A 25-year-old woman presented with mental deterioration and progressive aphasia over the preceding 4 years. At age 23, she often lost her way home. At age 24, she complained of visual hallucinations and had incontinence of faeces. She had been treated with antipsychotic medication for schizophrenia-like symptoms by a psychiatrist for 2 years before presenting at our hospital. Her mother and maternal grandfather have chronic thyroiditis; there is no intermarriage among relatives. Physical examination revealed mild thyroid grand swelling but otherwise normal physical findings. Neurological examination revealed decreased intellectual function: her Mini-Mental State Examination score was 7/30, and the revised form of the Wechsler Adult Intelligence Scale showed a verbal intelligent quotient (IQ) <45, performance IQ <45 and IQ <40. Examination of her optic fundi was normal, which is unusual in lysosomal storage diseases. Her lower extremities showed mild spasticity and pes cavus. Deep tendon reflexes were downgoing at the patella and normal at the Achilles tendon, and plantar reflexes were bilaterally positive, indicating primary and secondary motor neuron involvement. The patient did not complain of sensory disturbance, dysaesthesia or paraesthesia. She was able to walk with a mild steppage gait.
Laboratory tests revealed some autoimmune antibodies related to chronic thyroiditis: antithyroid peroxidase antibody (anti-TPO-Ab) 0.6 (COI (cut-off index) ≤0.3) U/ml, antithyroglobulin antibody (Tg-Ab) 15.1 (COI ≤0.3) U/ml, and thyroid hormone and thyroid-stimulating hormone levels within the normal range (). In addition, autoantibodies against the amino-terminal of NAE3
(a marker for Hashimoto encephalopathy) were also negative. The cerebrospinal fluid (CSF) protein level was clearly high at 130 mg/dl (normal <60 mg/dl) with a low immunoglobulin G (IgG) index of 0.63, and without detectable levels of myelin basic protein (MBP) or multiple sclerosis specific oligoclonal IgG band patterns. Anti-TPO-Ab, Tg-Ab and anti-NAE antibodies were not tested in CSF.
Results of blood laboratory tests
Ultrasound of the thyroid gland showed a normal internal signal without any tumourous images. Brain MRI showed almost symmetrical volume loss, especially around the cerebral ventricles, and diffuse high signals in white matter on fluid attenuated inversion recovery and T2 weighted images, although the U-fibres were conserved (). Diffusion weighted images showed high signals at the edges of these lesions. In the apparent diffusion coefficient (ADC)-map images, these lesions also presented high signals, which were considered demyelinative changes spreading from deep white matter to the subcortical area. This was confirmed by magnetic resonance spectroscopies showing the typical decrease in N-acetyl aspartate and increase in choline (data not shown). No evidence of tumours was detected by whole body CT scan or by gastroscopy or colonoscopy. EEG showed diffuse θ-activity.
Figure 1 Specific MRI and pathological findings in metachromatic leukodystrophy. (A) Fluid attenuated inversion recovery (FLAIR), T2W, DW and ADC-map images of MRI showed symmetrical volume loss and diffuse demyelination in white matter. FLAIR and T2WI high signal (more ...)
Nerve conduction studies () showed approximately half speed motor conduction velocity with almost normal compound muscle action potential voltage on the patient's median, ulnar and peroneal nerves and also undetectable sensory neuron action potential at the ulnar, tibial and sural nerves, suggesting demyelination of both the motor and sensory peripheral nerves. Lack of abnormal temporal dispersion indicated diffuse demyelination rather than chronic inflammatory demyelinating polyneuropathy or Guillain–Barre syndrome. The sensory evoked potential study of median nerves showed that bilateral N9 peaks were not induced and the interval latency between N13 and N20 peaks was over twice normal. In the motor evoked potential (MEP) study of the right first dorsal muscle and abductor pollicis muscle, MEP latency and central motor conduction time calculated with F wave latency were both nearly twice normal at the upper and lower extremities, indicating that the conduction velocity of peripheral and central nerves was remarkably delayed.
Moreover, pathology findings from peripheral sural nerve biopsy revealed drop-out of large myelinated fibres, thinning of myelin ovoid structures and red metachromatic deposits (which appeared brown in the toluidine blue stained samples) in non-fixed frozen sections, a specific finding of MLD (). The same deposits appeared green under polarised light. Electron microscopy showed electron-dense deposits to be Schwann cells with a herringbone pattern (), a disease-specific finding of MLD. In the fresh frozen muscle sections from the left biceps muscle, there were no abnormal increased mitochondria or ragged-red fibres.
ARSA activity in peripheral white blood cells (WBC) was significantly decreased at 10.0 (normal 98.3 ±22.2) nmol/mg protein/h, while the following were all normal: α-galactosidase, β-galactosidase, α-glucosidase, β-glucosidase, β-hexosaminidase, β-hexosaminidase A, α-mannosidase, β-mannosidase, α-fucosidase and β-glucuronidase. Direct sequencing of the ARSA gene in genomic DNA from the peripheral WBC revealed c.203T>C (L68P) in exon 15
and c.1226C>T (T409I) in exon 86
, so we considered our patient had compound heterozygous mutations causing MLD.
The authors diagnosed MLD with autoimmune Hashimoto thyroiditis. We assumed that the patient's psychotic disorders were due to demyelination in deep white matter mainly caused by low ARSA activity and not to any other autoimmune enchephalitis related to Hashimoto thyroiditis. Bone marrow transplantation is planned for this patient.