Differential Diagnosis in Neurology

Topic 10. Differential Diagnosis of Peripheral Neuropathy

10.6. The Neuropathies of Disordered Lipid Metabolism

Metachromatic Leukodystrophy

  • General characteristics:
    • Late-infantile (most common)
    • Juvenile
    • Adult-onset
    • Galactosyl sulfatide accumulation in glia, Schwann cells and macrophages
    • AD variant: aryl sulfatase activity is absent; absence of an activator enzyme
    • Metachromasia due to lamellar material in leukocytes
    • Demyelination of CNS and PNS
    • Heterozygotes retain 50% of normal enzyme activity
  • Genetics: chromosome 22; aryl sulfatase A gene
  • Clinical features:
    • Late infantile variant:
      • Age of onset 1–2 years; normal early development
      • Ataxia weakness and hypotonia
      • Absent reflexes; neuropathy present
      • Progressive dementia, dysarthria, spasticity
      • Terminal stages; rigidity quadriparesis; seizures, optic atrophy and myoclonic jerks
  • Juvenile MLD
  • Clinical features:
    • Incidence is 25% of late infantile form
    • Onset between 3–20 years; usually first decade
    • Prominent behavioral manifestations
    • Gait disorder
    • Depressed or absent reflexes
    • Choreoathetoid movements
    • Insidiously progressive

Adult Onset Metachromatic Leukodystrophy

  • General features:
    • Clinical features:
      • Rare
      • Onset late second and third decade
      • Dementia
      • Cerebellar ataxia
      • Optic atrophy
      • Psychiatric and behavioral manifestations
      • Spasticity
  • MRI:
    • Cortical atrophy (symmetrical)
    • Posterior predominant increase in T2-weighted signal
    • Sparing of u fibers
  • Pathology:
    • Segmental demyelination/remyelination of peripheral nerve:
      • Zebra bodies; prismatic inclusions, and myelin figures
    • Urine: metachromasia in leukocytes
    • Metachromatic deposits within Schwann cells and macrophages
    • Assay of aryl sulfatase activity in blood leukocytes and serum
  • EMG:
    • Demyelinating polyneuropathy with slow motor nerve conduction velocities
    • SNAPs are absent or reduced

Rare Variants of Metachromatic Leukodystrophy (MLD)

  • General features:
    • Multiple sulfatase deficiency
    • Genetics:
      • AR; SUMF1gene
      • Absence of aryl sulfatase A, B and C
  • Clinical presentation:
    • Resembles the late infantile form
    • Associated ichthyosis, hepatic and splenic enlargement; skeletal deformities

Cerebroside Activator Protein Deficiency Variant

  • General features:
    • Genetics:
      • Chromosome 10; saponin B gene
      • Normal activity of aryl sulfatase A and B; deficiency of saponin B (cerebroside sulfate activator protein)
  • Clinical presentation:
    • Similar to late infantile form

Globoid Cell Leukodystrophy (Krabbe's Disease); Galactosyl Ceramide Lipidosis

  • General features:
    • Genetics:
      • AR; gene chromosome 14 (deletions; insertions; point mutation)
      • Deficiency of galactosylceramide B-galactosidase
  • Clinical presentation (infantile form):
    • Onset 3–6 months of age
    • Arrest and deterioration of motor and intellectual development
    • Hypertonus (limb and axial)
    • Optic atrophy; deafness
    • Tonic seizures
    • Intermittent fever
    • Loss of deep tendon reflexes six months after onset of neuropathy

Adult Onset Variant

  • General features:
    • Dementia
    • Demyelinating, sensorimotor neuropathy
    • Later onset of disease has a more protracted course
  • Laboratory:
    • Assay of galactosyl ceramide B galactosidase activity in leukocytes or cultured fibroblasts
  • MRI:
    • Diffuse cerebral atrophy
  • EMG:
    • Demyelinating sensorimotor neuropathy; reduced motor NCVs
  • Pathology:
    • Multi nucleated globoid cells seen in CNS white matter
    • Decreased myelinated nerve fiber density and segmental demyelination
    • Prismatic and tubular inclusions seen in Schwann cells and endoneurial macrophages

Adrenoleukodystrophy

  • General features:
    • Genetics:
      • X-linked recessive; chromosome Xq28
      • Peroxisomal disease; failure of B-oxidation of long chain fatty acid (VLCFA-C22:0–C26.0)
      • Protein encoded: ATP binding cassette transporter (ABC) located in the peroxisomal membrane
      • No phenotype-genotype relationship with any mutation
  • Clinical presentation:
    • Onset in childhood (4–8 years of age) in males
    • Cognitive decline
    • Spastic quadriplegia
    • Blindness
    • Adrenal insufficiency
    • Sensorimotor peripheral neuropathy
    • Seizures
  • MRI:
    • Cortical atrophy
    • T2 increased signal symmetrically, posteriorly in the centrum semiovale of the parietooccipital lobes
  • Pathology:
    • Sensory CNS demyelination
    • Lamella inclusions in brain macrophages, Schwann cells and the adrenal cortex

Adrenomyeloneuropathy

  • General features:
    • Genetics
  • Clinical presentation:
    • Onset in adolescence or adult life
    • May be preceded by hypoadrenalism
    • Spastic paraplegia
    • Motor sensory demyelinating neuropathy
    • Hypoadrenalism and hypogonadism
    • Female carriers; spastic paraparesis and adrenal insufficiency
  • EMG:
    • Axonal sensorimotor neuropathy; some demyelination
  • Pathology:
    • Loss of myelinated and unmyelinated axons; some onion bulb formation
    • Schwann cell inclusions
  • Rare phenotypes:
    • Isolated adrenal insufficiency
    • Progressive cerebral dysfunction in adulthood

Dyslipidemias

Abetalipoproteinemia (Bassen Kornzweig Disease)

  • General features:
    • Genetics:
      • Chromosome 4 q 22–24; AR
      • Gene encodes a microsomal triglyceride transfer protein; important in the lipidation of Apo B to form lipoprotein complexes
  • Clinical presentation:
    • Fat malabsorption in infancy that subsides with age
    • Onset of neurological symptoms during the first decade or less than 20 years of age
    • Depressed reflexes prior to symptoms
    • Ataxia first sign
    • Dysarthria
    • Cerebellar ataxia
    • Proprioceptive loss
    • Generalized muscle weakness
    • Babinski signs noted in some patients
    • Rare sensorimotor polyneuropathy (loss of touch, temperature, pain)
    • Pigmentary retinal degeneration
    • Pes cavus and scoliosis
    • Ceroid myopathy (rare)
    • Cardiomyopathy occurs
    • Heterozygotes occur
  • Laboratory:
    • Absence of plasma apolipoprotein B containing lipoproteins:
      • Very low density and low density lipoproteins
      • Reduced chylomicrons, cholesterol and triglycerides and free fatty acids
    • Acanthocytes in the peripheral blood
    • Low or absent vitamin E levels in the serum
    • Slight anemia
    • Vitamin K deficient clotting factors (minimal clotting disorders)
  • EMG:
    • Motor NCVs are normal or minimally reduced; SNAPs are decreased in amplitude or are absent
  • Pathology:
    • Dysmyelination of large myelinated AA and AB fibers; demyelination of the dorsal columns

Familial Hypobetalipoproteinemia

  • General features:
    • Genetics:
      • Some patients have mutations of Apo-B gene (often truncations)
      • Heterozygotes demonstrate serum abnormalities of low density lipoproteins; usually asymptomatic
  • Clinical presentation:
    • Homozygotes are symptomatic
    • Similar to Bassen Kornzweig Disease; less severe
  • Laboratory:
    • Acanthocytes in the peripheral blood

Andersen's Disease (Glycogen storage disease, type IV)

  • General features
    • Absence of chylomicrons in plasma
    • Failure to secrete Apo B containing chylomicron from the intestine
  • Clinical presentation:
    • Similar to Bassen Kornsweig disease (BK disease)
    • Acanthocytes in the peripheral blood

Cholesterolosis (Cerebrotendinous Xanthomatosis)

  • General features:
    • Genetics:
      • AR; chromosome 2 is location of the gene encoding the enzyme sterol 27-hydroxylase
      • Blocks bile acid synthesis
  • Clinical presentation:
    • Onset in late childhood or adolescence
    • Tuberous cutaneous xanthomas on extensor surfaces and tendon's; Achilles tendon and elbows often early site of xanthomas
    • Premature atherosclerosis
    • Cataracts
    • Dementia is gradual but progressive
    • Spasticity
    • Ataxia
    • Sensorimotor neuropathy (components of both axonal and demyelinating); sensory greater than motor
  • Laboratory:
    • High plasma cholestanol; normal cholesterol
    • Fibroblast analysis of 27-hydroxylase gene
  • EMG:
    • Slowed sensory NCVs
  • Pathology:
    • Nerve biopsy; decreased large myelinated fibers primarily (demyelinating); some axonopathy
    • Some lipid inclusions in Schwann cells

Sphingomyelin Lipidosis (Niemann–Pick Disease)

  • Classified into 4 types:
    • Type I (A) – infantile variant:
      • Genetics:
        • Gene located on chromosome 11; encodes sphingomyelinase
      • Clinical features:
        • Disease of infancy
        • Cherry red macula; deterioration of retinal ganglion cells; choroid seen which is red
        • Accumulation of sphingomyelin in liver and spleen
        • Dementia
        • Seizures
        • Rare neuropathy characterized by:
          • segmental myelination/demyelination
          • decreased motor NCVs
        • Pathology:
          • Schwann cells and axon lipid inclusions
          • Endothelial foam cells
    • NPD Type II (B):
      • Genetics:
        • Mutations in sphingomyelinase gene on chromosome 11
      • Clinical features:
        • Onset in childhood
        • Hepatosplenomegaly
        • No neurological complications
        • Survive into adulthood
      • Laboratory evaluation:
        • Deficient ASM activity in leukocytes
    • NPD Type III C and Type IV:
      • Genetics:
        • Normal ASM activity
      • Clinical features:
        • Onset in childhood
        • Hepatosplenomegaly
        • Ataxia
        • Vertical gaze palsy
        • Cognitive deterioration
        • Spasticity
        • Neuropathy is only present in type IV (Nova Scotia variant)
        • Adult presentation of type III:
          • Psychosis
          • Dementia
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