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Neurology India, Vol. 58, No. 1, January-February, 2010, pp. 109-111 Case Report Intra familial phenotypical variations in adrenoleukodystrophy Jayaprakash Gosalakkal, Anand Prasad Balky1 Department of Pediatric Neurology, University Hospitals of Leicester NHS Trust, 1 Clinical fellow in Pediatric Neurology, Leicester Royal Infirmary, Leicester, United Kingdom (UK) Correspondence Address: Dr. Anand Prasad, Flat 11, Room 4, Douglas court,Walnut street Leicester, United Kingdom, dranandprasad@gmail.com Date of Acceptance: 02-Nov-2009
Code Number: ni10023 DOI: 10.4103/0028-3886.60418 Abstract Adrenoleukodystrophy (ALD) is an X-linked recessively inherited peroxisomal disorder, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. It has a wide phenotypical variability ranging from symptomatic childhood cerebral form to the asymptomatic with biochemical defects only; sometimes within the same family. We report a family of three siblings diagnosed with ALD confirmed with the mutations in ABCD1 gene having phenotypical variability ranging from pure adrenal insufficiency to progressive neurodegeneration in the same family. The mother was identified as the carrier and maternal uncle was diagnosed with Adrenomyeloneuropathy. We discuss the variable presentation in our family and the possible causes of phenotypical variability.Keywords: Adrenoleukodystrophy, adrenomyeloneuropathy, phenotypical variations Introduction X-Linked Adrenoleukodystrophy (ALD) is an inherited, progressive neuro-metabolic disorder of peroxisomal metabolism leading to an accumulation of very long chain fatty acids (VLCFA) [1] with phenotypical variability in presentation. The incidence of ALD is 1 in 20,000 male births; [2] however, the incidence of phenotypical variations occurring in the same family is uncommon. We report a family of three brothers who have been affected with the different phenotypes of X-linked ALD and their maternal uncle with adrenomyeloneuropathy (AMN). The diagnosis was confirmed by biochemical, imaging and genetic testing. Materials and Methods This study was based on a family which presented to our inpatient service. The index case was initially identified based on magnetic resonance imaging (MRI) and assessment of adrenal function and very long chain fatty acid levels. The sibling and parents were subsequently tested for adrenoleukodystrophy and carrier state. The genetic analysis was carried out by our molecular genetics lab. The mutation was identified by multiple ligand probe amplification. The maternal uncles history was obtained from the mother and subsequently confirmed on case note and lab review. Case Report A boy presented to us at seven-years of age with a history of sudden loss of vision and unsteady walking. He had a past history of behavioral, hearing problems and progressive deterioration in school performance. His neurological examination was unremarkable. All routine laboratory investigations produced normal results. The magnetic resonance imaging (MRI) [Figure - 1] revealed bilateral extensive white matter changes involving the parieto-occipital region with symmetrical involvement of the cortico-spinal tracts suggestive of ALD. The VLCFAs were reported to be elevated [Table - 1]. A synacthen test confirmed cortisol insufficiency. There was a rapid regression of his clinical symptoms leading to poor auditory discrimination, dysarthria and seizures. He developed feeding difficulties requiring gastrostomy feeds and poor bowel and bladder control. The symptoms were consistent with the childhood cerebral fulminant form of ALD. The progressive and advanced nature of his condition precluded bone marrow transplantation. His elder sibling was 11-years old and had a history of poor vision. He had a vision of 6/12 in left eye and 6/9 in right eye with right lateral gaze nystagmus since birth. Except for cognitive delay, he had no other significant illnesses in the past and the rest of his neurological examination was normal. His VLCFA was found to be elevated. The magnetic resonance spectroscopy (MRS) and MRI were typical of ALD [Figure - 2]a and b. He underwent a synacthen test confirming adrenal insufficiency. His visual evoked potential (VEP) showed a significant delay suggesting demyelination. He had a high loes score [3] of 12 with a relatively normal MRS. A bone marrow transplant (BMT) was carried out. Presently he is on Lorenzo′s oil with hydrocortisone and the neuropsychological assessment shows increased processing problems, showing a slowly progressive adolescent form of ALD. The younger brother aged seven-years had ocular albinism and congenital nystagmus since four months of age. His development was normal.Neuropsychological assessment showed an average intellectual ability. Neurological examination was normal. His VLCFA and Phytanate levels were raised [Table - 1]. A Synacthen test confirmed primary adrenal insufficiency. MRI had shown a minimal increase in posterior white matter signal with a normal MRS. The diagnosis was confirmed by genetic analysis in all siblings. Presently he is on Lorenzo′s oil and hydrocortisone with six-monthly MRI and MRS imaging and yearly neuropsychological assessments being reported as normal showing ALD with Addison′s disease only. Mother of the children was tested and found to be a carrier for the same genetic mutation of the ABCD1 gene but had no clinical features. The maternal uncle was found to have the adult form of ALD, AMN. Discussion Adrenoleukodystrophy belongs to the group of peroxisomal disorders with impairment of the beta oxidation system. It is an X-linked disorder with its main clinical feature of adrenal cortical insufficiency and demyelination in the central nervous system. The first clinical cases were described in 1923 by Simmerling and Creutzfeldt. [4] The X-Linked mode of inheritance was suggested by Fanconi [5] and co-workers. The gene deficient in X-ALD is ABCD1. The clinical variants of ALD include the childhood cerebral (most common), adolescent, adult, ALD with Addison′s disease only, asymptomatic patients with biochemical defects only and the adult form of ALD-AMN. [6] Affected males are normal until four to eight years of age, when they manifest behavior problems and failure in school as a result of rapid regression of auditory discrimination, spatial orientation, speech, and writing. In rare instances seizures may be the initial manifestation. As the disease progresses, further signs of damage to the white matter include spastic quadriparesis, swallowing difficulty, and visual loss culminating in a vegetative state. [7] The adolescent cerebral form manifests signs and symptoms of cerebral involvement between 10 to 21 years of age. In the adult cerebral form of ALD, dementia, psychiatric disturbances, seizures and spastic paraparesis develop after age 21. [8] The various phenotypes have been recognized to occur within the same pedigree. [9] The cause of the phenotypic variability is unknown. It is not due to the nature of the mutation [10] or the severity of the defect in very-long-chain fatty oxidation. [11] A Chinese study of 89 patients concluded that the clinical phenotype had no definite relationship with the nature of gene mutation. A single mutation may result in different phenotypes, missense mutation being the most common. [12] Several theories had been suggested for the wide range of phenotypic variability within individuals in a single family carrying the mutant allele. A 2-locus epistatic (dominant, recessive) model had been proposed by Maestri [13] suggesting that under a dominant epistatic model, a single M allele at an autosomal modifier locus decreases the severe effects of the disease leading to milder AMN phenotype, only males with genotype mm would have ALD. Under a recessive epistatic model, two copies of M alleles are necessary to have the milder AMN phenotype. The recurrence risk for a second affected male depends on the frequency of the protective allele at the modifier locus. A possible cause of phenotypic diversity could be a consequence of the interaction of ALDP with other proteins as speculated by Valle and Gartner. [14] A close relative of ALDP, ALDRP, has recently been identified and has been proposed as a phenotypic modifier.[15] Non genetic factors are also responsible in determining the phenotypic variation as described in monozygotic twins, having phenotypic heterogeneity. [16] Accurate information about the relative frequency of the various forms of ALD is needed for counselling and for the selection and evaluation of therapeutic approaches. It is unclear currently what phenotype a male fetus or asymptomatic child with the genetic abnormality of ALD will develop. Therapies range from using Lorenzo′s oil to bone marrow transplantation. Risk-benefit analysis of bone marrow transplantation requires knowledge of the phenotype frequencies. References
Copyright 2010 - Neurology India The following images related to this document are available:Photo images[ni10023f2.jpg] [ni10023t1.jpg] [ni10023f1.jpg] |
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