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Symptomatic female heterozygotes for adrenoleukodystrophy: A report of two unrelated cases and review of the literature
Symptomatic female heterozygotes for adrenoleukodystrophy: a report of t w o unrelated cases and review of the literature
Terence J. O ' B r i e n MBBS P e t e r G. G a t e s MBBS FRACP E d w a r d Byrne DSc MD FRACP Department of ClinicalNeurosciences,St Vincent's Hospital,Victoria,Australia
We report two cases of unrelated female heterozygotes for adrenoleukodystrophy (AI,D) who have developed progressive neurological disease. Both presented with a progressive myelopathy in midlife and one has since also developed a peripheral neuropathy. Both women had elevated very long chain fatty acid (VLCFA) levels. One patient has been on Lorenzo's oil for 2 years with normalisatlon of her plasma VLCFA assays but her condition has progressed relentlessly and the second discontinued Lorenzo's oil after I month due to unacceptable weight loss. Review of the literature reveals that significant neurological symptoms develop in 15-20% of female heterozygotes and that abnormalities on neurological examination occur in up to 55%. Despite a not excessively rare estimated gene frequency of 1/20,000 the diagnosis of a symptomatic heterozygote for AI,D is rarely made in the absence of an affected male relative with most patients misdiagnosed as suffering from multiple sclerosis. Journal of Clinical Neuroscience 1996, 3 (2): 166-170
© Pearson Professional 1996
Keywords: Adrenoleukodystrophy, Myelopathy, X-linked recessive, Genetic
Introduction The most c o m m o n form of adrenoleukodystrophy (ALD) is a genetic X-linked recessive disorder characterised by an accumulation of saturated very long chain fatty acids (VLCFA) with progressive central demyelination and adrenal failure. 1 The exact prevalence of the gene is uncertain but probably occurs at an incidence of about 1 in 20,0002 and has been mapped to the Xq28 band linked to the gene for red-green colour vision pigments? The disorder results from an impairment in the perioxisomal ]3-oxidation of saturated very long chain fatty acids (VLCFAs).2 Much circumstantial evidence has suggested that the primary abnormality is defective function of the perioxisomal enzyme lignoceroyl-CoA synthetase (also known as VLCFA-CoA synthetase) but definite proof of this has been elusive? Recently, deletions have been found in 6 out of 85 patients with ALD in a gene in the Xq28 band. 4 This gene codes for a protein belonging to the ATP-binding cassette (ABC) superfamily of transporters (the cystic fibrosis transmembrane conductance regulator protein and the multi-drug-resistance protein are other examples) suggesting the primary deficit may be the impaired perioxisomal membrane transport of VLCFA-CoA synthetase. 5 This, however, does not explain the wide phenotypic variation seen even within families and segregation analysis suggests the existence of an autosomal modifier locus. 6
166
Neurological disease is believed to develop at some stage in almost all males with tile ALD gene, however female heterozygotes may also develop symptoms. We report two unrelated heterozygote cases, which are to our knowledge the first reported from Australasia, and review the literature relating to the incidence, clinical features and diagnosis of symptomatic 'carriers' of ALD as well as current trials of treatment and prevention.
Clinical records Case A A 53-year-old woman began at age 34 to trip while running. By 1977 she found that her legs felt stiff, heavy and difficult to lift. By 1988 she required a stick to walk and suffered with troublesome leg stiffness. She has one living sister who is asymptomatic. Two brothers died at aged 11 and 17 years after two year illnesses involving progressively impaired cerebral function with associated deafness and blindness. Twin brothers died neonatally. Her mother and father died at age 83 and 61, respectively, of unrelated causes and had no relevant symptoms (Fig. 1). On examination she had a moderate spastic paraparesis with brisk reflexes in the legs, extensor plantar responses and absent abdominal reflexes. There was a
J. Clin. Neuroscience Volume 3 Number 2 April 1996
Female adrenoleukodystrophy
Case reports
®
•
o.oll
0.049
Case A
11
I
Proven/Presumed Homozygote
O
Proven Heterozygote
[~
G
X
Unaffected AsymptomaticNot Tested Deceased
O
41
0.082 0.300
Case B
~t0.076 r0.491
1o.128 0.489
Fig. 1 Family studies of two symptomatic heterozygotes for adrenomyeloneuropathy. *Superscript figures denote the plasma C26:C22 ratios (normal < 0.035) and subscript figures denote the fibroblast C26"C22 ratios (normal < 0.150),
mild decrease in proprioception and vibration in her feet and Romberg's test was positive. Otherwise neurological and general examination was within normal limits. Cervico-thoracic myelography, MRI of spinal cord, nerve conduction studies, visual evoked potentials and CSF examination were normal. A diagnosis o f symptomatic carrier o f ALD was confirmed by finding elevated VLCFA ratios in plasma and cultured skin fibroblasts (Table 1). H e r sister's plasma VLCFA levels were n o r m a l (Fig. 1). She was c o m m e n c e d on a diet low in saturated VLCFAs and, since September 1991, this has been supp l e m e n t e d with a mixture o f glycerol trioleate (C18:1) and glycerol trierucate (C22:1) oils ('Lorenzo's oil') with normalisation of plasma VLCFA assays. However, her condition has continued to deteriorate so that she now requires the aid of two sticks and leg splints to mobilise. Nerve conduction studies now show mild slowing in velocity consistent with a mild demyelinating neuropathy. Moderate thrombocytopaenia has required temporary cessation o f the oil.
Table 1 Plasma and skin fibroblast saturated VLCFA assaysfrom two unrelated symptomatic female heterozygotes for ALD
C26:C22 ratio Plasma (n < 0.035*) Fibroblast (n < 0.150") C24:C22 ratio Plasma (n < 0.150")
Case A
Case B
0.049 1.306
0.063 0.510 1.361
* Normal rangeswere supplied by the Department of Chemical Pathology, Adelaide Children's Hospital
Table 2 Clinical features in symptomatic female heterozygotes (from10,TM) Clinical features
Gait disturbance Distal sensory impairment (esp. vib.) Hyperreflexia in legs Dementia Fluctuating neurological features Adrenal insufficiency Abnormal BERS Abnormal NCS Brain MRI abnormalities
Proportion of patients
85% 88% 77% 9% 4% 1% 35% 22% 16%
Case B A 44-year-old woman presented in J a n u a r y 1993 with 3-4 months o f severe spasms in her legs and mild difficulty with walking. T h e r e were no sensory or sphincter disturbances or other neurological symptoms. A brother died at the age 41 years with confirmed a d r e n o m y e l o n e u r o p a t h y (AMN) following a 16 year
illness with progressive myelopathy and adrenal dysfunction. 9 T h e rest of the family also had VLCFA assays perf o r m e d on plasma and skin fibroblasts with our patient, her two daughters and two sisters all having elevated levels. H e r mother's plasma assay was borderline but fibroblast assay was in the heterozygote range. All other
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Case reports members o f the family have remained asymptomadc (Fig. 1). O n examination her gait was mildly unsteady and stiff legged. She was red-green colour blind (as was her brother). Hip flexion was bilaterally mildly weak but power elsewhere was normal. Tone was increased in the legs with a few beats of ankle clonus, relatively brisk reflexes and extensor planters. Motor examination in the u p p e r limbs was normal. Sensory testing revealed impaired pain and temperature sensation in the lower limbs, but was otherwise normal. MRI of her thoracic cord, nerve conduction studies and evoked potentials were all normal. Treatment was c o m m e n c e d with dietary restriction o f saturated VLCFAs and 'Lorenzo's oil' but this was aband o n e d after I m o n t h due to an unacceptable weight loss o f 5 kg.
Discussion VLCFAs accumulate as cholesterol esters and form lamellar cytoplasmic inclusions in cells of the adrenal cortex, testes, central nervous system (CNS) white matter, and peripheral nervous system. 7 These cells b e c o m e progressively swollen and eventually atrophy and die. 2 T h e mechanism of tissue damage has not b e e n clearly established and there is not a clear relationship between VLCFA levels and clinical expression. 1 In areas o f active myelin destruction in the brain of ALD sufferers, there is a marked perivascular m o n o n u c l e a r cell infiltration leading to the suggestion that there may be an a u t o i m m u n e c o m p o n e n t in the pathogenesis of the cerebral form. 1,7 T h e r e is a large increase in a m o u n t o f VLCFAs in phosphatidylcholine even in morphologically unaffected brain and this could act as an antigen for the i m m u n e attack. 8 However, there is very little or no inflammatory infiltrate f o u n d in other affected organs or in the myeloneuropathic forms o f the disease3 The phenotype of X-linked ALD varies widely even within the same k i n d r e d ) Five major clinical subtypes are described in males with the ALD gene. 1° T h e most comm o n (affecting 48% o f patients) is childhood cerebral ALD which affects boys less than 11 years of age. 1°'11 A d r e n o m y e l o n e u r o p a t h y (AMN) is the next most comm o n f o r m (26%) and presents in m e n over 21 years, l°'u O t h e r rarer phenotypes are: adolescent cerebral (5%) which occurs between 11-21 years, Addison's disease without neurological involvement (11%) and adult cerebral (3%).10 T h e proportion o f males with the biochemical defect who remain free o f the disease is still unclear? Neurological disability in female heterozygotes for the ALD gene was previously t h o u g h t to be relatively u n c o m m o n ) However, the Kennedy Institute has now collected data on m o r e that 1100 heterozygotes and f o u n d that 15-20% develop symptomatic spastic paraparesis. 6 In addition, neurological examinations perf o r m e d on a sample o f nearly 100 of these women f o u n d that 55% had at least mild neurological abnormalities (Moser H., personal communication). As with our cases, affected women usually first develop symptoms between
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Female adrenoleukodystrophy 30-50 years (mean 43 _+ 11 years). 1 T h e manifestations resemble AMN but are milder, o f later onset, progress more slowly and adrenal dysfunction is extremely rare32 Stiffness and clumsiness in the legs are usually the first symptoms (85%). T h e most c o m m o n clinical signs are hyperreflexia (,77%), spastic paraparesis (66%) and impaired vibration sense(88%). TM Neuropathy, which has developed in our first patient, occurs in a minority and sphincter, disturbance often develops later in the course. 1 O t h e r clinical features are u n c o m m o n : cerebral involvem e n t (9%); fluctuating neurological symptoms (4%); and adrenal dysfunction (1%). l° T h e diagnosis is rarely made in women without an affected male relative l° and many are misdiagnosed as suffering from multiple sclerosis (MS) until they have a son who develops ALD. 1 Confirmation that a patient is a carrier of the ALD gene is made on assays by high p e r f o r m a n c e gas liquid chromatography of VLCFA levels and ratios in plasma, and if necessary cultured skin fibroblasts. 1,13Analysis of plasma allows identification of 88% o f obligate heterozygotes, and with the inclusion of the fibroblast assay this increases to 93%. False positives do not appear to occur even in other diseases of the white matter. TM In patients from appropriate families, linkage analysis with the DNA p r o b e DXS52, which is strongly linked to the ALD gene (LOD score 13.77), can provide further diagnostic accuracy) Evoked responses (especially BElLs and SSERs) are abnormal in 35% o f symptomatic women. TM Oligoclonal bands may be present in the CSF, further increasing the confusion with MS. 1 Nerve conduction studies reveal slow conduction velocities in a minority o f patients. 15 CT or MRI show characteristic changes in the majority of males with ALD 16 and about 50% with AMN 1° and can detect abnormalities in a minority of presymptomatic ALD and AMN patients. 16a7MRI of the brain has been reported to show white matter lesions in 16% of symptomatic females. 1° These may occur in the internal capsule, cerebral peduncle and optic radiation. 18Also, a recent report has suggested decreased spinal diameter as a marker for the development of symptoms in heterozygotes. 1° At present there is no proven successful prevention or treatment for any of the phenotypes o f ALD but a number of approaches have u n d e r g o n e active investigation. Dietary restriction of saturated VLCFA proved ineffective because a significant p r o p o r t i o n of VLCFA are p r o d u c e d by e n d o g e n o u s synthesis) T h e addition of mono-unsaturated oils decreases the rate o f synthesis o f saturated VLCFA probably by competition for the microsomal elongation system. 2° Glycerol trioleate oil (C18:1) was successful in reducing plasma VLCFA assays by about 50% over several m o n t h s 21 but, despite an initial suggestion of improved peripheral nerve function, it failed to significandy affect the clinical course of the disease. 2 T h e addition of glycerol trierucate (C22:1) to the glycerol trioleate ('Lorenzo's Oil') is remarkably successful in reducing plasma saturated VLCFAs to normal within 4 weeks. 22 A 5 year therapeutic trial co-ordinated at the Kennedy Krieger Institute is now in its fourth year and has involved over 250 patients (Moser HW., personal
J. Clin. Neuroscience Volume 3 Number 2 April 1996
Female adrenoleukodystrophy
Case reports
communication), the results so far indicate that it does not significantly affect the course of established childh o o d ALD 6 and probably not AMN in adultsY ,24 although there was some i m p r o v e m e n t in peripheral nerve function and red cell m e m b r a n e viscosity.21 A recently published smaller trial from Europe also concluded that 'Lorenzo's oil' was ineffective in AMN patients although the 5 symptomatic heterozygotes on the trial remained stable clinically and radiologically over approximately 2 years' follow up. 25 T h e efficacy of the oil in preventing the development of symptoms in asymptomatic patients with the biochemical deficit is still unanswered but, of 86 boys on the trial, 11 have developed ALD including one who began treatm e n t at 2 years of age and had maintained normal plasma VLCFA levels (Moser HW., personal communication). Bone marrow transplants have been unsuccessful in patients with advanced ALD and may aggravate the neurological deficit. 2s However, more recently, this was tried in a boy with early clinical features of cerebral ALD and resulted in normalisation of plasma VLCFAs and reversal of the mild clinical and MRI abnormalities at 2 years. 29 Bone marrow transplantation has now been p e r f o r m e d on a n u m b e r of other boys with early ALD and the preliminary results have been very encouraging. 6 However, this approach is not an option for the m o r e benign phenotypes in view of its associated morbidity and so other successful treatments are desperately required. Results o f trials o f immunosuppression, plasma exchange, gamma globulin and the administration of gangliosides, clofibrate and carnitine have all been disappointing. 6
Conclusion Neurological symptoms develop in 15-20% of female heterozygotes for the ALD gene. T h e diagnosis is frequently missed as adrenal dysfunction is extremely rare in affected women. T h e diagnosis should be considered in any women with an unexplained progressive paraparesis in midlife especially with a compatible family history. Female relatives of patients with ALD/AMN should have VLCFA assays p e r f o r m e d to identify those at risk and for genetic counselling. T h e r e is currently no proven prevention or treatment for any of the ALD phenotypes.
Acknowledgements We gratefully appreciate the contribution of Dr E.E Robertson and the D e p a r t m e n t of Chemical Pathology, Adelaide Children's Hospital for p e r f o r m i n g the VLCFA assays and for suppling the normal ranges for these results. Received8 May 1994 Accepted for publication 4 July 1994
Correspondence and offprint requests: Dr Peter G. Gates Department of Clinical Neurosciences St Vincent's Hospital Victoria Parade, Fitzroy Victoria 3065 Australia
References 1. Moser HW, Moser AB. Adrenoleukodystrophy (X-linked). In: Scriver CR, Beaudet AL, Sly WS et al (eds): The Metabolic Basis of Inherited Disease, 6th edn, chap 58. New York: McGraw-Hill, 1989: pp 1511-1532. 2. Moser WM, Bergin A, Naidu S, Ladenson P. Adrenoleukodystrophy. Endocrinol Metab Clin North Am 1991; 20: 29%318. 3. Wanders RJA, Van Roermund CWT, Lageweg Wet al. X-linked adrenoleukodystrophy: biochemical diagnosis and enzyme defect.J Inher Metab Dis 1992; 15: 634-644. 4. MosserJ, Douar A, Sarde C et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABe transporters. Nature 1993; 361: 726-730. 5. Valle D, GarmerJ. Penetrating the perioxisome. Nature 1993; 361: 682-683. 6. Moser HW, Moser AB, Smith KD et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy.J Inher Metab Dis 1992; 15: 645-664. 7. PowersJM. Adrenoleukodystrophy (adreno-testiculoleuko-myelo-neuropathic complex). Clin Neuropathol 1985; 4: 181-199. 8. Theda C, Moser A, PowersJM, Moser HW. Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination. J Neurol Sci 1992; 110: 195-204. 9. Berkovic SF, ZajacJD, Warburton DJ et al. Adrenoleukodystrophy - clinical and biochemical diagnosis. Aust N ZJ Med 1983; 13: 594-600. 10. Moser HW, Moser AB, Naidu S, Bergin A. Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy. Dev Neurosci 1991; 13: 254-261. 11. Moser HW, Moser AE, Singh I, O'Niell BE Adrenoleukodystrophy: survey of 303 cases. Biochemistry, diagnosis, and therapy. Ann Neurol 1984; 16: 628-641. 12. Moser HW, Naidu S, Kumar AJ, Rosenbaum AE. The adrenoleukodystrophies. CRC Crit Rev Neurobiol 1987; 3: 29-88. 13. Auborg P, Bougneres PF, Rocchiccioli E Capillary gas-liquid chromatographic-mass spectrometric measurement of very long chain (C22to C26) fatty acids in microliter samples of plasma. J Lipid Res 1985; 26: 263-267. 14. Moser HW, Moser AB, TrojakJE, Supplee SW. Baltimore AB. Identification of female carriers of adrenoleukodystrophy.J Pediatr 1983; 103: 54-59. 15. O'Neill BP, Moser HW, Saxena KM, Marmion LC. Adrenoleukodystrophy: clinical and biochemical manifestations in carriers. Neurology 1984; 34: 798-801. 16. Aubourg P, Adamsbaum C, Lavallard-Roussean MC et al. Brain MRI and electrophysiological abnormalities in preclinical and clinical adrenomyeloneuropathy. Neurology 1992; 42: 85-91. 17. Aubourg P, Sellier N, ChaussainJL, Kalifa G. MRI detects cerebral involvement in neurologically asymptomatic patients with adrenoleukodystrophy. Neurology 1989; 39: 1619-1622. 18. Uchiyama M, Hata Y, Tada S. MR imaging of adrenoleukodystrophy. Neuroradiology 199"1;33: 25-29. 19. Snyder RD, KingJN, Keck GM, Orrison WW. MR imaging of the spinal cord in 23 subjects with ALD-AMN complex. AJNR 1991; 12: 1095-1098. 20. Rizzo WB, Phillips MW, Dammann AL et al. Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels. Ann Neurol 1987; 21: 232-239. 21. Moser AB, BorelJ, Odone A et al. New dietary therapy for adrenoleukodystrophy. Biochemical and clinical results in 36 patients. Ann Neurol 1987; 21: 240. 22. Rizzo WB, Leshner RT, Odone BA et al. Dietary erucic acid therapy for x-linked adrenoleukodystrophy. Neurology 1989; 39: 1415-1422.
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Case reports 23. Moser HW. Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope. Ann Neurol 1993; 34: 121-122. 24. Kaplan PW, Tusa RJ, ShankroffJ et al. Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol thralled and lorenzo oil. Ann Neurol 1993; 34:169-174. 25. Aubourg P, Adamsbaum C, Lavallard-Rousseau M et al. A two year trial of oleic and erucic acids ('Lorenzo's oil') as treatment for adrenomyeloneuropathy. N Engl J Med 1993; 329: 745-752. 26. Rizzo WB. Lorenzo's oil - hope and disappointment. N EnglJ Med 1993; 329: 801-802.
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Female adrenoleukodystrophy 27. Zinkham WH, Kickler T, BorelJ, Moser HW. Lorenzo's oil and thrombocytopenia in patients with adrenoleukodystrophy. N EnglJ Med 1992; 328: 1126-1127. 28. Moser HW, Tatschka PJ, Brown FRet al. Bone marrow transplant in adrenoleukodystrophy. Neurology 1984; 34: 1410-1417. 29. Auburg P, Blanche S,Jambaque I et al. Reversal of early neurologic and neuroradiological manifestations of x-linked adrenoleukodystrophy by bone marrow transplantation. N EnglJ Med 1990; 322: 1860-1866.
J. Clin. Neuroscience Volume 3 Number 2 April 1996
Terence J. O ' B r i e n MBBS P e t e r G. G a t e s MBBS FRACP E d w a r d Byrne DSc MD FRACP Department of ClinicalNeurosciences,St Vincent's Hospital,Victoria,Australia
We report two cases of unrelated female heterozygotes for adrenoleukodystrophy (AI,D) who have developed progressive neurological disease. Both presented with a progressive myelopathy in midlife and one has since also developed a peripheral neuropathy. Both women had elevated very long chain fatty acid (VLCFA) levels. One patient has been on Lorenzo's oil for 2 years with normalisatlon of her plasma VLCFA assays but her condition has progressed relentlessly and the second discontinued Lorenzo's oil after I month due to unacceptable weight loss. Review of the literature reveals that significant neurological symptoms develop in 15-20% of female heterozygotes and that abnormalities on neurological examination occur in up to 55%. Despite a not excessively rare estimated gene frequency of 1/20,000 the diagnosis of a symptomatic heterozygote for AI,D is rarely made in the absence of an affected male relative with most patients misdiagnosed as suffering from multiple sclerosis. Journal of Clinical Neuroscience 1996, 3 (2): 166-170
© Pearson Professional 1996
Keywords: Adrenoleukodystrophy, Myelopathy, X-linked recessive, Genetic
Introduction The most c o m m o n form of adrenoleukodystrophy (ALD) is a genetic X-linked recessive disorder characterised by an accumulation of saturated very long chain fatty acids (VLCFA) with progressive central demyelination and adrenal failure. 1 The exact prevalence of the gene is uncertain but probably occurs at an incidence of about 1 in 20,0002 and has been mapped to the Xq28 band linked to the gene for red-green colour vision pigments? The disorder results from an impairment in the perioxisomal ]3-oxidation of saturated very long chain fatty acids (VLCFAs).2 Much circumstantial evidence has suggested that the primary abnormality is defective function of the perioxisomal enzyme lignoceroyl-CoA synthetase (also known as VLCFA-CoA synthetase) but definite proof of this has been elusive? Recently, deletions have been found in 6 out of 85 patients with ALD in a gene in the Xq28 band. 4 This gene codes for a protein belonging to the ATP-binding cassette (ABC) superfamily of transporters (the cystic fibrosis transmembrane conductance regulator protein and the multi-drug-resistance protein are other examples) suggesting the primary deficit may be the impaired perioxisomal membrane transport of VLCFA-CoA synthetase. 5 This, however, does not explain the wide phenotypic variation seen even within families and segregation analysis suggests the existence of an autosomal modifier locus. 6
166
Neurological disease is believed to develop at some stage in almost all males with tile ALD gene, however female heterozygotes may also develop symptoms. We report two unrelated heterozygote cases, which are to our knowledge the first reported from Australasia, and review the literature relating to the incidence, clinical features and diagnosis of symptomatic 'carriers' of ALD as well as current trials of treatment and prevention.
Clinical records Case A A 53-year-old woman began at age 34 to trip while running. By 1977 she found that her legs felt stiff, heavy and difficult to lift. By 1988 she required a stick to walk and suffered with troublesome leg stiffness. She has one living sister who is asymptomatic. Two brothers died at aged 11 and 17 years after two year illnesses involving progressively impaired cerebral function with associated deafness and blindness. Twin brothers died neonatally. Her mother and father died at age 83 and 61, respectively, of unrelated causes and had no relevant symptoms (Fig. 1). On examination she had a moderate spastic paraparesis with brisk reflexes in the legs, extensor plantar responses and absent abdominal reflexes. There was a
J. Clin. Neuroscience Volume 3 Number 2 April 1996
Female adrenoleukodystrophy
Case reports
®
•
o.oll
0.049
Case A
11
I
Proven/Presumed Homozygote
O
Proven Heterozygote
[~
G
X
Unaffected AsymptomaticNot Tested Deceased
O
41
0.082 0.300
Case B
~t0.076 r0.491
1o.128 0.489
Fig. 1 Family studies of two symptomatic heterozygotes for adrenomyeloneuropathy. *Superscript figures denote the plasma C26:C22 ratios (normal < 0.035) and subscript figures denote the fibroblast C26"C22 ratios (normal < 0.150),
mild decrease in proprioception and vibration in her feet and Romberg's test was positive. Otherwise neurological and general examination was within normal limits. Cervico-thoracic myelography, MRI of spinal cord, nerve conduction studies, visual evoked potentials and CSF examination were normal. A diagnosis o f symptomatic carrier o f ALD was confirmed by finding elevated VLCFA ratios in plasma and cultured skin fibroblasts (Table 1). H e r sister's plasma VLCFA levels were n o r m a l (Fig. 1). She was c o m m e n c e d on a diet low in saturated VLCFAs and, since September 1991, this has been supp l e m e n t e d with a mixture o f glycerol trioleate (C18:1) and glycerol trierucate (C22:1) oils ('Lorenzo's oil') with normalisation of plasma VLCFA assays. However, her condition has continued to deteriorate so that she now requires the aid of two sticks and leg splints to mobilise. Nerve conduction studies now show mild slowing in velocity consistent with a mild demyelinating neuropathy. Moderate thrombocytopaenia has required temporary cessation o f the oil.
Table 1 Plasma and skin fibroblast saturated VLCFA assaysfrom two unrelated symptomatic female heterozygotes for ALD
C26:C22 ratio Plasma (n < 0.035*) Fibroblast (n < 0.150") C24:C22 ratio Plasma (n < 0.150")
Case A
Case B
0.049 1.306
0.063 0.510 1.361
* Normal rangeswere supplied by the Department of Chemical Pathology, Adelaide Children's Hospital
Table 2 Clinical features in symptomatic female heterozygotes (from10,TM) Clinical features
Gait disturbance Distal sensory impairment (esp. vib.) Hyperreflexia in legs Dementia Fluctuating neurological features Adrenal insufficiency Abnormal BERS Abnormal NCS Brain MRI abnormalities
Proportion of patients
85% 88% 77% 9% 4% 1% 35% 22% 16%
Case B A 44-year-old woman presented in J a n u a r y 1993 with 3-4 months o f severe spasms in her legs and mild difficulty with walking. T h e r e were no sensory or sphincter disturbances or other neurological symptoms. A brother died at the age 41 years with confirmed a d r e n o m y e l o n e u r o p a t h y (AMN) following a 16 year
illness with progressive myelopathy and adrenal dysfunction. 9 T h e rest of the family also had VLCFA assays perf o r m e d on plasma and skin fibroblasts with our patient, her two daughters and two sisters all having elevated levels. H e r mother's plasma assay was borderline but fibroblast assay was in the heterozygote range. All other
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167
Case reports members o f the family have remained asymptomadc (Fig. 1). O n examination her gait was mildly unsteady and stiff legged. She was red-green colour blind (as was her brother). Hip flexion was bilaterally mildly weak but power elsewhere was normal. Tone was increased in the legs with a few beats of ankle clonus, relatively brisk reflexes and extensor planters. Motor examination in the u p p e r limbs was normal. Sensory testing revealed impaired pain and temperature sensation in the lower limbs, but was otherwise normal. MRI of her thoracic cord, nerve conduction studies and evoked potentials were all normal. Treatment was c o m m e n c e d with dietary restriction o f saturated VLCFAs and 'Lorenzo's oil' but this was aband o n e d after I m o n t h due to an unacceptable weight loss o f 5 kg.
Discussion VLCFAs accumulate as cholesterol esters and form lamellar cytoplasmic inclusions in cells of the adrenal cortex, testes, central nervous system (CNS) white matter, and peripheral nervous system. 7 These cells b e c o m e progressively swollen and eventually atrophy and die. 2 T h e mechanism of tissue damage has not b e e n clearly established and there is not a clear relationship between VLCFA levels and clinical expression. 1 In areas o f active myelin destruction in the brain of ALD sufferers, there is a marked perivascular m o n o n u c l e a r cell infiltration leading to the suggestion that there may be an a u t o i m m u n e c o m p o n e n t in the pathogenesis of the cerebral form. 1,7 T h e r e is a large increase in a m o u n t o f VLCFAs in phosphatidylcholine even in morphologically unaffected brain and this could act as an antigen for the i m m u n e attack. 8 However, there is very little or no inflammatory infiltrate f o u n d in other affected organs or in the myeloneuropathic forms o f the disease3 The phenotype of X-linked ALD varies widely even within the same k i n d r e d ) Five major clinical subtypes are described in males with the ALD gene. 1° T h e most comm o n (affecting 48% o f patients) is childhood cerebral ALD which affects boys less than 11 years of age. 1°'11 A d r e n o m y e l o n e u r o p a t h y (AMN) is the next most comm o n f o r m (26%) and presents in m e n over 21 years, l°'u O t h e r rarer phenotypes are: adolescent cerebral (5%) which occurs between 11-21 years, Addison's disease without neurological involvement (11%) and adult cerebral (3%).10 T h e proportion o f males with the biochemical defect who remain free o f the disease is still unclear? Neurological disability in female heterozygotes for the ALD gene was previously t h o u g h t to be relatively u n c o m m o n ) However, the Kennedy Institute has now collected data on m o r e that 1100 heterozygotes and f o u n d that 15-20% develop symptomatic spastic paraparesis. 6 In addition, neurological examinations perf o r m e d on a sample o f nearly 100 of these women f o u n d that 55% had at least mild neurological abnormalities (Moser H., personal communication). As with our cases, affected women usually first develop symptoms between
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Female adrenoleukodystrophy 30-50 years (mean 43 _+ 11 years). 1 T h e manifestations resemble AMN but are milder, o f later onset, progress more slowly and adrenal dysfunction is extremely rare32 Stiffness and clumsiness in the legs are usually the first symptoms (85%). T h e most c o m m o n clinical signs are hyperreflexia (,77%), spastic paraparesis (66%) and impaired vibration sense(88%). TM Neuropathy, which has developed in our first patient, occurs in a minority and sphincter, disturbance often develops later in the course. 1 O t h e r clinical features are u n c o m m o n : cerebral involvem e n t (9%); fluctuating neurological symptoms (4%); and adrenal dysfunction (1%). l° T h e diagnosis is rarely made in women without an affected male relative l° and many are misdiagnosed as suffering from multiple sclerosis (MS) until they have a son who develops ALD. 1 Confirmation that a patient is a carrier of the ALD gene is made on assays by high p e r f o r m a n c e gas liquid chromatography of VLCFA levels and ratios in plasma, and if necessary cultured skin fibroblasts. 1,13Analysis of plasma allows identification of 88% o f obligate heterozygotes, and with the inclusion of the fibroblast assay this increases to 93%. False positives do not appear to occur even in other diseases of the white matter. TM In patients from appropriate families, linkage analysis with the DNA p r o b e DXS52, which is strongly linked to the ALD gene (LOD score 13.77), can provide further diagnostic accuracy) Evoked responses (especially BElLs and SSERs) are abnormal in 35% o f symptomatic women. TM Oligoclonal bands may be present in the CSF, further increasing the confusion with MS. 1 Nerve conduction studies reveal slow conduction velocities in a minority o f patients. 15 CT or MRI show characteristic changes in the majority of males with ALD 16 and about 50% with AMN 1° and can detect abnormalities in a minority of presymptomatic ALD and AMN patients. 16a7MRI of the brain has been reported to show white matter lesions in 16% of symptomatic females. 1° These may occur in the internal capsule, cerebral peduncle and optic radiation. 18Also, a recent report has suggested decreased spinal diameter as a marker for the development of symptoms in heterozygotes. 1° At present there is no proven successful prevention or treatment for any of the phenotypes o f ALD but a number of approaches have u n d e r g o n e active investigation. Dietary restriction of saturated VLCFA proved ineffective because a significant p r o p o r t i o n of VLCFA are p r o d u c e d by e n d o g e n o u s synthesis) T h e addition of mono-unsaturated oils decreases the rate o f synthesis o f saturated VLCFA probably by competition for the microsomal elongation system. 2° Glycerol trioleate oil (C18:1) was successful in reducing plasma VLCFA assays by about 50% over several m o n t h s 21 but, despite an initial suggestion of improved peripheral nerve function, it failed to significandy affect the clinical course of the disease. 2 T h e addition of glycerol trierucate (C22:1) to the glycerol trioleate ('Lorenzo's Oil') is remarkably successful in reducing plasma saturated VLCFAs to normal within 4 weeks. 22 A 5 year therapeutic trial co-ordinated at the Kennedy Krieger Institute is now in its fourth year and has involved over 250 patients (Moser HW., personal
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Case reports
communication), the results so far indicate that it does not significantly affect the course of established childh o o d ALD 6 and probably not AMN in adultsY ,24 although there was some i m p r o v e m e n t in peripheral nerve function and red cell m e m b r a n e viscosity.21 A recently published smaller trial from Europe also concluded that 'Lorenzo's oil' was ineffective in AMN patients although the 5 symptomatic heterozygotes on the trial remained stable clinically and radiologically over approximately 2 years' follow up. 25 T h e efficacy of the oil in preventing the development of symptoms in asymptomatic patients with the biochemical deficit is still unanswered but, of 86 boys on the trial, 11 have developed ALD including one who began treatm e n t at 2 years of age and had maintained normal plasma VLCFA levels (Moser HW., personal communication). Bone marrow transplants have been unsuccessful in patients with advanced ALD and may aggravate the neurological deficit. 2s However, more recently, this was tried in a boy with early clinical features of cerebral ALD and resulted in normalisation of plasma VLCFAs and reversal of the mild clinical and MRI abnormalities at 2 years. 29 Bone marrow transplantation has now been p e r f o r m e d on a n u m b e r of other boys with early ALD and the preliminary results have been very encouraging. 6 However, this approach is not an option for the m o r e benign phenotypes in view of its associated morbidity and so other successful treatments are desperately required. Results o f trials o f immunosuppression, plasma exchange, gamma globulin and the administration of gangliosides, clofibrate and carnitine have all been disappointing. 6
Conclusion Neurological symptoms develop in 15-20% of female heterozygotes for the ALD gene. T h e diagnosis is frequently missed as adrenal dysfunction is extremely rare in affected women. T h e diagnosis should be considered in any women with an unexplained progressive paraparesis in midlife especially with a compatible family history. Female relatives of patients with ALD/AMN should have VLCFA assays p e r f o r m e d to identify those at risk and for genetic counselling. T h e r e is currently no proven prevention or treatment for any of the ALD phenotypes.
Acknowledgements We gratefully appreciate the contribution of Dr E.E Robertson and the D e p a r t m e n t of Chemical Pathology, Adelaide Children's Hospital for p e r f o r m i n g the VLCFA assays and for suppling the normal ranges for these results. Received8 May 1994 Accepted for publication 4 July 1994
Correspondence and offprint requests: Dr Peter G. Gates Department of Clinical Neurosciences St Vincent's Hospital Victoria Parade, Fitzroy Victoria 3065 Australia
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Case reports 23. Moser HW. Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope. Ann Neurol 1993; 34: 121-122. 24. Kaplan PW, Tusa RJ, ShankroffJ et al. Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol thralled and lorenzo oil. Ann Neurol 1993; 34:169-174. 25. Aubourg P, Adamsbaum C, Lavallard-Rousseau M et al. A two year trial of oleic and erucic acids ('Lorenzo's oil') as treatment for adrenomyeloneuropathy. N Engl J Med 1993; 329: 745-752. 26. Rizzo WB. Lorenzo's oil - hope and disappointment. N EnglJ Med 1993; 329: 801-802.
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Female adrenoleukodystrophy 27. Zinkham WH, Kickler T, BorelJ, Moser HW. Lorenzo's oil and thrombocytopenia in patients with adrenoleukodystrophy. N EnglJ Med 1992; 328: 1126-1127. 28. Moser HW, Tatschka PJ, Brown FRet al. Bone marrow transplant in adrenoleukodystrophy. Neurology 1984; 34: 1410-1417. 29. Auburg P, Blanche S,Jambaque I et al. Reversal of early neurologic and neuroradiological manifestations of x-linked adrenoleukodystrophy by bone marrow transplantation. N EnglJ Med 1990; 322: 1860-1866.
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