What Is Your Diagnosis?
NeuroQuiz Section Editor: Lawrence S. Honig, MD, PhD, Columbia University, New York, New York.
A 40-year-old right-handed man previously functioning well at a high-level occupation presented with a 2-year history of increasing drug and alcohol abuse leading to attendance at multiple rehabilitation programs, which, however, was unsuccessful. His behavior resulted in loss of employment. His family noted additional symptoms of impulsivity, wandering off for unclear reasons, unwarranted agitation, and loss of social inhibitions. He would make uncharacteristically blunt and inappropriate comments about the personal appearance of others, and he had hypersexuality including public sexual behavior. His medical history revealed only hyperlipidemia, shoulder rotator cuff surgery, and cholecystectomy. His family history was negative for neuropsychiatric disease in his parents and siblings. Neuropsychiatric examination revealed impulsiveness, overfriendliness, emotional incontinence, inattentiveness, and some psychomotor slowing but preserved language and memory functions. His Mini-Mental State Examination score was 26 of 30. Cranial nerve, motor, sensory, and reflex examination findings were remarkable only for diffuse relative hyporeflexia. Neuropsychological testing showed diffuse dysfunction with borderline IQ, judged to be about 30 points below his expected level, but relatively intact episodic memory. T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (Figure 1) showed severe white matter hyperintensity that was frontally dominant and reported as of unclear etiology; T1-weighted imaging performed with gadolinium contrast (Figure 2) showed corresponding T1 hypointensity but no abnormal contrast enhancement. Brain technetium Tc 99m hexamethylpropylene amine oxime single-photon emission computed tomography (HMPAO-SPECT) showed frontal hypoperfusion (Figure 3). Cerebrospinal fluid showed a white blood cell count of 2/μL (to convert to x109/L, mutliply by 0.001), a red blood cell count of 0/μL, a protein level of 87 mg/dL, a glucose level of 63 mg/dL (to convert to millimoles per liter, multiply by 0.0555), a β-amyloid 42 level of 454 pg/mL, a total tau level of 307 pg/mL, and phosphorylated tau level of 62 pg/mL. He was treated with antipsychotics and had mild improvement in behavior but no marked change in his neuropsychiatric syndrome.
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Correct Answer: Metachromatic leukodystrophy.
What is your diagnosis?
The syndrome is one of dementia principally involving frontal regions. Magnetic resonance imaging shows white matter signal abnormality on the T2-FLAIR sequence, which is confluent in the frontal lobes but also shows temporal and parietal involvement. There is some accompanying diffuse cerebral atrophy. While the possibility of frontotemporal dementia with subcortical gliosis was considered, the relatively young age of the patient, the lack of autosomal dominant family history, the diffuse, symmetric, and severe nature of the white matter changes, and the diffuse hyporeflexia in the setting of significant brain white matter disease are all suggestive of the diagnosis of metachromatic leukodystrophy. Adrenoleukodystrophy is more likely to present with posterior white matter disease and at this age is more likely to present with spasticity and hyperreflexia. There was no evidence of episodic events such as might be seen in multiple sclerosis, CADASIL, or hypertensive leukoencephalopathy (also, there was no history of hypertension), and the diffuse symmetrical nature of the white matter disease also made these disorders unlikely. Blood testing for leukocyte arylsulfatase revealed an abnormally low but detectable activity of 0.3 U/10 billion cells (reference range, >2.5 U/10 billion cells). Further tests in urine and tissue confirmed arylsulfatase deficiency and the presence of the genetic autosomal recessive disorder of metachromatic leukodystrophy. Low but detectable enzyme levels are typically associated with adult onset during the third or fourth decade of life, as in this case. This lysosomal deficiency disorder, localizing to chromosome 22, involves degeneration of both central myelin, as seen in the brain magnetic resonance imaging, and demyelination of the peripheral nervous system leading to gait disorder and hyporeflexia. Neurophysiological studies did confirm severely decreased nerve conduction velocities.