Leukodystrophies

Diagnostic Approach

• Clinical
• Biochemical
• Electrophysiology
• Imaging
• Histopathology
• Molecular genetic studies 1
 Leukodystrophies-Diagnostic Approach

• Overlapping symptomatology : Diagnostic algorithm may

be difficult

• Better to have template of clinical phenotypes

• Detailed developmental history : Acquisition / loss of skills

– Baseline delay in milestones

– Loss of acquired mile stones
2
Neurodiscussion series with Dr.Lakshmi Achar
 Leukodystrophies-Diagnostic Approach

I will make it a better table … just took a scanned pic to show you….

(From Veena Kalra Practical pediatric neurology )

Neurodiscussion series with Dr.Lakshmi

3
Achar
 LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
AGE & PATTERN OF ONSET

Neurodiscussion series with Dr.Lakshmi Achar

 Age
 Infantile & Late infantile : Krabbe's, MLD, Canavans
Alexander, PMD
 Juvenile : MLD, Krabbe's, ALD
 Adult

 Pattern
 Acute
 Insidious

Metabolic disorders have a variable phenotype,

and imaging features, depending on the age of 4
onset.
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
MODE OF INHERITANCE

Neurodiscussion series with Dr.Lakshmi Achar

 Autosomal recessive
 Metachromatic Leukodystrophy
 Krabbe’s leukodystrophy

 Canavan’s disease

 Megalencephalic leukodystrophy with subcortical cysts

 Vanishing white matter disease

 X-linked recessive
 Pelizeus Merzbacher
 Adrenoleukodystrophy

 Sporadic
 Alexander disease
5
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
KEY CLINICAL FEATURE

Neurodiscussion series with Dr.Lakshmi Achar

Motor
 Gait difficulty,falls : Late infantile MLD
 Hemiparesis : Juvenile Krabbe's LD
 Spastic Parapresis : Juvenile Krabbe's LD

Cognitive decline, Personality & behavioural changes

ALD, Juvenile MLD
Enlarging head
Vision failure & Deafness : ALD, Juvenile Krabbe

Relatively preserved intellect : Megalencephalic LD with

Subcortical cysts

6
 LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
COURSE OF ILLNESS & PROGRESSION
Progression to stage 4 within 1-2 yrs

Neurodiscussion series with Dr.Lakshmi Achar

Infantile & Late infantile MLD & Krabbe's disease

Slowly progressive course over several years

Pelizeus Merzbacher disease, Juvenile MLD & Krabbe's

Slowly progressive with intervening deterioration

Vanishing whitematter disease

Mild clinical course

Megalencephalic leukodystrophy with subcortical cysts

Episodic course 7
Mitochondrial disease
 LEUKODYSTROPHIES- CLINICAL EXAMINATION

Dysmorphism

Neurodiscussion series with Dr.Lakshmi Achar

Skin : Cutaneous melanosis, icthyosis,
photosensitivity, hypomelanosis,
hyperpigmentation
Hair : Kinky , brittle , Frizzly
Eye : Optic atrophy, cataract, cherry red spot,
Retinitis pigmentosa
Organomegaly

Leukodystrophy patients are not generally dysmorphic.

8
Presence of systemic features point to a different etiology
.
 Hair & Leukoencephalopathies

Neurodiscussion series with Dr.Lakshmi Achar

Brittle hair- Trichothiodystrophy Kinky hair- Menkes

9
Giant axonal Neuropathy-Frizzly hair Silvery hair- Griscelli syndrome
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
HEAD CIRCUMFERENCE

Neurodiscussion series with Dr.Lakshmi Achar

 Macrocephaly
 Canavan disease
 Alexander disease

 Megalencephalic leukodystrophy with subcortical cysts

 L2 hydroxy glutaric aciduria

 Congenital muscular dystrophy

10
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
NEUROLOGICAL EXAMINATION
 Spastic ataxic syndrome
 Optic atrophy, deafness

Neurodiscussion series with Dr.Lakshmi Achar

 Hypotonia

 Combination of Spasticity and diminished jerks

Selective tract involvement

Optic tract : ALD
Auditory pathway : ALD
Pyramidal tract : Krabbe's
Cerebellar : Vanishing white matter
disease
11
UMN & LMN featrues : MLD
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH
PERIPHERAL NEUROPATHY

 Obvious/Subtle
 Metachromatic

Leukodystrophy
 Krabbe's Leukodystrophy

 Pelizeus Merzbacher disease

 PMD like diseae

 Hyccin defect

(Hypomyelination with
congenital cataract)
 Neurogastrointestinal

encephalomyopathy
12
LEUKODYSTROPHIES-DIAGNOSTIC APPROACH

Neurodiscussion series with Dr.Lakshmi Achar

Pattern Recognition on MRI

13
 14

Schiffman et al. Neurology 2009;72:750

 Neurodiscussion series with Dr.Lakshmi Achar
15
NORMAL MYELINATION PATTERN
LEUKODYSTROPHY
MRI PATTERN RECOGNITION

Neurodiscussion series with Dr.Lakshmi Achar

 Pattern of white matter involvement
Diffuse/confluent
 Subcortical U fiber involvement
 Presence of cysts

 Contrast enhancement

16
LEUKODYSTROPHY
MRI PATTERN RECOGNITION
Confluent

Neurodiscussion series with Dr.Lakshmi Achar


 Frontal
 Parieto occipital
 Subcortical
 Periventricular predominant
 Diffuse cerebral
 Posterior fossa predominance

17
LEUKOENCEPHALOPATHIES
SPECIAL MRI CHARACTERISTICS

Neurodiscussion series with Dr.Lakshmi Achar

 Cystic white matter degeneration
 Anterior temporal lobe cysts

 Enlarged perivascular spaces/small cysts

 Additional gray matter lesion: Cortical dysplasia,basal

ganglia
 Calcium deposits
 Contrast enhancement

18
 Leukoencephalopathies

LEUKODYSTROPHY :MRI PATTERN RECOGNITION

Frontal Predominance

19
 Leukoencephalopathies

LEUKODYSTROPHY
MRI PATTERN RECOGNITION
Parieto-occipital predominance

20
LEUKODYSTROPHY :MRI PATTERN
RECOGNITION
Periventricular & deep white matter

MLD Krabbe’s
21
LEUKODYSTROPHY :MRI PATTERN
RECOGNITION
Diffuse cerebral

MLC1 Canavan disease VWD

22
 Leukoencephalopathies

MLD
Alexander disease X-linked ALD Kearns sayre syndrome

23

Juvenile NCL Vanishing white matter CTX Laminin B deficiency

Disease
Schiffman et al. Neurology 2009;72:750
LEUKODYSTROPHY :MRI PATTERN RECOGNITION
HYPOMELINATION
 Diffuse process without
the presence of focal
lesions
 T1W images look better
than T2W images
 MRI may actually look
like MRI of a normal child
at a younger age.

24
METACHROMATIC LEUCODYSTROPHY
AR, Chr22, Arylsulfatase A, Saposin B deficiency

Types- Late infantile, Juvenile, Adult.

 Late infantile MLD- Onset around
first year of life
 gait abnormalities and ataxia

 hypotonia

 peripheral neuropathy

 Subsequently
 spastic tetraplegia

 bulbar and pseudobulbar

symptoms
 mental regression

 Juvenile onset MLD

 Behavioural problems
 Cognitive decline
25
 Gait difficulty
 Leukoencephalopathies

METACHROMATIC LEUKODYSTROPHY-MRI

Tigroid skin pattern Leopard skin pattern Cerebellar white matter involvem

Late infantile -Occipital predominance

Juvenile & adult onset - Frontal predominance
26
 Leukoencephalopathies

KRABBE'S LEUKODYSTROPHY
AR, Chr14, Galactosylceramide galactosidase, Globoid cells.

Types- Early Infancy, Late infantile, Juvenile, Adult.

 Phenotypes
 classic early-onset infantile form –
 <6 months of age
 irritability and crying

 Rigidity and tonic spasms

 peripheral nerve conduction velocity

is reduced

 late-infantile onset form

 6 months to 3 years of life
 ataxia, weakness, spasticity, and

dysarthria.
27

Cheon et al. RadioGraphics 2002; 22:461–476

 Leukoencephalopathies

KRABBE'S LEUKODYSTROPHY
Juvenile onset form
 4 and 19 years
 optic atrophy

 progressive spastic parapresis/tetra

paresis
 peripheral neuropathy

 50% have preserved mental

function.

28
 Leukoencephalopathy- Peroxisomal disorde

ADRENOLEUCODYSTROPHY (ALD)
X, ALD gene (ABCD 1), ChrXq28, ↓ Acyl-CoA synthetase, VLCFA
Childhood, Presymptomatic, Adolescent, Adult cerebral;
AMN; Addison only; Symptomatic female carriers.

 Childhood form
 onset is between 4 and 8 years
 subtle cognitive decline
 occasionally - acute onset with focal
seizure

 Later on
 spasticity

 pseudobulbar signs
 dementia

 cortical disturbances of vision and

hearing

 Adrenocortical insufficiency

 Death results after a few months to 29

several years.
 Important to screen male siblings
 Leukoencephalopathy- Peroxisomal disorde

ADRENOLEUKODYSTROPHY
Imaging
 Hyperintensity (T2, FLAIR)
 Splenium
 peritrigonal WM
 Corticospinal tracts/ fornix/
commisural fibres/ visual &
auditory pathways.
 Leading edge enhancement

30
 Leukoencephalopathies

ADRENOLEUKODYSTROPHY- MRI

Internal capsule Pyramidal tract Gad. enhancement

31
 Leukoencephalopathies

PELIZAEUS MERZBACHER DISEASE

X-linked recessive, PLP gene,
Types- Connatal, Classic

Connatal PMD
 Severe form
 Nystagmus which become prominent within
the first few weeks
 Stridor
 Infants are typically hypotonic,weak cry,
poor feeding
 Severe delay, motor functions never
achieved
Infantile PMD
 Delay in mile stones, motor more than
cognition
 Hypotonia,
 Nystagmus
 Later on nystagmus can improve, but 32
spasticity choreiform movements
 Leukoencephalopathies

CANAVAN DISEASE
AR, ASPA gene, Chr17-p13, ↓ Aspartoacylase, Macrocephaly
Types- Congenital, Infantile, Juvenile

 Infantile form - most common

 Macrocephaly
 Hypotonia, spasticity, Seizures.
 Blindness, decerebration
 Death within 4 years
 Imaging
 Diffuse Confluent demyelination
 Early U-fibre involvement
 Centripetal
 GP & thalamus involved
 Putamen & caudate relatively spared.

 MRS
 Elevated NAA peak
33
ALEXANDER DISEASE
AD, GFAP Mutation, Chr 17q21, Macrocephaly
Types- Infantile, Juvenile, Adult onset

Clinical

Infantile onset
Developmental delay
Macrocephaly
Seizures
Progressive spasticity

Imaging

Diffuse white matter

involvement
Subcortical U fibers involved
Braistem involved 34
Periventricular hypointensity on
T2
 Leukoencephalopathies

MEGALENCEPHALIC LEUKODYSTROPHY WITH

SUBCORTICAL CYSTS
 Large head noted during
infancy
 Motor delay
 Relatively preserved
intelligence
 May have seizures- “Impact
seizures”
 Long survival
 Spastic ataxic syndrome
 Severe imaging findings in
contrast to mild clinical course
35
 Leukodystrophies

VANISHING WHITE MATTER DISEASE

 Autosomal recessive disease

 Chronic neurological deterioration

with ataxia as the prominent symptom

 Progressive disease intervened by

periods of stabilisation

 Extreme sensitivity to febrile illness,

minor head trauma, fright –Acute
neurological deterioration & coma

 Five subunits of eukaryotic

translation initiation factor eIF2B 36
 Leukodystrophy Mimicks

Maple syrup urine disease

Phenyl ketonuria

GM1 Gangliosidosis-Type 1

Muscle disorders - L2 hydroxy glutaric aciduria

Mitochondrial disease

Zellweger spectrum disorders

Biotinidase deficiency
37
CONCLUSION
 knowledge about myelination pattern is essential in
evaluation of children with white matter disease.

 Leukoencephalopathies are heterogenous disorders.

 Systematic clinical & imaging approach can easily

identify the known leukodystrophies.

 Clinicaland imaging pattern recognition may help in

defining new disease entities.
38
Thank you……

39