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Detailed information of METACHROMATIC LEUKODYSTROPHY
METACHROMATIC LEUKODYSTROPHY
DEFINITION:
A lysosomal storage disorder characterized by the accummulation
of lipid (sulfatide) primarily in the central nervous system (CNS)
resulting in 3 clinical variants.
EPIDEMIOLOGY:
- incidence: 1/100,000
- age of onset:
- 12-18 months (Type I); 4-12 years (Type II); after puberty
(Type III)
- risk factors:
- familial - autosomal recessive
- chrom.#: 22q13.31-qter
- gene: arylsulfatase A (ARSA)
- M = F
PATHOGENESIS:
- arylsulfatase A is a lysosomal enzyme which catalyzes the
hydrolysis of the 3-O-sulfate linkages of cerebroside sulfate (sulfatide)
to form galactocerebroside
- deficiency of arylsulfatase A in MLD first reported by in
1963 by Austin
- a sphingolipid activator protein (SAP-1) is necessary for
the in vivo hydrolysis of sulfatide
- in MLD, galactosyl sulfatide and to a smaller extent
lactosyl sulfatide accumulate in the white matter of the CNS, in
the peripheral nerves, and to a lesser extent in the kidneys,
gallbladder, and other visceral organs
- accumulation of sulfatides in the myelin sheath results in
the progressive breakdown of membranes of the myelin sheath
2. Genetic Defect
- genetic defects -> deficiency of arylsulfatase A activity ->
accumulation of sulfatide within lysosomes in the CNS white
matter -> neurological manifestations
- three clinical variants:
- deficiency of ARSA activity is most marked in the late
infantile form with higher residual ARSA activity found in the
other forms
CLINICAL FEATURES:
- normal development up to 12-18 months of age although
some patients may have delays prior to 12 months - onset of
developmental delay followed by a rapid regression by the
end of the 2nd year of life
- progressive hypotonia and motor weakness
- usually begins in the lower limbs with progression
to the upper limbs
- never walk, slow in learning to walk, or if already
walking begin to stagger with frequent falling, toe
walking, and/or unsteady requiring support to stand or
walk (gait disturbance with eventual loss of ambulation)
- knee hyperextension with genu recurvatum
- initial decreased or absent deep tendon reflexes
- eventually limbs become hypertonic with exaggerated
reflexes and extensor plantar responses
2. Speech/Language
- dysarthria and aphasia with speech deterioration
leading to loss of speech
3. Cognitive
- mental regression
- eventual loss of all meaningful contact with the
environment
2. Others
- ataxia
- dysphagia with bulbar and pseudobulbar palsies
eventually requiring nasogastric or G-tube feeds -
intermittent pain in the arms and legs
- irritability
- muscle wasting
- myoclonic seizures
- peripheral neuropathy
- truncal titubation
- urinary incontinence with urinary tract infections
2. Ophthalmologic Manifestations
- nystagmus
- greyish discolouration of the macula
- optic atrophy -> blindness
2. Type II (Juvenile Form)
- normal development up to 4-12 years of age
- loss of developmental milestones by the end of the first
decade
- in most cases, the gait disturbances precede the
behavioural-cognitive deterioration but in other cases, the
reverse occurs
- ataxia with progressive gait disturbances -> loss of
ambulation
- progressive hypertonia with tremor, postural
abnormalities, and/or leg scissoring
- diminished deep tendon reflexes
2. Speech/Language
- slurred speech with speech deterioration
3. Cognitive/Behavioural
- abnormal/bizarre behaviour
- daydreaming
- difficulty in following directions
- emotional difficulties
- mental deterioration
2. Others
- pseudobulbar palsy
- seizures
- urinary incontinence
2. Ophthalmologic Manifestations
- optic atrophy -> blindness
3. Type III (Adult Form)
- normal development up to puberty then present with
cognitive and behavioural abnormalities
- personality changes
- anxious, apathetic, bewildered, emotionally labile,
psychosis
- poor school or job performance
- decreased mental alertness, defective visual-spatial
discrimination, disorganized thinking, poor memory
- others
- alcoholism, depersonalization, inappropriate affect
2. Gross Motor
- progressive clumsiness and slowing
- increasing muscle tone -> spasticity of limbs
- increased deep tendon reflexes
- dystonic movements and pareses
2. Others
- generalized seizures
- peripheral neuropathy
- urinary incontinence
2. Ophthalmologic
- horizontal nystagmus
- optic atrophy -> blindness
INVESTIGATIONS:
- deficiency of arylsulfatase A activity in leukocytes and
cultured skin fibroblasts
- prenatal
- deficiency of enzyme activity in cultured chorionic villi
or amniocytes
2. Imaging Studies
- progressive loss of white matter due to demyelination
- cerebral atrophy with ventricular enlargement
3. Electrophysiologic Studies
- decreased nerve conduction velocities
- abnormal evoked potentials
4. Pathology
- spherical granular masses that stain metachromatically
(stain strongly positive with periodic acid-Schiff (PAS) and
Alcian blue or acetic acid-cresyl violet)
5. Others
- metachromatic granules in the urinary sediment
- excessive amounts of sulfatide excreted in the urine
2. CSF
MANAGEMENT:
- no treatment for the underlying disorder
- multidisciplinary approach:
- Paediatrics, Neurology, Ophthalmology, Orthopedics
- genetic counselling
- bone marrow transplantation is still experimental
2. Prognosis
- Type I - death in the 1st decade (2-4 years after diagnosis)
- Type II - death in the 2nd decade (4-6 years after
diagnosis)
- Type III - death in the 3rd decade (5-10 years after
diagnosis)
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Pediatric Database - METACHROMATIC LEUKODYSTROPHY
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