White matter disease Flashcards
Leukodystrophies and big heads
Alexander’s disease
AD, GFAP gene, 17q21.31 - though AD inheritance has been controversial, gain of function mutation
Patients with the infantile formL megalencephaly, developmental delay, seizures, psychomotor developmental delay, spasticity, and quadriparesis
Juvenile form: onset in childhood, more significant bulbar symptoms
Adult form: bulbar signs, hyperreflexia, dysautonomia, ataxia, and sleep apnea
Brain MRI demonstrates diffuse white matter T2 hyperintensity, predominantly in the frontal lobes and anterior cerebral regions, with involvement of the U fibers. In the adult-onset form, t_he “tadpole sign” on sagittal MRI results from dramatic thinning of the upper cervical spinal cord._ The brains of these patients are large, and histopathologically, there are Rosenthal fibers.
Characterized by intracytoplasmic astrocyte eosinophilic corkscrew inclusions (Rosenthal fibers, also seen in pilocytic astrocytomas)
Canavan’s disease
AR, caused by deficiency of aspartoacylase, leading to accumulation of N-acetylaspartic acid in the brain. ASPA gene on chromosome 17p13
Onset of symptoms btwn 10 weeks-4 months of life, poor fixation and tracking, psychomotor arrest and regression, irritability, feeding difficulties, hypotonia with poor head control and inability to sit, and subsequent spasticity. Megalencephaly (enlarged brain) is present.
Urinary N-acetylaspartic acid level is elevated, and MRI demonstrates diffuse symmetric T2 hyperintensity in the white matter, with characteristic involvement of the U fibers.
Magnetic resonance spectroscopy shows an increased peak of N- acetylaspartic acid. Cerebrospinal fluid is normal and there is no inflammation. There is no specific treatment available and death usually occurs in the second decade of life.
Spongiform changes in the white matter
Pelizaeus–Merzbacher disease
XLR, PLP1 on Xq22.2 ->abnormal synthesis of proteolipid protein 1.
Hypomyelinating leukodystrophya
S(x)s first few months of life, with intermittent nodding movements of the head, pendular nystagmus, and other abnormal eye movements. Ataxia, chorea, athetosis, dystonia, spasticity, and laryngeal stridor also occur, and psychomotor development arrests with subsequent regression. Late manifestations include seizures and optic atrophy. Pts w/ later onset may have slower progression, some survive into adulthood.
The MRI demonstrates diffuse hypomyelination characterized by T2 hyperintensity and loss of white matter with relative thinning of the corpus callosum. Pathologically, there is a noninflammatory demyelination (unlike Alexander’s) sparing the U fibers and islands of white matter. This patchy involvement gives it a “tigroid” appearance on MRI. Peripheral myelin is spared and, therefore, peripheral nerves are not involved.
Genetic testing is available for diagnosis, and there is no specific treatment.
Subcortical U-fibers
Connections between adjacent gyri of the brain.
They are among the last parts of the brain to myelinate (third or fourth decade) and have very slow myelin turnover.
Therefore, diseases of myelin metabolism will initially spare the U-fibers.
However, diseases of myelin production will involve all white matter indiscriminately including the U-fibers.
Metachromatic leukodystrophy - G/A/E
Lysosomal storage disorders: Sphingolipidoses
AR, 2/2 mutations in 1.) arylsulftase A gene resulting in arylsulfatase deficiency that leads to accumulation of sulfates or 2.) PSAP gene, leading to deficiency of a sphingolipid activator protein (SAP-B or saposin B) that normally stimulates the degradation of sulfatides by arylsulfatase A
Accumulates cerebroside sulfate
Metachromatic leukodystrophy - clinical
Lysosomal storage disorders: Sphingolipidoses
Central and peripheral demyelination
MRI with central demyelination sparing U-fibers (vs posterior demyelination in X-linked adrenoleukodystrophy)
Decreased velocity on NCS
Elevated CSF protein
Sxs: Infantile form - onset 1-2 years, absent DTRs, spastic quadriparxsis, dementia, optic atrophy, death; juvenile form - onset 3-16 years, initial decline in school performance, then ataxia, decreased DTRs, spastic quadraparesis, dementia. Can have seizures, bulbar symptoms, temor; adult form - more than 16, psychiatric symptoms, dementia, spastic paresis, optic atrophy, dystonia, may not have abnormal NCV
Dx: urine sulfatides elevated, enzyme activity may be decreased in leukocytes or fibroblasts but limitations
Tx: BMT, supportive
Krabbe disease (globoid cell leukodystrophy)
Lysosomal storage disorders: Sphingolipidoses
AR, deficiency of galactocerebroside B-galactosidase
Gene: GALC
Krabbe disease (globoid cell leukodystrophy - clinical)
Lysosomal storage disorders: Sphingolipidoses
Also see central and peripheral demyelination with MRI with central demyelination, sparing U-fibers (diffuse and not posteriorly predominant like X-linked adrenoleukodystrophy). Decreased velocity on nerve conduction studies. CSF with elevated protein.
S(x)s: Infantile form - begins 3-6 most with irritability = crabby baby, tonic spasms with stimulation, optic atrophy, blindness, deafness, unexplained fever, then opisthotonus, seizures, loss of bulbar function, death by 2 yo (also have demyelinating polyneuropathy with areflexa); late infantile form: begins 6 mos-3 years, irritability, failing vision, ataxia, motor deterioration, stiffness; adult form reported, can have normal NCS
Dx: Enzyme activity in fibroblasts or leukocytes. See multinuclear macrophages (globoid cell) in cerebral white mater.
Tx: supportive are for infantile (one small study showed benefit of unrelated umbilical cord blood stem cells when given to as(x) patients with infantile form), BMT for mild cases, later onset early in course of disease
X-linked adrenoleukodystrophy - G/A/E/Imaging
Defect in ABCD1, peroxisomal membrane transport protein, causes impaired beta-oxidation of VLCFA
Posterior white matter changes sparing U-fibers, can have rim of contrast enhancement differentiating it from other white matter diseases (except Alexanders)
On histology, lipid-laden histiocytes (circle), which activate microglia and causing perivascular lymphocytic infiltrate
X-linked adrenoleukodystrophy - clinical
MC peroxisomal disorder
Childhood cerebral form (40%) - symptoms start at 4-8 years old, behavior problems in school, ADHD, seizures, regression of spatial orientation, auditory discrimination, speech, spastic paraparesis, visual loss, impaired swallow, death wi 2 years - by 10 years old, impaired cortical response in 85%
Adult cerebral form - dementia, seizures, psychiatric symptoms, spastic paraparesis after age 21, rapid progression
5% with adrenomyeloneuropathy (45%): slowly progressive spastic paraparesis, impaired vibratory sense in legs, bladder dysfunction, begins in 3rd decade, loss of myelinated axons in spinal cord and peripheral nerves, Addison’s disease in 67%, abnormal cerebral white matter in half, subtle cognitive deficits *Also some with pure adrenal form
Tx: Steroid replacement therapy, “Lorenzo’s oil” (4:1 glyceryl trioleate-glyceryl trierucate) to reduce levels of very long-chain fatty acids in plasma, may be beneficial in young asymptomatic patients but not in patients with neurologic deficits. Bone marrow transplantation may have a role in early stages of the disease.
