Transcript Pediatric Leukodystrophy

Leukodystrophy
Tyler Reimschisel, MD
September 6, 2013
Clinical Presentations of IMD
• Intoxication
– Urea cycle defects
• Energy Failure
– Mitochondrial disease
– Glycogen storage disease
• Complex Molecule
– Lysosomal storage disease
– Glycogen storage disease
– Peroxisomal storage disorders
Diseases that Cause
Leukodystrophy
Some examples
• Adrenoleukodystrophy
• Metachromatic leukodystrophy
• Tay-Sachs
• Krabbe
• Canavan
• Mitochondrial
Clinical Presentation of
Leukodystrophy
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Developmental delay: relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+/- dysmorphisms
Testing for Leukodystrophy
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Lysosomal enzyme profile
VLCFA (very long chain fatty acids)
Urine organic acids
Lactate
Pyruvate: not clinically useful lab due to
timing; in equilibrium with alanine
• Alanine (order via Plasma amino acids)
Pelizaeus-Merzbacher
• Xq22 mutation in proteolipid protein 1 (PLP1)
• Onset in first few months of life with rotary
head movements, rotary nystagmus, & motor
delay
• Then ataxia, tremor, choreoathetosis,
spasticity
• Seizures
• Optic atrophy and ocular impairments
• MRI: Reversal of gray-white signal due to
diffuse dymyelination
Pelizaeus-Merzbacher
Gal-GalNAc
Nana-Gal-Glc-Cer
GM1 (- Galactosidase)
GalNAc-Gal-Gal-Glc-Cer
GalNAc
Nana-Gal-Glc-Cer
GM2 (-Hexosaminidase A)
Nana-Gal-Glc-Cer
Neuraminidase
Sandhoff
(-Hexosaminidase
A & B)
Gal-Gal-Glc-Cer
Fabry (-Galactosidase)
Gal-Glc-Cer
Glc-Cer
Gaucher (-Glucosidase)
SO3H-Gal-Cer
Gal-Cer
Ceramide
Phosphorylcholine-Cer
(Sphingomyelin)
Farber (Ceraminidase)
Sphingosine
Krabbe
• AR defect of galactocerebroside-betagalactosidase on chromosome 14
• Pure neurologic condition
• Onset at 3-8 months of age
• Irritability, intermittent fevers, heightened
startle reflex, feeding problems
• Develop seizures, opisthotonus
• Deafness and blindness by 9 months
• MRI:
KRABBE DISEASE
Metachromatic Leukodystrophy
• AR defect of arylsulfatase-A
• Leukodystrophy as well as disease of adrenal
glands, kidneys, pancreas, liver
Metachromatic Leukodystrophy
• 3 Presentations
– Late infantile (18-24 months)
• Gait disturbance, hypotonia to hypertonia, regression,
involuntary movements, neuropathy, cherry red spot
– Juvenile (4-10 years)
• Bradykinesia, poor school performance, ataxia,
movement disorder, neuropathy, slower progression
– Adult
• After puberty get personality and mental changes,
cortical and cerebellar regression to frank dementia in
third to fourth decade
Metachromatic Leukodystrophy
L.B.
• 4-year-old girl with GDD, hypotonia, & worsening
ataxia
– Development at 12-18 month level
– Hyperactivity, inattention and aggression (Tenex)
• Family history
– Maternal cousin with chromosome deletion
– Paternal half-sister with B12 deficiency (?)
• Labs
– CMA, karyotype, FRX, purine/pyrimidines, biotinidase,
MECP2, AS/PWS, EEG, brain MRI (9/2010)
First Visit
• Labs: PAA, acylcarnitine profile, vitamin
B12, homocysteine, MMA level, creatine
metabolites
• Repeat brain MRI consistent with MLD
Second Visit
• Lysosomal enzyme panel, VLCFA,
coenzyme Q10 level
– Arylsulfatase A level 1.5 (low)
– GM1, mannosidosis, fucosidosis, Krabbe,
Tay-sachs normal
Follow Up Testing
• No mutations in arylsulfatase A gene
• Parental testing showed normal
arylsulfatase A enzyme activity
Additional Testing
• Arylsulfatase B enzyme activity at 4-5%
normal
• Huge peak of sulfatides in patient
• Multiple sulfatase deficiency diagnosed
• Molecular testing pending
Multiple Sulfatase Deficiency
• AR, mutations in sulfatase-modifying factor-1 gene
(SUMF1) on 3p26
• Austria: 1 in 1.4 million individuals
• Affects 12 sulfatase enzymes
– Post-translation modification defect in which cystein residue
of enzyme is not activated
– Defect in enzyme that causes oxidation of a thiol group in
cysteine to generate an alpha-formylglycine residue
– Alpha-formylglycine residue may accept the sulfate during
sulfate ester cleavage by hydrolysis
– Examples: arylsulfatase, steroid sulfatase, heparan
sulfatase, N-acetylglucosamine-6-sulfatase
Multiple Sulfatase Deficiency
• 3 phenotypes
– Neonatal MSD: severe mucopolysaccharidosis
– Late infantile MSD: late-onset MLD
– Juvenile MSD
• Combined features of MLD, Hunter,
Sanfilippo A, Morquio, Maroteaux-Lamy, Xlinked ichthyosis
Canavan
• AR deficiency of asparto-acylase
• Macrocephaly, lack of head control, and
developmental delays by the age of three to five
months
• Develop severe hypotonia and failure to achieve
independent sitting, ambulation, or speech
• Hypotonia eventually changes to spasticity
• Life expectancy is usually into the teens
• Diagnosis of Canavan disease relies upon
demonstration of very high concentration of N-acetyl
aspartic acid (NAA) in the urine
Canavan disease
Courtesy Dr Isabelle Desguerre, Paris Necker Hospital
Canavan disease
NAA
Courtesy Dr. Ralph Lachman
L-2-Hydroxyglutaric Aciduria
• Underlying defect unknown
• Clinical
– Normal to mild delays in infancy and early childhood
– Slowly progressive encephalopathy
– Variable rate of progressive ataxia, seizures,
pyramidal signs, movement disorder (dystonia,
tremor, choreoathetosis), dementia
– 50% with macrocephaly
• Laboratory: no metabolic decompensation,
increased plasma lysine, elevated 2hydroxyglutaric acid in urine
Brain MRI
L-2-Hydroxyglutaric Aciduria
• Neuroimaging
– Severe cerebellar atrophy
– Mildly swollen white matter with gyral effacement
– Leukoencephalpathy more prominent closer to
cerebral cortex
– Increased signal intensity in dentate and striatum
• Differential Diagnosis
– D-2-hydroxyglutaric aciduria presents earlier
– GAII causes elevations of D-2-hydroxyglutaric acid
• Treatment - none
Alexander Disease
• AD mutation in GFAP at 17q21.31
• Onset at around 6 months (birth – 2 yrs)
• Psychomotor regression, spasticity and
seizures
• Juvenile patients have ataxia and spasticity
• Adult patients have MS-like presentation
• Diffuse demyelination, especially in frontal
lobes
Alexander Disease
Brain MRI: Leigh Syndrome
From Osborn. Neuroradiology, 2000
Brain MRI
From Osborn. Neuroradiology, 2000
Peroxisome Function
• Synthesis
– Plasmologens (ether-phospholipids)
– Bile acid from mevalonate
• Catabolism
– -oxidize very long chain fatty acids (esp C24:0
and C26:0), pristanic acid and bile acid
intermediates
– -oxidize phytanic acid (chlorophyll derivative) to
pristanic acid
– Lysine via pipecolic acid and glutaric acid
– Glyoxylate to prevent conversion to oxalate
Peroxisomal Disorders
• 16 disorders
– 15 are autosomal recessive
– 1 is X-linked (adrenoleukodystrophy)
• Predominant features
– Dysmorphisms
– Neurologic dysfunction
– Liver disease
Peroxisomal Disorders
• Biosynthesis Defects
– Zellweger spectrum disorders (ZD, IRD, NR)
– Rhizomelia chondrodysplasia punctata
• Single Peroxisomal Enzyme Deficiencies
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Adrenoleukodystrophy (ABCD1 on Xq28)
RCDP type 2 (GNPAT on 1q42.1-42.3)
RCDP type 3 (AGPS on 2q33)
Refsum (PHYH/PAHX on 10p15-p14)
Glutaric aciduria type 3 (?)
Mulibrey nanism (TRIM on 17q22-23)
9 others
Peroxisomal Biogenesis
• Peroxisomes multiply by division
• Proteins carried from free polyribosomes to
peroxisomes by
peroxisomal targeting signals (PTS)
• PTS1
– Last 3 carboxy terminal amino acids
– PTS1 receptor encoded by PEX5
• PTS2
– Stretch of 9 amino acids
– PTS2 receptor encoded by PEX7
Peroxisomal Biogenesis
• PTS receptors deliver proteins to
peroxisomal protein import machinery
• Import machinery transports proteins
across membrane
• Transporter complex has at least 15
peroxins (PEX1, 2, 3, 5, 6, 10, 12, 13,
14, 16, 19, 26)
Zellweger Spectrum Disorders
• CZ, NALD, and IRD
• Genetic heterogeneity
• Dysmorphism (large fontanelle, high forehead, abn ears,
micrognathia, low/broad nose, redundant skin folds)
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Neuronal migration disorders and delayed myelination
Seizures
Hypotonia
Sensorineural deafness
Ocular abnormalities (retinopathy, cataracts, ON atrophy)
Liver disease (hepatomegaly, cholestasis, hyperbilirubinemia)
Failure to thrive
Death in first year of life
Zellweger Syndrome
From Google Images
ZELLWEGER SYNDROME
Zellweger Spectrum Disorders
• Classic Zellweger (CZ)
• Neonatal adrenoleukodystrophy (NALD)
– Somewhat less severe than CZ
– May lack dysmorphisms altogether
– Neonatal or infantile onset of seizures, hypotonia, and
progressive leukodystrophy
– May have pachypolymicrogyria
• Infantile Refsum disease (IRD)
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Least severe phenotype, regression over time
May be asymptomatic at birth
No progressive leukodystrophy
Variable expressivity of cognitive dysfunction
Deafness and vision changes (retinopathy)
May survive to adulthood
Adrenoleukodystrophy/
Adrenomyeloneuropathy
• Most common peroxisomal disorder (1/20,000)
• Mutation in ABCD on Xq28 leads to defect in
peroxisomal uptake of VLCFA
• ALD: progressive neurologic disorder that begins at 512 years
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Boys with new onset school difficulties & ADHD
Visuo-spatial deficits and hearing loss
Spasticity, ataxia, maybe seizures
Hypoglycemia, salt losing, hyperpigmentation
Rx: steroids, presymptomatic stem cell transplant, Lorenzo’s
oil ineffective (oleic and erucic acids)
• AMN: early adulthood progressive spastic paraparesis,
cerebral demyelination (males)
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD