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273 Prognosis of patients with X-linked adrenoleukodystrophy (X-ALD) who have not received bone marrow transplants
A99
Abstracts Results: The presented patient was considered until the age of 5 years to have a mild clinical course and morphology, particularly showing little tendency to form cysts within swollen subcortical white matter. On neurological examination at age of 5 years, he showed signs of pyramidal, cerebellar and bulbar dysfunction, as well as marked macrocephaly with head circumference 60cm (i.e. 7cm above 98th percentile). Proton MRS examination showed reduced spectra of N-acteylaspartic acid and creatine within altered white matter indicating axonal pathology and loss which correspond to his clinical deterioration. Follow-up MRI/proton MRS after 2 years‘ creatine intake showed an improvement which was in accordance with his intellectual progress and regression of some deviant neurological signs as well as stabilization of head growth. There was no further formation of the cysts, even white matter changes were less extensive. Proton MRS demonstrated reduction of Nacetylaspartic acid and creatine within altered white matter, though no progression from the initial findings. Con&&on: In the absence of causal treatment for this disorder we propose that supplementation might support the survival of the neuroaxonal system and in this way counteract the process of demyelination.
273 Prognosis of patients with X-linked adrenoleukodystrophy (X-ALD) who have not received bone marrow transplants H MOSER, L BEZMAN,
G RAYMOND
Kennedy Krieger Institute and Departments of Neurology and Pediatrics, and Johns Hopkins University, USA
Bone marrow transplant is the most effective therapy for boys with X-linked adrenoleukodystrophy (X-ALD) with early and progressive cerebral involvement, but the decision about when it should be offered is difficult because of the high risk of the procedure and the extremely wide variability of natural history. Recent analysis of natural history show that only 30-35% of XALD patients develop the severe childhood form by 10 years of age. Patients with the severe form should be identified early since bone marrow transplant is most effective when performed early, while those who develop the milder adult variants should not be subjected to a high-risk procedure. Unfortunately it is not possible to predict whether an asymptomatic child is ‘destined’ for the mild or the severe forms. As an alternate approach, we have analysed the rate of progression of X-ALD in 297 patients who were not transplanted but followed up in our clinic. The patients were subdivided into 16 groups based on age and disease severity. Kaplan-Meier plots in respect to survival and disease progression will be presented for each group. Age and disease severity have a profound influence on prognosis. Use of these charts permits the physician and family to make a more precise assessment of the benefit-risk ratio of bone marrow transplant for an X-ALD patient as a function of age and disease severity.
280 Adenylosuccinase deficiency: An unusual cause of early-onset severe epilepsy associated with acquired microcephaly M C NASSOGNE, C SAINT-MARTIN, M F VINCENT
B HENROT, C BONNIER, S MARIE, G VAN DEN BERGHE, G SiBIRE,
Service de Neurologie Pe’diatrique, Service de Radiologie Pgdiatrique, Cliniques universitaires Saint&c; Groupe de Recherches me’taboliques, Christian de Duve International Institute of Cellular Pathology, Brussels, Belgium
Adenylosuccinase deficiency, an autosomal recessive inborn error of purine synthesis, was first described in 1984 by Jaeken and van den Berghe. The cardinal implications are variable psychomotor delay often accompanied by epilepsy and autisic features. Diagnosis is made by detection of abnormal purine metabolites in body fluids. We report a girl who presented with early onset epilepsy, associated with acquired microcephaly and severe psychomotor retardation, as the most prominent symptoms. This girl is the first child of unrelated parents. Pregnancy and delivery were unevenful. Birth head circumference was 33cm (25th centile). Physical and neurological examination were normal. The neonatal period was unremarkable. At 3 weeks of age, the baby developed partial motor seizures of the upper right limb and valproate was introduced. At 9 months of age, she developed spasms and benefited from vigabatrin, followed by adrenocorticotropic hormone with good control of seizures. At 2.5 years of age, general examination revealed normal growth. Neurological examination showed microcephaly (42cm, more than 4 SD below normal) associated with severe axial hypotonia without any head control and moderate tetraparesia with limb hypotonia. Tendon reflexes were present and symmetrical. There was strong psychomotor retardation with poor visual contact, and lack of language and motor skills such as voluntary prehension and sitting. In addition, the girl showed repetitive behaviour with stereotypic movements of her hands. Epileptic seizures were characterized as sudden spasms with flexion and extension of the whole body. They are at present well stabilized by valproic acid associated with pheneturide. Routine blood were normal. TORCH screening was negative. Metabolic and cerebrospinal fluid investigations were normal. Electrocardiography, echocardiography, abdominal ultrasound were normal. ECG at 2.5 years showed a slow background rhythm with multifocal and asynchronous spikes and sharp waves, predominantly in both temporal regions. Brain MRI was normal at 3 weeks of age, but showed slight cerebral atrophy at 1 year. At 2.5 years, it revealed a complete but thin corpus callosum and a moderate vermian atrophy and generalized atrophy with diffuse white matter abnormalities. The Braton-Marshall test was positive in urine, suggesting deficiency of adenylsocuccinase. This diagnosis was confirmed by the measurement of urine and cerebrospinal fluid SAICAriboside and S-Ado by high performance liquid chromatography. DNA analysis revealed a point mutation on one allele, resulting in the substitution of arginine by histidine at position 426 (R426H) in the enzyme protein. The second mutation is under investigation. Neurological diseases with simultaneous occurrence of early-onset epilepsy and acquired microcephaly are rare.
Abstracts Results: The presented patient was considered until the age of 5 years to have a mild clinical course and morphology, particularly showing little tendency to form cysts within swollen subcortical white matter. On neurological examination at age of 5 years, he showed signs of pyramidal, cerebellar and bulbar dysfunction, as well as marked macrocephaly with head circumference 60cm (i.e. 7cm above 98th percentile). Proton MRS examination showed reduced spectra of N-acteylaspartic acid and creatine within altered white matter indicating axonal pathology and loss which correspond to his clinical deterioration. Follow-up MRI/proton MRS after 2 years‘ creatine intake showed an improvement which was in accordance with his intellectual progress and regression of some deviant neurological signs as well as stabilization of head growth. There was no further formation of the cysts, even white matter changes were less extensive. Proton MRS demonstrated reduction of Nacetylaspartic acid and creatine within altered white matter, though no progression from the initial findings. Con&&on: In the absence of causal treatment for this disorder we propose that supplementation might support the survival of the neuroaxonal system and in this way counteract the process of demyelination.
273 Prognosis of patients with X-linked adrenoleukodystrophy (X-ALD) who have not received bone marrow transplants H MOSER, L BEZMAN,
G RAYMOND
Kennedy Krieger Institute and Departments of Neurology and Pediatrics, and Johns Hopkins University, USA
Bone marrow transplant is the most effective therapy for boys with X-linked adrenoleukodystrophy (X-ALD) with early and progressive cerebral involvement, but the decision about when it should be offered is difficult because of the high risk of the procedure and the extremely wide variability of natural history. Recent analysis of natural history show that only 30-35% of XALD patients develop the severe childhood form by 10 years of age. Patients with the severe form should be identified early since bone marrow transplant is most effective when performed early, while those who develop the milder adult variants should not be subjected to a high-risk procedure. Unfortunately it is not possible to predict whether an asymptomatic child is ‘destined’ for the mild or the severe forms. As an alternate approach, we have analysed the rate of progression of X-ALD in 297 patients who were not transplanted but followed up in our clinic. The patients were subdivided into 16 groups based on age and disease severity. Kaplan-Meier plots in respect to survival and disease progression will be presented for each group. Age and disease severity have a profound influence on prognosis. Use of these charts permits the physician and family to make a more precise assessment of the benefit-risk ratio of bone marrow transplant for an X-ALD patient as a function of age and disease severity.
280 Adenylosuccinase deficiency: An unusual cause of early-onset severe epilepsy associated with acquired microcephaly M C NASSOGNE, C SAINT-MARTIN, M F VINCENT
B HENROT, C BONNIER, S MARIE, G VAN DEN BERGHE, G SiBIRE,
Service de Neurologie Pe’diatrique, Service de Radiologie Pgdiatrique, Cliniques universitaires Saint&c; Groupe de Recherches me’taboliques, Christian de Duve International Institute of Cellular Pathology, Brussels, Belgium
Adenylosuccinase deficiency, an autosomal recessive inborn error of purine synthesis, was first described in 1984 by Jaeken and van den Berghe. The cardinal implications are variable psychomotor delay often accompanied by epilepsy and autisic features. Diagnosis is made by detection of abnormal purine metabolites in body fluids. We report a girl who presented with early onset epilepsy, associated with acquired microcephaly and severe psychomotor retardation, as the most prominent symptoms. This girl is the first child of unrelated parents. Pregnancy and delivery were unevenful. Birth head circumference was 33cm (25th centile). Physical and neurological examination were normal. The neonatal period was unremarkable. At 3 weeks of age, the baby developed partial motor seizures of the upper right limb and valproate was introduced. At 9 months of age, she developed spasms and benefited from vigabatrin, followed by adrenocorticotropic hormone with good control of seizures. At 2.5 years of age, general examination revealed normal growth. Neurological examination showed microcephaly (42cm, more than 4 SD below normal) associated with severe axial hypotonia without any head control and moderate tetraparesia with limb hypotonia. Tendon reflexes were present and symmetrical. There was strong psychomotor retardation with poor visual contact, and lack of language and motor skills such as voluntary prehension and sitting. In addition, the girl showed repetitive behaviour with stereotypic movements of her hands. Epileptic seizures were characterized as sudden spasms with flexion and extension of the whole body. They are at present well stabilized by valproic acid associated with pheneturide. Routine blood were normal. TORCH screening was negative. Metabolic and cerebrospinal fluid investigations were normal. Electrocardiography, echocardiography, abdominal ultrasound were normal. ECG at 2.5 years showed a slow background rhythm with multifocal and asynchronous spikes and sharp waves, predominantly in both temporal regions. Brain MRI was normal at 3 weeks of age, but showed slight cerebral atrophy at 1 year. At 2.5 years, it revealed a complete but thin corpus callosum and a moderate vermian atrophy and generalized atrophy with diffuse white matter abnormalities. The Braton-Marshall test was positive in urine, suggesting deficiency of adenylsocuccinase. This diagnosis was confirmed by the measurement of urine and cerebrospinal fluid SAICAriboside and S-Ado by high performance liquid chromatography. DNA analysis revealed a point mutation on one allele, resulting in the substitution of arginine by histidine at position 426 (R426H) in the enzyme protein. The second mutation is under investigation. Neurological diseases with simultaneous occurrence of early-onset epilepsy and acquired microcephaly are rare.