Acta Neuropathol (1992) 84:461 - 464
Acl:a I ropatholog:ca (~ Springer-Verlag 1992
Case report
Neuropathology of biotinidase deficiency M. Honavar 1, I. Janota 1, B. G. R. Neville 2, and R. A. Chalmers 3 i Department of Neuropathology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK 2 Neurosciences Unit, Institute of Child Health, Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK 3 Department of Child Health, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK ReceivedMarch 6, 1992/Revised,accepted April 21, 1992 Summary. A patient with biotinidase deficiency and a progressive neurological disorder died just before the biochemical diagnosis was established. Post-mortem examination of the brain and spinal cord revealed necrotising lesions similar to those in Leigh's disease and Wernicke's encephalopathy. Unlike these two conditions, the regions affected included the hippocampus and parahippocampal cortex. In addition there was severe focal oedema in deep cerebral grey matter, the brain stem, and the spinal cord. These lesions appear to result from a number of severe metabolic disturbances, perhaps linked to an underlying disordered pyruvate metabolism. The nature of the pathology explains why a neurological deficit may persist despite treatment. Key words: Biotinidase deficiency - Necrotising encephalopathy - Neuropathology
D-Biotin is a water-soluble vitamin which acts as a coenzyme in four important carboxylation reactions in man, mitochondrial pyruvate carboxylase, propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase and cytosolic acetyl CoA carboxylase. It is, thus, essential in the key metabolic processes of gluconeogenesis, fatty acid synthesis and amino acid catabolism. It is bound to the apocarboxylases in a reaction catalysed by holocarboxylase synthetase [6, 14]. Biotin is recycled for re-utilisation and obtained from bound sources in the diet via the action of biotinidase, which cleaves biotin from the e-amino group of lysine in biocytin and other biotinyl-peptides derived from degradation of the holocarboxylases [14]. Two major autosomal biotin-responsive multiple carboxylase deficiencies that are recessively inherited are known [10, 13, 14]. A neonatal form presents in the first few weeks of life with lethargy, hypotonia, seizures and vomiting. This is associated with metabolic acidosis and Correspondence to: M. Honavar
an overt abnormal organic aciduria [4] in which the defect lies in holocarboxylase synthetase [3, 5, 7]. A juvenile form presents in the early months of life variously with skin rash, alopecia, respiratory distress and neurological features including seizures, hypotonia, myoclonus, ataxia, optic atrophy, hearing loss and, in the majority but not all of symptomatic individuals, with a less prominent but characteristic organic aciduria [2, 11, 12, 15, 16]. The defect in the juvenile form is a deficiency of biotinidase. Biochemical abnormalities in both forms arise from combined deficiencies of the carboxylases and include lactic acidosis and an increased urinary excretion of lactate, 3-hydroxypropionate, methylcitrates and 3-methyIcrotonylglycine. The concentrations of these metabolites may be low or absent in some cases of biotinidase deficiency [2, 14]. More than 40 patients with biotinidase deficiency have been reported. Early diagnosis is important because of the severe neurological features and the potentially fatal course of the disease. Response to treatment with pharmacological doses of D-biotin is rapid but neurological damage may remain, with sensory-neural deafness, visual defects, ataxia and mental retardation [12]. Few reports of fatal outcome have been recorded, and little is known of the neuropathology of the disease. We report here a patient of biotinidase deficiency who presented with a progressive neurological disorder with virtual absence of abnormal organic aciduria who died just prior to biochemical diagnosis. The post-mortem findings in brain and spinal cord resemble those described in Leigh's disease and Wernicke's encephalopathy. Case report This boy was the 4th child of healthy unrelated parents and was born followinga normal pregnancy and delivery. An older boy and girl are normal. The 3rd pregnancy resulted in a stillbirth with holoprosencephaly. He gained weight slowly and at the age of 2 weeks he was observed to be floppy. He walked unsteadily at the age of 10 months and remained unsteady. From the age of 14
462 months, he developed a number of bulbar problems including stridor, difficulty with swallowing and episodes of choking. His motor abilities slowly deteriorated and his hair became progressively more sparse. At the age of 17 months, he had very little hair, he could sit and just crawl but could not stand or walk and his arms were weak and unsteady. His general cognitive development was at a 13-15 month level and he was alert and appeared to be still learning. Visual assessment showed that he could see fixed balls down to 1/4 inch at 3 metres. The fundi showed increased fine pigmentation and early optic atrophy. He was hypotonic with proximal weakness and the tendon reflexes were preserved but depressed. There was laryngomalacia. The following investigations were normal: electromyography and nerve conduction velocities, EEG, CT head scan, skeletal survey, lysosomal storage disease enzyme studies, immunoglobulins, phytanic acid, urine and blood amino acids, blood lactate and pyruvate measurements, copper, caeruloplasmin, initial screening for organic acids. Abnormal investigations included a slightly raised a-fetoprotein at 22 rag/1 (normal 8 mg/I and abnormal broad visual evoked response with a reduced electroretinogram which increased on dark adaptation. Plasma ammonia was 60 gmol/l (normal 35 ~moYl). He deteriorated rapidly and died at the age of 19 months. Results of urinary organic acid analysis using gas chromatographymass spectrometry (GC-MS) on a sample obtained shortly before death (results available just after the patient died) showed moderately increased 3-hydroxy isovalerate at 260 mmol/mol creatinine (normal
Acl:a I ropatholog:ca (~ Springer-Verlag 1992
Case report
Neuropathology of biotinidase deficiency M. Honavar 1, I. Janota 1, B. G. R. Neville 2, and R. A. Chalmers 3 i Department of Neuropathology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK 2 Neurosciences Unit, Institute of Child Health, Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK 3 Department of Child Health, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK ReceivedMarch 6, 1992/Revised,accepted April 21, 1992 Summary. A patient with biotinidase deficiency and a progressive neurological disorder died just before the biochemical diagnosis was established. Post-mortem examination of the brain and spinal cord revealed necrotising lesions similar to those in Leigh's disease and Wernicke's encephalopathy. Unlike these two conditions, the regions affected included the hippocampus and parahippocampal cortex. In addition there was severe focal oedema in deep cerebral grey matter, the brain stem, and the spinal cord. These lesions appear to result from a number of severe metabolic disturbances, perhaps linked to an underlying disordered pyruvate metabolism. The nature of the pathology explains why a neurological deficit may persist despite treatment. Key words: Biotinidase deficiency - Necrotising encephalopathy - Neuropathology
D-Biotin is a water-soluble vitamin which acts as a coenzyme in four important carboxylation reactions in man, mitochondrial pyruvate carboxylase, propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase and cytosolic acetyl CoA carboxylase. It is, thus, essential in the key metabolic processes of gluconeogenesis, fatty acid synthesis and amino acid catabolism. It is bound to the apocarboxylases in a reaction catalysed by holocarboxylase synthetase [6, 14]. Biotin is recycled for re-utilisation and obtained from bound sources in the diet via the action of biotinidase, which cleaves biotin from the e-amino group of lysine in biocytin and other biotinyl-peptides derived from degradation of the holocarboxylases [14]. Two major autosomal biotin-responsive multiple carboxylase deficiencies that are recessively inherited are known [10, 13, 14]. A neonatal form presents in the first few weeks of life with lethargy, hypotonia, seizures and vomiting. This is associated with metabolic acidosis and Correspondence to: M. Honavar
an overt abnormal organic aciduria [4] in which the defect lies in holocarboxylase synthetase [3, 5, 7]. A juvenile form presents in the early months of life variously with skin rash, alopecia, respiratory distress and neurological features including seizures, hypotonia, myoclonus, ataxia, optic atrophy, hearing loss and, in the majority but not all of symptomatic individuals, with a less prominent but characteristic organic aciduria [2, 11, 12, 15, 16]. The defect in the juvenile form is a deficiency of biotinidase. Biochemical abnormalities in both forms arise from combined deficiencies of the carboxylases and include lactic acidosis and an increased urinary excretion of lactate, 3-hydroxypropionate, methylcitrates and 3-methyIcrotonylglycine. The concentrations of these metabolites may be low or absent in some cases of biotinidase deficiency [2, 14]. More than 40 patients with biotinidase deficiency have been reported. Early diagnosis is important because of the severe neurological features and the potentially fatal course of the disease. Response to treatment with pharmacological doses of D-biotin is rapid but neurological damage may remain, with sensory-neural deafness, visual defects, ataxia and mental retardation [12]. Few reports of fatal outcome have been recorded, and little is known of the neuropathology of the disease. We report here a patient of biotinidase deficiency who presented with a progressive neurological disorder with virtual absence of abnormal organic aciduria who died just prior to biochemical diagnosis. The post-mortem findings in brain and spinal cord resemble those described in Leigh's disease and Wernicke's encephalopathy. Case report This boy was the 4th child of healthy unrelated parents and was born followinga normal pregnancy and delivery. An older boy and girl are normal. The 3rd pregnancy resulted in a stillbirth with holoprosencephaly. He gained weight slowly and at the age of 2 weeks he was observed to be floppy. He walked unsteadily at the age of 10 months and remained unsteady. From the age of 14
462 months, he developed a number of bulbar problems including stridor, difficulty with swallowing and episodes of choking. His motor abilities slowly deteriorated and his hair became progressively more sparse. At the age of 17 months, he had very little hair, he could sit and just crawl but could not stand or walk and his arms were weak and unsteady. His general cognitive development was at a 13-15 month level and he was alert and appeared to be still learning. Visual assessment showed that he could see fixed balls down to 1/4 inch at 3 metres. The fundi showed increased fine pigmentation and early optic atrophy. He was hypotonic with proximal weakness and the tendon reflexes were preserved but depressed. There was laryngomalacia. The following investigations were normal: electromyography and nerve conduction velocities, EEG, CT head scan, skeletal survey, lysosomal storage disease enzyme studies, immunoglobulins, phytanic acid, urine and blood amino acids, blood lactate and pyruvate measurements, copper, caeruloplasmin, initial screening for organic acids. Abnormal investigations included a slightly raised a-fetoprotein at 22 rag/1 (normal 8 mg/I and abnormal broad visual evoked response with a reduced electroretinogram which increased on dark adaptation. Plasma ammonia was 60 gmol/l (normal 35 ~moYl). He deteriorated rapidly and died at the age of 19 months. Results of urinary organic acid analysis using gas chromatographymass spectrometry (GC-MS) on a sample obtained shortly before death (results available just after the patient died) showed moderately increased 3-hydroxy isovalerate at 260 mmol/mol creatinine (normal
