History and Physical
A 2-year-old girl with no prior history presented with a new gait disorder. At daycare, she experienced progressive worsening of motor clumsiness and psychomotor skills, without cognitive impairment. She was noted to walk poorly and fall easily, with no abnormalities identified on orthopedic examination. Neurologic examination revealed truncal ataxia with osteotendinous hyporeflexia and extremity hypertonia. Sensory examination was normal and language function was preserved. Basic blood and urine analyses were normal. CSF was notable for elevated protein of 112 mg/dL (normal 15–45). Neurophysiology revealed a demyelinating peripheral neuropathy with reduced motor and sensory nerve conduction velocities. Head CT and brain MRI showed diffuse cerebral white matter abnormality. The diagnosis was confirmed by skin biopsy for fibroblasts with enzymatic and molecular testing.
Diagnostic Workup
Brain MRI shows confluent and symmetric involvement of the periventricular and deep white matter, including splenium of corpus callosum, with initial preservation of the subcortical U fibers. With disease progression, there is linear sparing of perivascular regions in a “tigroid” pattern ( Fig. 30.1 ). With gadolinium administration, cranial and spinal nerve enhancement can be demonstrated ( Fig. 30.2 ).
Metachromatic leukodystrophy. Brain MRI, (A) sagittal T1, (B) axial T2, (C) axial T1 show abnormal signal in the corpus callosum and periventricular white matter with sparing of subcortical fibers and perivascular spaces creating a “tigroid” pattern.
Metachromatic leukodystrophy. Brain MRI, (A) sagittal FLAIR, (B) axial T2, (C and D) axial T1 with contrast show diffuse T2/FLAIR white matter hyperintensity with sparing of the perivascular regions ( arrows ) creating a “tigroid” pattern. The cranial nerves are diffusely enlarged and enhancing ( arrowheads ). FLAIR , Fluid-attenuated inversion recovery.
Clinical Differential Diagnosis
Genetic leukodystrophies can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion. These are generally childhood-onset conditions with predominant motor involvement, including hypotonia and pyramidal and cerebellar signs. Cognitive deterioration is usually slow, with a low incidence of seizures. Brain MRI shows predominant involvement of white matter.
Certain leukodystrophies are linked to specific metabolic defects, for example globoid cell leukodystrophy (Krabbe disease), multiple sulfatase deficiency, saposin B deficiency, mucolipidoses, fucosidosis, and hexosaminidase A deficiency. Metabolic workup and molecular testing will provide a definitive diagnosis.
Neurotransmitter defects, dopamine-responsive dystonia, and infantile cerebral palsy can have similar clinical features.
Imaging Differential Diagnosis
Krabbe disease: As with many leukodystrophies, Krabbe disease shows distinct imaging features and ages of onset for different clinical subtypes. The subtypes that can resemble X-linked ALD are the juvenile and adult forms, with deep white matter and/or isolated corticospinal tract involvement.
Acute demyelination: Diffuse demyelination can be bilateral and symmetric but occurs acutely following an osmotic or infectious insult.
Gangliosidoses: In the gangliosidoses, there are diffuse white matter abnormalities with heterogeneous signal intensity of the thalami and basal ganglia. The thalami show bilateral and symmetric hyperdensity on CT, hyperintensity on T1-weighted, and hypointensity on T2-weighted MRI ( Fig. 30.3 ).
