibroblast enzyme level

– Wilson’s disease-serum ceruloplasmin level, serum copper

– Amino acids

– Urinary organic acids

– Uric acid level

• Urine

– Reducing substances, Organic acids,24 hr (MPS)

• Imaging

– Skull & Vertebrae, Long bones

– CT/MRI

• Biopsy

– Skin, Bone marrow, nerve, brain

• Diagnosis

– Important for genetic counseling

• Outcome

– Invariably fatal

Neuro degenerative Disorders- summary

30/12/10 Dr.Hariaharan.V, RMMC 67

Disorder Biochemical defect incidence

Lysosomal storage disorders-Sphingolipidoses

GM1 gangliosidosis-Infantile b- Galactosidase 1:1,00,000

-Juvenile b- Galactosidase

GM2 Gangliosidoses-Tay-Sach’s Hexosaminidase A 1 in 3,00,000

-Sandhoff’s Hexosaminidase A & B 1:3,00,000

-Krabbe’s Galactocerebrosidase 1 in 1,00,000

Juvenile GM2 gangliosidosis hexosaminidase

Adult GM2 gangliosidosis hexosaminidase

Metachromatic Leukodystrophy 1:40,000

Late Infantile Arylsulfatase A

Juvenile Arylsulfatase A

Neuronal ceroid Lipofuscinosis 1:50,000

Infantile Palmitoyl Protein Thioesterase Tripeptidyl Peptidase 1Late infantileJuvenile

AdrenoLeukodystrophy VLCFA oxidation(auto dom) 1:40,000

Sialadosis Neuraminidase 1:40,00,000

Symptom complex Disorder Investigation Tissue

Coarse facies, ostosis, hepatosplenomegaly, hernias, corneal clouding  

Late infancy, childhood •  MPS, Fucosidosis, Mannosidosis, Mucolipidosis,

• MPS spot • U

• MPS electrophoresis • U

• GAG quantification • U

• Oligosaccharides • U

 • Enzyme activity • L,F,CVS, AF

Extrapyramidal symptoms, hepatitis, portal hypertension, KF ring

•  Gaucher disease •  Niemann Pick disease •  Wilson Disease

•  Bone marrow examination  

• Enzyme activity • L,F, CVS, AF

• Copper • U, S, Liver

• Ceruloplasmin  

• Liver biopsy  

Cognitive regression, ataxia, seizures, visual impairment

•  Adrenoleukodystrophy •  Neuronal ceroid lipofuscinosis •  Mitochondrial disorders •  Subacute sclerosing pan-encephalitis

•  Lactate • S

•  Biopsy •Skin, rectal, conjunctival

•  Nerve conduction  

•  MRI  

•  Lactate •S, CSF

•  MRI, MRS  

• Immunoglobulins • S, CSF

Supporting investigations Electroencephalogram, electroretinogram, electromyography, nerve conduction studies, Magnetic resonance imaging, magnetic Resonance spectroscopy, DNA study

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 leukodystrophyKrabbe leukodystrophy Bone marrow transplantation

Metachromatic Metachromatic leukodystrophyleukodystrophy

Bone marrow transplantation

AdrenoleukodystrophyAdrenoleukodystrophy Glyceryl trioleate and trierucate,steroids for adrenal insufficiency, diet low in VLCFA, bone marrow transplantation

MucopolysaccharidosisMucopolysaccharidosis Bone marrow transplantation,recombinant human -L-iduronidaseα

Menkes kinky hair Menkes kinky hair syndromesyndrome

Copper sulfate

Neurodegenerative

disorders

Specific treatment modality

Mitochondrial encephalopathiesMitochondrial encephalopathies 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

Counseling the families and educating the public about these

potentially preventable disorders is very important

Dr. Amit VatkarPediatric Neurologist, Navi Mumbai

MBBS, DNB

Email: vatkaramit@yahoo.comContact No.: +91-8767844488

Visit us at: http://pediatricneurology.in/

THANK YOU !