A 48 year old Caucasian man was referred because of progressing pain, numbness, and stiffness of his lower limbs during 3-4 years. Lower urinary tract symptoms were absent. Neurological examination revealed hyperactive tendon reflexes in both arms and legs and bilateral Babinski reflexes. Except from a slightly increased tone distally in his legs he had an overall normal muscle tone and no limb weaknesses. The only abnormal sensory finding was an impaired sense of vibration in his first toes. He developed erectile dysfunction and reduced libido at 49 years of age. It was treated with sildenafil, tadalafil and later testosteronundecanoat with almost no effect.
Neurological examination at 55 years of age revealed a moderate lower limb spastic paraplegia, hyperactive deep tendon reflexes in both arms and legs, Babinski’s sign bilaterally, distally impaired thermal sensation and decreased sense of vibration distally of the knees, confirming clinical progression during the seven years.
The following investigations were normal: Routine blood biochemistry, including vitamin B12 concentration, methylmalonic acid, glycosylated hemoglobin, HTLV1 and HTLV2 (Human T-cell Lymphotropic Viruses), p-ANCA and c-ANCA (Anti-Neutrophil Cytoplasmic Antibodies), ANA (Anti-Nuclear Antibodies), HIV, syphilis, and arylsulfatase A activity. Cerebrospinal fluid analysis showed an increased spinal protein level of 0.78 g/l (normal 0.15-0.50 g/l), absent oligoclonal bands, and no Borrelia Burgdorferi antibodies.
Electrophysiological studies including EMG (electromyography), ENG (electroneurography), SSEP (somatosensory evoked potentials), and VEP (visual evoked potentials) were normal. MEP (motor evoked potentials) showed increased central conduction time (CCT) to muscles in the upper and lower extremities. The muscles investigated were biceps brachii (BB), flexor carpi radial is (FCR), first dorsal interosseus (FDI), tibialis anterior (TA), and abductor hallucis (AH). The CCT was increased by 45% and 34% to the right and left FCR, respectively. The CCT to the right side FDI was increased by 22% and the left side was normal. The CCT to TA was increased by 25% and 56% and to AH by 26% and 30% to right and left side, respectively. The CCT to both BB was normal. Peripheral conduction time was increased by 20% and 23% to right and left TA, respectively, and also to the right AH with 18%. The peripheral conduction times to BB, FCR and FDI were all normal.
The profile of saturated very long chain fatty acid (VLCFA) of serum was diagnostic of AMN, showing a ratio between C24 and C22 of 146% (normal 40-105%) and a ratio between C26 and C22 of 6.0% (normal 0-3%).
The AMN diagnosis was confirmed by identification of a novel c.2005C>T mutation in the ABCD1 gene (Reference sequence: NM00033.3) predicting an amino acid shift from histidine to tyrosine at position 669 p. His669Tyr.
An ACTH stimulation test showed no adrenal insufficiency, but testosterone was slightly decreased (9.2 to 13 nmol/l; normal 10.0-28 nmol/l).
Repeated MRI’s (magnetic resonance imaging) of the brain and spinal cord during five years were normal. Short echo time MRS (magnetic resonance spectroscopy) studies were performed at ages 49, 50, 51, 53, and 55 years. The ratios of N-acetylaspartate (NAA), total choline (Cho), and mI to total Cr were calculated and results deviating more than 2 standard deviations (SD) from normal were regarded as abnormal. MRS showed elevated mI/Cr. The mI/Cr ratios were stable over time and on average 27% increased compared to the normal controls during the six years of study. The NAA/Cr ratios were low in the normal range or decreased to just below the normal range, but the NAA/Cr ratios did not change significantly over time. The Cho/Cr ratio stayed in the normal range all six years of study (Figure
Brain Magnetic Resonance Spectroscopy. Short echo time magnetic resonance spectra acquired at three Tesla from left and right occipito-parietal primarily white matter and from mid-occipital primarily grey matter in the patient at age 52 years.
The patient had increasing pain from his legs during the years. The pain was described as initially a pricking and tingling sensation but later a constant, night and day, burning, stabbing pain, which was not precipitated by contact, temperature or movements.
The pain in his lower limbs was initially treated with peripheral analgesics, which had no effect. Later tizanidin, levodopa, amitriptylin, oxacarbazepin, and pregabalin were tried but all resulting in unacceptable side effects with no benefit.
Based on the involvement of an immune/inflammatory process in the pathogenesis of ALD/AMN, the increased CSF protein and the MRS data, immunosuppressive therapy with IVIG was initiated as a last resort. Treatment with IVIG was initialized in an in-house standard scheme of 30 g IVIG a day for three consecutive days every third month when the patient was 49 years old. Trying to increase the interval between treatments was unsuccessful because of worsening of the pain. The treatment was continued during five years approximately every third month and was administered when the symptoms deteriorated with increasing pain. The treatment led to clear improvement, reducing his pain from 9 to 3 on a “visual analogue scale” of 10.