leukodystrophies diagnostic approach by dr mohan t shenoy

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 stones2

Neurodiscussion series with Dr.Lakshmi Achar

Neurodiscussion series with Dr.Lakshmi Achar

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Leukodystrophies-Diagnostic Approach

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

(From Veena Kalra Practical pediatric neurology )

LEUKODYSTROPHIES-DIAGNOSTIC APPROACH

AGE & PATTERN OF ONSET

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 onset.

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MODE OF INHERITANCE

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

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KEY CLINICAL FEATURE

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

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COURSE OF ILLNESS & PROGRESSION

Progression to stage 4 within 1-2 yrs Infantile & Late infantile MLD & Krabbe's disease

Slowly progressive course over several years Pelizeus Merzbacher disease, Juvenile MLD & Krabbe's

Slowly progressive with intervening deteriorationVanishing whitematter disease

Mild clinical course Megalencephalic leukodystrophy with subcortical cysts

Episodic course Mitochondrial disease

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LEUKODYSTROPHIES- CLINICAL EXAMINATION

Dysmorphism

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. Presence of systemic features point to a different etiology .

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Brittle hair- Trichothiodystrophy Kinky hair- Menkes

Giant axonal Neuropathy-Frizzly hair Silvery hair- Griscelli syndrome

Hair & Leukoencephalopathies

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HEAD CIRCUMFERENCE

Macrocephaly Canavan disease

Alexander disease

Megalencephalic leukodystrophy with subcortical cysts

L2 hydroxy glutaric aciduria

Congenital muscular dystrophy

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NEUROLOGICAL EXAMINATION

Spastic ataxic syndrome

Optic atrophy, deafness

Hypotonia

Combination of Spasticity and diminished jerks

Selective tract involvement Optic tract : ALDAuditory pathway : ALDPyramidal tract : Krabbe'sCerebellar : Vanishing white matter

diseaseUMN & LMN featrues : MLD 11

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PERIPHERAL NEUROPATHY

Obvious/Subtle

Metachromatic

Leukodystrophy

Krabbe's Leukodystrophy

Pelizeus Merzbacher disease

PMD like diseae

Hyccin defect

(Hypomyelination with

congenital cataract)

Neurogastrointestinal

encephalomyopathy

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Pattern Recognition on MRI

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Schiffman et al. Neurology 2009;72:750

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NORMAL MYELINATION PATTERN

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LEUKODYSTROPHY

MRI PATTERN RECOGNITION

Pattern of white matter involvement

Diffuse/confluent

Subcortical U fiber involvement

Presence of cysts

Contrast enhancement

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LEUKODYSTROPHY


Confluent

Frontal

Parieto occipital

Subcortical

Periventricular predominant

Diffuse cerebral

Posterior fossa predominance

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LEUKOENCEPHALOPATHIES

SPECIAL MRI CHARACTERISTICS

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

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LEUKODYSTROPHY :MRI PATTERN RECOGNITION

Frontal Predominance

Leukoencephalopathies

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LEUKODYSTROPHY


Parieto-occipital predominance


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LEUKODYSTROPHY :MRI PATTERN

RECOGNITION

Periventricular & deep white matter

MLD Krabbe’s 21

LEUKODYSTROPHY :MRI PATTERN

RECOGNITION

Diffuse cerebral

MLC1 Canavan disease VWD

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Alexander disease X-linked ALD Kearns sayre syndromeMLD

Juvenile NCL Vanishing white matter

DiseaseCTX Laminin B deficiency

Schiffman et al. Neurology 2009;72:750


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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.

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METACHROMATIC LEUCODYSTROPHY

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

Gait difficulty

AR, Chr22, Arylsulfatase A, Saposin B deficiency

Types- Late infantile, Juvenile, Adult.

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Tigroid skin pattern Leopard skin pattern Cerebellar white matter involvement

METACHROMATIC LEUKODYSTROPHY-MRI

Late infantile -Occipital predominanceJuvenile & adult onset - Frontal predominance


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KRABBE'S LEUKODYSTROPHY

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.

AR, Chr14, Galactosylceramide galactosidase, Globoid cells.

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

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


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KRABBE'S LEUKODYSTROPHY

Juvenile onset form

4 and 19 years

optic atrophy

progressive spastic parapresis/tetra

paresis

peripheral neuropathy

50% have preserved mental

function.


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ADRENOLEUCODYSTROPHY (ALD)

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 several years.

Important to screen male siblings

X, ALD gene (ABCD 1), ChrXq28, ↓ Acyl-CoA synthetase, VLCFA

Childhood, Presymptomatic, Adolescent, Adult cerebral; AMN; Addison only; Symptomatic female carriers.

Leukoencephalopathy- Peroxisomal disorders

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ADRENOLEUKODYSTROPHY

Imaging

Hyperintensity (T2, FLAIR)

Splenium

peritrigonal WM

Corticospinal tracts/ fornix/

commisural fibres/ visual &

auditory pathways.

Leading edge enhancement

Leukoencephalopathy- Peroxisomal disorders

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Internal capsule Pyramidal tract Gad. enhancement


ADRENOLEUKODYSTROPHY- MRI

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X-linked recessive, PLP gene,

Types- Connatal, Classic

PELIZAEUS MERZBACHER DISEASE

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 spasticity choreiform movements


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AR, ASPA gene, Chr17-p13, ↓ Aspartoacylase, Macrocephaly

Types- Congenital, Infantile, Juvenile

CANAVAN DISEASE

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


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AD, GFAP Mutation, Chr 17q21, Macrocephaly

Types- Infantile, Juvenile, Adult onset

ALEXANDER DISEASE

Clinical

Infantile onsetDevelopmental delayMacrocephalySeizuresProgressive spasticity

Imaging

Diffuse white matter involvementSubcortical U fibers involvedBraistem involvedPeriventricular hypointensity on T2Contrast enhancement

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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


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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

Leukodystrophies

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Leukodystrophy Mimicks

Maple syrup urine disease

Phenyl ketonuria

GM1 Gangliosidosis-Type 1

Muscle disorders - L2 hydroxy glutaric aciduriaMitochondrial disease

Zellweger spectrum disorders

Biotinidase deficiency

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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.

Clinical and imaging pattern recognition may help in defining new disease entities.

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Thank you……

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leukodystrophies diagnostic approach by dr mohan t shenoy

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