Differential Diagnosis in Neurology

16.8. Peroxisome Single Enzyme Defects of Adolescence and Adulthood

X-Linked Adrenal Leukodystrophy

• General considerations:
  • Genetics:
    • X-linked recessive disorder of beta oxidation of very long chain fatty acids (VLCFA)
    • Defect of lignoceric-CoA synthetase
    • A member of the ATP binding transporter family
    • Involved in the transport of fatty acyl CoA substrates across the peroxisomal membrane
    • Accumulation of VLCFA is associated with neurologic damage
  • Sub types occur within families
  • Different sub types occur within kindreds
  • Manifesting female carriers occur
  • Common link among the disorder is:
    • An excess of VLCFA esters (carbon chain length greater than 22)
    • Detected in plasma, cultured fibroblasts and affected tissues
• Clinical features:
  • Adolescent form:
    • Onset is 11–21 years of age
    • Dementia
    • Hearing loss
    • Visual deficit
    • Pyramidal deficits
    • Extrapyramidal dysfunction
    • Cerebellar signs
    • Increased pigmentation
    • Adrenal failure manifested by:
      • Episodic vomiting and diarrhea
      • Hypotension
      • Severe weakness and fatigue
      • Low serum sodium and high serum potassium

Adult Cerebral Type Leukodystrophy

• Clinical features:
  • Schizophrenia like symptoms
  • Dementia
  • Spasticity
  • Aphasia
  • Auditory and visual deficits
  • Aphasia
  • May or may not have adrenal insufficiency

Adrenal Insufficiency without Neurological Symptoms

• Clinical features:
  • High risk of late neurologic disease
  • Oldest patient described with Addison's disease is 78

Asymptomatic Carriers of the Genetic Defect with Elevated Very Long Chain Fatty Acid (VLCFA)

• Clinical features:
  • High risk of later neurologic symptoms
  • Oldest patients are males between 60–70 years of age

Adrenoleukodystrophy Female Heterozygotes

• General considerations:
  • Female carriers of the gene defect may develop neurologic symptoms
  • Non-random X-chromosome inactivation that favors expression of the mutant allele is the mechanism
  • Usually is the phenotype adrenomyeloneuropathy (AMN)
• Clinical features:
  • Onset in the fourth decade
  • Mild signs
  • Slowly progressive course

Adrenomyeloneuropathy (AMN)

• General considerations:
  • The slowly progressive phenotype
• Clinical features:
  • Onset age 20–30 years
  • Slowly progressive
  • 50% have cerebral involvement
  • Often presents with clumsiness and legs stiffness
  • Spastic paraplegia
  • Impotence and incontinence
  • Sparing of the upper arms
  • Adrenal insufficiency in 60–70% of patients
  • Adrenal symptoms may precede neurological signs and symptoms

Differential Diagnosis of AMN

• Demyelinating disease
• Familial spastic paraparesis
• Spinocerebellar atrophy

• Pathology:
  • Caudal rostral progression of the leukodystrophy
  • Occipital, parietal, temporal lobes most severely affected
  • Bilateral symmetrical lesions
  • Severe demyelination of:
    • Optic nerves
    • Fornix
    • Hippocampal commissure
    • Posterior cingulum
    • Partial sparing of the subcortical arcuate fibers
    • Corpus callosum
    • Internal capsule
  • Brainstem and spinal cord less affected:
    • Involvement of descending tracts only
  • AMN involvement of:
    • Brainstem (minimal)
    • Cerebellum (moderate)
    • Lumbar corticospinal tracts
    • Cervical fasciculus gracilis
    • Dorsal spinocerebellar tracts
  • Advancing demyelination:
    • Sparing of axons
    • PAS + macrophages
  • Neurons generally preserved
  • Peripheral nerves:
    • Loss of large and small diameter fibers
  • Adrenal glands are atrophic
  • EM examination:
    • Needle like trilaminar bodies
    • May also be found in nerves, conjunctiva and skin
• Diagnostic evaluation:
  • Excess of VLCFA (greater than 22 carbons) in:
    • Plasma
    • Cultured fibroblasts
    • Affected tissue
• MRI evaluation of the cerebral forms of ALD:
  • Involve the corpus callosum
  • Primarily posteriorly
  • Symmetrical T2 weighted signal posterior > anterior
  • Minimal if any, involvement of arcuate fibers

Unusual Leukodystrophies That May Be Seen in Adulthood with Dementia

Pelizaeus Merzbacher 

• General considerations:
  • Genetics:
    • X-linked inheritance
    • Well documented female patients have been described
    • X q21.33–22 location of myelin proteolipid gene (PLP):
      • Mutations
      • Duplications of the gene
      • Little correlation between genotype and phenotype
      • Mutation of PLP gene:
        • Noted in X-linked spastic paraplegia (SPG2)
        • Pelizaeus Merzbacher
• Clinical features:
  • Onset of nystagmus in infancy (horizontal with torsional rotary components)
  • Stridor
  • Spasticity
  • Developmental delay
  • Ataxia
  • Seizures occur in some patients
  • Optic atrophy by age 5
  • Death may occur at any age up to fifth decade
• Laboratory evaluation:
  • Abnormal brainstem auditory potentials
• MRI:
  • Lack of periventricular myelin
• Pathology:
  • Brain is atrophic
  • Cerebellar atrophy
  • Loss of myelin with tigroid pattern of residual myelin
  • Lack of oligodendroglia
  • Increased astrocytes

Alexander's Disease

• General considerations:
  • Genetics:
    • GFAP mutations
• Clinical features:
  • Onset in infancy or later childhood
  • Adult form described
  • Dementia
  • Seizures
  • Spasticity
• Adult form:
  • Dysphagia
  • Ataxia
  • Brainstem cranial nerve dysfunction
  • Psychological deterioration
  • Focal disease (brainstem) has been reported
  • Macrophalli
  • Regression of developmental milestones
• MRI:
  • Increased T2 signal primarily in the brainstem
• Pathology:
  • Large brain
  • Indurated white cortical ribbon
  • Diffuse demyelination; rarefaction of white matter
  • Innumerable Rosenthal fibers:
    • Around blood vessels
    • Subpial
    • Subependymal zones
    • Contain GFAP and α-B-crystallin
    • Gliosis
• MRI evaluation:
  • Increased T2 weighted signal primarily in the brainstem