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Leukodystrophy - PowerPoint PPT Presentation

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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.

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Tyler Reimschisel, MD

September 6, 2013

Clinical presentations of imd
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
Diseases that Cause Leukodystrophy

Some examples

  • Adrenoleukodystrophy

  • Metachromatic leukodystrophy

  • Tay-Sachs

  • Krabbe

  • Canavan

  • Mitochondrial

Clinical presentation of leukodystrophy
Clinical Presentation of Leukodystrophy

  • Developmental delay: relentless regression

  • Seizures

  • UMN signs

  • Failure to thrive (less common)

  • +/- dysmorphisms

Testing for leukodystrophy
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







GM1 (- Galactosidase)



A & B)


GM2 (-Hexosaminidase A)


Fabry (-Galactosidase)



Niemann-Pick A/B



Gaucher (-Glucosidase)







(Arylsulfatase A)


(- Galactosidase)

Farber (Ceraminidase)



  • 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:

Metachromatic leukodystrophy
Metachromatic Leukodystrophy

  • AR defect of arylsulfatase-A

  • Leukodystrophy as well as disease of adrenal glands, kidneys, pancreas, liver

Metachromatic leukodystrophy1
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


  • 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
First Visit

  • Labs: PAA, acylcarnitine profile, vitamin B12, homocysteine, MMA level, creatine metabolites

  • Repeat brain MRI consistent with MLD

Second visit
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
Follow Up Testing

  • No mutations in arylsulfatase A gene

  • Parental testing showed normal arylsulfatase A enzyme activity

Additional testing
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
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, heparansulfatase, N-acetylglucosamine-6-sulfatase

Multiple sulfatase deficiency1
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


  • 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
Canavan disease

Courtesy Dr Isabelle Desguerre, Paris Necker Hospital

Canavan disease1


Canavan disease

Courtesy Dr. Ralph Lachman

L 2 hydroxyglutaric aciduria
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

L 2 hydroxyglutaric aciduria1
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
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

Brain mri leigh syndrome
Brain MRI: Leigh Syndrome

From Osborn. Neuroradiology, 2000

Brain mri1
Brain MRI

From Osborn. Neuroradiology, 2000

Peroxisome function
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
Peroxisomal Disorders

  • 16 disorders

    • 15 are autosomal recessive

    • 1 is X-linked (adrenoleukodystrophy)

  • Predominant features

    • Dysmorphisms

    • Neurologic dysfunction

    • Liver disease

Peroxisomal disorders1
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
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 biogenesis1
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
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
Zellweger Syndrome

From Google Images

Zellweger spectrum disorders1
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, Lorenzo’s oil ineffective (oleic and erucic acids)

  • AMN: early adulthood progressive spastic paraparesis, cerebral demyelination (males)