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
Developmental delay: relentless regression
Seizures
UMN signs
Failure to thrive (less common)
+/- dysmorphisms
Testing for Leukodystrophy
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
Ceramide
Sphingosine
Glc-Cer
Gal-Glc-Cer
Gal-Cer SO
3
H-Gal-Cer
Phosphorylcholine-Cer
(Sphingomyelin)
Gal-Gal-Glc-Cer
GalNAc-Gal-Gal-Glc-Cer
Nana-Gal-Glc-Cer
GalNAc
Nana-Gal-Glc-Cer
Gal-GalNAc
Nana-Gal-Glc-Cer
Gaucher (-Glucosidase)
Farber (Ceraminidase)
Fabry (-Galactosidase)
Neuraminidase
GM
2
(-Hexosaminidase A)
GM
1
(- Galactosidase)
Sandhoff
(-Hexosaminidase
A & B)
Krabbe
AR defect of galactocerebroside-beta-
galactosidase 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, X-
linked 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
NAA
Courtesy Dr. Ralph Lachman
Canavan disease
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 2-
hydroxyglutaric 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
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)
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)
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 5-
12 years
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, Lorenzos
oil ineffective (oleic and erucic acids)
AMN: early adulthood progressive spastic paraparesis,
cerebral demyelination (males)
CLASSIC X-ALD
CLASSIC X-ALD
X-ALD