We describe a 9-year-old boy who showed typical neurologic manifestations i.e.,
progressive behavioral changes, intellectual impairment, visual disturbances and hearing loss,
cerebellar and pyramidal signs with characteristic neuroimaging features, which led us to
make a clinical deagnosis of ALD. It was confirmed later by demonstration of increased
VLCFA levels in RBC membrane using HPLC. He has no family history of neurologic or
endocrine disorder. Prophylactic antiepileptic medicaion could not prevent the development
of seizure disorder

Chang, Kee-Hyun

Han, Seol-Heui

Lee, Sang-Kun

Lee, Sang-Sok

Myung, Ho-Jin

Roh, Jae-Kyu

SNU Open Repository and Archive

,771c~ Seoul Jorrr~rrrl oJ' bfct/ic.iric~ L'ol. 30. No. 1.73 78. I24(1rrh 1.989 Adrenoleukodystrophy -A Case Report- Seol-Heui Har;, Sang-Kun Lee, Jae-Kyu Roh, Sang-Bok Lee, Ho-Jin Myung and Kee-Hyun Chang* =Abstract=We describe a 9-year-old boy who showed typical neurologic manifestations i.e., progressive behavioral changes, intellectual impairment, visual disturbances and hearing loss, cerebellar and pyramidal signs with characteristic neuroimaging features, which led us to make a clinical deagnosis of ALD. It was confirmed later by demonstration of increased VLCFA levels in RBC membrane using HPLC. H e  has n o  family history of neurologic or endocrine disorder. Prophylactic antiepileptic medicaion could not prevent the development of seizure disorder. K e y  words: Adrenoleukodystrophy, Very long chain fatty acids, High-performance liquid chroma- tography, MR imaging. 1983; Moser et a/. 1984). INTRODUCTION Adrenoleukodystrophy (ALD) is an X-linked re- cessive disease of childhood associated with rapidly progressive demyelination of cerebral white matter and varying degrees of adrenal cor- tical failure (Schaumburg et al. 1975). Most affected boys are between the ages of 5 and '10 years when the first symptoms are noted; the initial clinical presentations are usually an alteration in behavior ranging from a with- drawn state to aggressive outbursts and intellec- tual impairment. Neurologic deterioration is then relentlessly progressive and includes loss of vi- sion and/or hearing, disturances of gait and coor- dination, long tract signs, and ultimate deteriora- tion to a vegetative state and finally death. Sei- zures are a late manifestation. Although the primary enzymatic defect in ALD is still un- known, recent investigations have disclosed that the metabolic defects occur in the oxidation of very long chain fatty acids (VLCFA) (Igarashi et a/. 1976; Moser et a/. 1981 ; Kobayashi et a/. CASE REPORT H.Y., a 9-year-old boy, was admitted to the Seoul National University Hospital because of progressive visual disturbance and hearing loss that had begun at 8 years of age. He was the first child of healthy young pa- rents. He had no family history of neurologic or endocrine disorder. Following an unremarkable pregnancy and delivery, he weighed 3.15 kg at birth. Growth and development milestones were normal. He appeared to be a bright child and was in perfect health until 8 months prior to study when he became poorly attentive and his school performance began to decline. Over the next few months, he developed a gait disturb- ance, dysarthria and drooling. His examination on admssion revealed a small wasted and somewhat dull-looking child. He was alert but expressionless. There was no abnormal skin pigmentation, and blood pressure was 90-100/60-70. Visual acuity was below 0.0410.04, and visual f ield examination on penmetry revealed r~ght upper quadrant islands. Audiometry d~sclosed a bilateral sensorineural hearng loss (SNHL). Strength and sensations Fig. 1 .  a-d Non-contrast scans show areas of decreased attenuation In the deep w h ~ t e  mater (arrows) around the ventricular tr~gone (a,b). Contrast scan shows characteristic peripheral enhancement (E, arrow) (c,d). were normal, but he had spastic lower limbs. Tendon stretch reflexes were exaggerated with extensor plantar responses and sustained ankle clonus, bilaterally. He also showed bilateral dys- metria on finger to nose testing and showed spastlc awkward gait. Laboratory studies were as follows; normal hemogram and blood smear, urinalysis, calc~um 10.0 mg/100 ml, phosphorus 5.0 mg1100 ml, and serum aspartate aminotrans- ferase (SGOT) 13 units. Metachromatic granule was negative in the urine. Serum cortisol was 4.3 / ~ g / m l  in a morning sample and 20.3 , ~ g / m l  in an evening sample. ACTH stimulation test re- vealed normal response. A Computed Tomography (CT) of the brain performed elsewhere demonstrated low density Fig 2 H ~ g h  f ~ e l d  strength MRI (2 0 Tesla) prec~sely show~ng  varlous levels pathways affected by d~sease ( S p ~ n  Echo TR - 3,000 ms, TE - 80 msec) a Sect~on at the level of the pons shows d ~ s c r ~ t e  pyianlladl tract ~nvolvement (arrows) b MR lrnaqe at the level of m ~ d b r a ~ n  d~scloses c e r e ~ ~ ~ ~ ~ l  peduncle ~nvolvement (arrows) h MI? lrnage at  the level of frontal horns reveals ~nvolvernent of sp len~um of corpus callosurn and parleto occ~p~ td l  w h ~ t e  matter lesions of the subcortical w h ~ t e  matter adjacent t o  t he  vent r icu lar  t r lgone ,  ex tend ing  in to  parieto-occipital areas (Fig.1 -a) with an enhanc- ing r im that  is more  p rominen t  anteriorly (Flg.1-b). A Magnetic Resonance lmaglng (MRI) scan (GS SPECTRO-20,000) revealed an area of high-intensity, symmetric, periventricular signal in the white matter of parletal lobes, discrete pyramidal tract involvement within the brainstem. lesions of the lateral cerbral peduncle and In- volvement of splenium of corpus callosurn (Fig.2). Electroencephalography (EEG) showed localized frontal slowing but no deflnite epileptl- form activity. After initial diagnostic work-up, he was put on an antiepillptic medication (Phenytoln 200 mglday) to prevent possible selzure attacks. Two months after discharge, he developed a focal seizure with secondary generalization while his serum phenytoln level was maintained within the therapeutic ranges. On h ~ s  second admis- sion, all other cl~nical features got worse than before. His speech deteriorated almost to unln- telligibility. He could hardly walk out alone with- out assistance. On his third admission 6 months after in~tial diagnosis, he developed status epileptlcus. Dur- ing his last admission, for the analysis of VLCFA, venous blood was obtained with hepar~n-Na as an anticoagulant from the patient and the plasma and washed RBC's were prepared as suggested by Kobayshi et a1 (1983). The samples were stored at -60 C untll analyzed. Although the ac- tive seizure ceased, he could not regain his con- sclousness. The c h ~ l d  was discharged to the care of his parents in a vegetative state. DISCUSSION Adrenoleukodystrophy (ALD) refers to a group of degenerative disorders characterlzed by wide- spread demyelination and relentless neurological deterloration. Because the phenotype is varied, rt has been classified Into three maln subtypes; childhood ALD, adrenomyeloneuropathy (AMN) and neonatal ALD (Moser et a/. 1984). As previously mentioned, the most common childhood form IS distinguished by ~ t s  prom~nent cllnical features; slowly progresive behavioral changes, ~ntellectual impairment, loss of vision and/or hearing, cerebellar and pyramrdal slgns with or without evidence of adrenal lnsufficlency in a boy who has been in perfect health. Chi ldhood ALD and A M N  are f requent ly observed in the same kindred and have an X-linked hereditary trait. AMN usually does not begin until the second or thlrd decade or even later, and the disorder is characterized by adrenal lnsufflciency, variable hypogonadism, a slowly progressive demyelination in the splnal cord and in peripheral nerves that causes spastic para- paresis and distal polyneuropathy (Griffin et a/. 1977). So it is now considered to be a more indolent variant of childhood ALD. Another form, neonatal ALD is now obviously different from childhood ALD, not only in inheritance pattern (autosomal recessive) but also in clinical man- ifestation; abnorml facial features, moderate to severe hypotonia, hepatomegaly and retinitis pig- mentosa (Moser et a/. 1980; Aubourg et a/. 1 986). Because all neurological features were typicl of ALD, the clinical diagnosis was not so difficult in this patient, No family history of adrenal or neurologic disease could be elicited. After completing the initial diagnostic work- up, the boy was on prophylactic antiepileptic medication, but it was impossible to prevent, as might have been expected, the seizure attack caused by the progression of disease. Since lgarashi et a/. (1976) found abnormal accumulation of VLCFA in cholesterol ester frac- tions from cerebral white matter and adrenal glands of a patient with ALD, increased VLCFA levels have been found in other tissues and body fluids suggesting that ALD is a systemc metabolic disorder of this class of fatty acids (Igarashi et a/. 1976; Kobayashi et a/. 1983; Moser et a/. 1984; Rizzo et a/. 1984; Singh et a/. 1 984). Although the specific enzymatic defects in ALD remain to be further established, studies showing impaired VLCFA oxidation in fibroblasts and leukocytes suggest that it is one of the peroxisomal disorders. Because of functional de- rangement in peroxisomes, where the /? -oxida- tion of fatty acids occurs, there results in accu- mulations of VLCFA in the tissues (Lazarow 1987). The most consistently observed increase is that of hexacosanoic acid (C26:O) (Watkins et a/. 1987). Although typicl ALD shows clinical signs of adrenal failure such as cutaneous pig- mentation, hypotension or vomiting, drenal insuf- ficiency is not always clinically manifested. There are numerous reports of CT findings in ALD. The typical CT features, as seen in our patient, were large symmetric, low-density le- sions with peripheral enhancement that involved white matter of the occipital, posterior parietal, and temporal lobes (i.e., peritrigonal areas). Ex- tension of these lesions progressively involves the splenium of corpus callosum (Greenberg et a/. 1977; Chiro et a/. 1980; Aubourg and Diebler 1982). However, atypical findings, i.e., front1 lobe involvement, predominantly unilateral involve- ment, calcifications within the white matter le- sion, and mass effect were also described (Chiro et a/. 1980; lnoue et a/. 1983). Recently a few reports have described MRI appearance of ALD and concluded that MRI is superior to CT in the demonstration of nervous system involvement (Bewermeyer et a/. 1985; Young et a/. 1983; Huckman et a/. 1986). Kumar et a/. (1987) described more detailed MR images in their six patients with ALD and suggested that MRI is the first imaging modality to demonstrate both auditory and visual pathway structural dis- ease in ALD. The present case certainly emphasizes the im- portance of the MRI. The scan obtained on the 7th hospital day revealed discrete pyramidal tract involvement within the brainstem, involvement of auditory and visual pathways and extensive white matter lesion. These MRI findings are so characteristic that anyone can make diagnosis of ALD in a appropriate clinical settings. Open adrenal biopsy has been the most reli- able test for the diagnosis of ALD, but there have been a few autopsy proven cases with nor- mal adrenal function (Schaumburg et a/. 1975; Kim et a/. 1988). Lamellar inclusions observed in conjunctival or skin biopsies may help the di- agnosis but are still not confirmative (Arse- nio-Nunes et a/. 1981). Therefore, demonstration of increased hexaco- sanoic acid (C26:O) becomes indispensable for the confirmation of ALD, and it is possible to identify female carriers of ALD by verifying the increased plasma VLCFA level (Moser et a/. 1983). Techniques for the prenatal diagnosis of ALD were also established (Moser et a/. 1982). In our case, the increased plasma VLCFA level was demonstrated using HPLC during the third hospital admission (Table 1). In an analysis of VLCFA the hexacosanoate (C26:O) was most notably increased. We're planning to measure the plasma VLCFA levels of this patient's mother and his younger sister. Recently some reports (Rizzo et a/. 1986; Au- bourg and Diebler 1982) have demonstrated that dietary restriction of C26:O with oleic acid sup- Table 1. Very long chain fatty acids of sphingomyelin in erythrocyte memberanes C 2 4 : O  C 25:O C 26:O ---- --- Patlent 3.00 0.079 0.206 Control 2.45 0.060 0.100 (n=18) - +0.21 + 0.01 2 k 0.01 5 Values are expressed on the basis of C 22:O. Control values are expressed as mean _+ SD. plementation lowers plasma VLCFA levels, but its clinical implication needs further refinement. lgarashi M, Schaumburg HH, Powers J, Kishimoto Y, Kolondy E, Suzuki K: Fatty ac~d abnormality In adre- noleukodystrophy. J Neurochem. 1976, 26:851-860 lnoue Y, Fukuda T, Takashima AS, Onoyama Y, Kusuda S, Matsuoka 0,  Murata R: Adrenoleukody- strophy: New CT findings. AJNR. 1983, 4:951-954 Kim YH, Kim SK, Yang SW, Moon HR, Chi JG: A case of adrenoleukodystrophy. Seoul J Med. 1988, 29: 195-200 Kobayashi T, Katayama M, Suzuki S, Tomada H, Goto I, Kuroiwa Y: Adrenoleukodystrophy: detection of increased very long chain fatty acids by high- perf- ormance liquid chromatography. J Neurol. 1983, ACKNOWLEDGEMENT 2301209-215 Kumar AJ, Rosenbaum AE, Naidu S, Wener L, Citrin We are indebted to Takuro Koba~ashi M.D of CM, Lindenberg R, Kim WS, Zinreich SJ, Molliver the of NeuroJog~, Neurological Insti- ME, Mayberg HS, Maser HW: Adrenoleukodysfrophy: t u t e t  Of Medicine* K ~ u s h u  Correlating RI with CT, Radiology, 1987, Fukuoka, Japan, for analyses of VLCFAs that 165:497-504 appear ~n the table. 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Adrenoleukodystrophy 1례

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Adrenoleukodystrophy 1례

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