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Netherlands society of child neurology
Clinical Neurology nnd Neurosu~e~ 95 (1993) 329-330 0 1993 Eisevier Science Publishers B.V. All rights reserved 0303~8467!93/%06.00
329
CLINEU 00318
Society Proceedings
-.-
Netherlands Society of Child Neurology Amsterdam,The Ne~erlands,
Secretariat: Netherlands
4 December
1992
Society of Child Neurology
Division ofPaediatric Neumbgv, Universify Hospital Amstenfam, Ah&II,Meibeqdreef9, iI OSAZ (Received for publication
1. Inborn errors of GABA metabolism - J. Jaeken, Deyartrnent of Pediatrics, Metabolic Diseases, Wniversitair Ziekenhuis Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Three genetic and ~iinically impo~ant diseases due to a defect in the brain GABA me~bolism have been reported: py~doxine-~sponsive convulsions considered to be the consequence of a GABA-synthesis defect (glutamate decarboxylase deficiency) and two defects in the GABA catabolism. One is GABA transaminase deficiency and the other succinic semialdehyde dehydrogenase deficiency. GABA transaminase deficiency, in the one family reported, was associated with severe psychomotor retardation, hypotonia, hyperreflexia, minor convulsions, and growth acceleration. No efficient therapy was found. The key biochemical feature was grossly elevated free and conjugated GABA in the CSF. Succinic semialdehyde dehydrogenase deficiency is clinically characterized by mild to marked psychomotor retardation, hypotonia, nonprogressive ataxia and sometimes convulsions. More than 30 patients have been identified. The organic acid y-hy~oxybu~rate accumulates in body fluids, including urine, of these patients. It is suggested that in all children and adults with unexplained brain disease CSF should be obtained for GABA and homocarnosine determination, and urine for organic acid analysis. A trial with pyridoxine is indicated in unexplained convulsions up to the age of about 2 years.
2.
Neurofibromatosis type I: clinicaf and genetic aspects W.C.G. Ove~eg-Plandsoena, C.J. van Asperenb, “Pediatric ~e~~ro~o~~, and ‘~~i~~cal Genetics, and the ~nterd~sc~p~inu~J ~e~4ro~bromatos~s Workgrol~~, Academic Medical Center; Amsterdam, The Netherlands
According
to NIH (1988) criteria, NF I is present when a patient
exhibits: 6 or more cafe-au-lait spots (2 0.5 cm below 6 years, 2 1 cm 6-12 years, 2 1.5 cm over 12 years); axillar or generalized freckling; two or more Lisch nodules; bilateral optic pathway glioma; > 2 neurotibromata; 1 plexiform neurotibroma; a specific osseous defect; a first degree relative affected by NF I. In the Amsterdam multidisciplinary NF clinic, 190 individuals between 6 months and 65 years have been investigated since 1985. 94 were over 18 years, 96 below 18 years. A definite diagnosis of NFI was made in 162. Specific diagnostic and therapeutic
10 September,
Amsterdam. The Netherlunds
1993)
problems in children with NFI are discussed, such as macrocephaly, hypertelorism, tumors, polyneuropathy, learning disabilities, kyphoscoliosis, specific osseous defects, hypertension, results of brain imaging and associated disorders especially Noonan and Weaver syndrome. In 1987, the gene for NFI was mapped to chromosome 17qll.2. Subsequently, closely linked and intragenic markers became available for diagnostic procedures. In addition, the gene product has been identified as a 250 kDa protein, named ‘neurofibromin’. The absence of this tumor suppressor protein in NFI appears to facilitate cellular transformation by a ras proto-oncogene product. The practical application of the new diagnostic possibilities are discussed. 3.
MRI of white matter disorders in children - E. BoltshauseP, C. Kiinzle*, S. SchefeP, W. Wichma~b, A. Valavanisb, departments of “Pediatrics and ‘~euroradiolo~, ~n~versi~ ofZiirich, Z&i& ~wi~er~and
MRI, particularly T2 weighted images, is a sensitive method to visualize abnormal myelination of the white matter. From a didactic point of view, one can distinguish between disorders of primary myelin formation (dysmyelination) and those with secondary loss of normally formed myelin (demyelination, leukodystrophies in the strict sense). Typical examples of the first group are PelizaeusMerzbacher disease, Cockayne syndrome and Alexander’s disease, the second group includes metachromatic and adrenoleukodystrophy. Systematic analysis of the MRI findings (evaluation of dist~bution of lesions, involvement of subcortical fibers, calcification, cerebellar involvement?) may allow to recognize a pattern which might suggest the possibility of a particular disorder. However, depending on the stage of the condition, many individual cases cannot be clearly attributed to a specific pattern, and it is not even always possible to distinguish between dys- and demyelination. Similar white matter changes can occur in cases of Leigh’s disease, aminoaciduria and organic aciduria, as well as in some peroxisomal and mitochondrial disorders. Differentiation of genetically determined dysmyelination from “acquired” gliosis may not always be possible in infants. To complicate the matter even further, marked white matter changes have been found incidentally in apparently healthy individuals. The MRI results have to be interpreted in the context of clinical findings and other additional investi8atioi~s.
330 4.
Peroxisomai disorders - P.G. Bartha*b, R.J.A. Wanders”, R.B.H. Schutgens”, B.M. van GeePb, E.B. HaverkorY and J. Assie&, Departments of “Pediatrics, bNeuroloo, ‘Dietetics and dEndocrinology, Academic Medical Center: Amsterdam, The Netherlands
Peroxisomes are organelles bounded by a single membrane, present in all vertebrate cells (except red blood cells). Their relevance to human genetic disease was discovered by their apparent absence on routine electronmicroscopy in patients with the cerebrohepatorenal (Zellweger) syndrome, later also in infantile Refsum syndrome and neonatal adrenoleukodystrophy. This triad is now collectively known as disorders of peroxisomal assembly: group I. In these disorders an inherited defect in peroxisomal assembly, and hence in multiple peroxisomal pathways exists. In group II, mostly confined to rhizomelic chondrodysplasia calcilicans punctata, peroxisomes are morphologically present and at least two peroxisoma1 metabolic pathways are clinically affected. In group III only one peroxisomal enzyme is deficient and the peroxisomes are morphologically well preserved. The latter group includes the important X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex (XALD/AMN) as well as a number of isolated peroxisoma1 P-oxidation defects. Complementation analysis has revealed that at least 8 genes control peroxisomal assembly. This has also proven the close (allelic) relationship between mild and severe generalized peroxisomal disorders. Recently, a mild variant of rhizomelic chondrodysplasia calcilicans punctata (group 11) has been discovered. The wealth of peroxisomal pathology is exemplified by abnormalities in neuronal migration, dysmyelination, leukodystrophy, as retinal degeneration, cataract, bone dysplasias or liver disease. Further research will bear relevance to the importance of peroxisomal metabolism for development and maintenance of the central nervous system, and in this regard “rare cases” add precious material to our understanding of brain functioning before and after birth. Diagnosis of genetic peroxisomal disorders is clinically important because of the feasibility of prenatal diagnosis in all the disorders presently known. Therapeutic interest is focused on measures intended to decrease the storage of very long chain fatty acids (> C22) in adrenoleukodystrophy, and more recently, on the ill-understood long chain fatty acid deficiency (C22:6n-~3, docosahexaenoic acid) in generalized peroxisomal disorders that may be amenable to therapy. In the Netherlands, coordination of therapeutic trials aimed at XALDiAMN has been through the Dutch XALD/AMN Workgroup. 5.
achieved
Congenital muscle disease - L.M.E. Smit, Department of Pediatric Neurology, Free University Hospital, Amsterdam, The NetherIan&
Neonatal paresis, often in combination with congenital contractures, has its own differential diagnosis. More frequently hypotonia and slow motor development become graduatly apparent and diagnosis is delayed until paresis and exercise intolerance become obvious in infancy or in later childhood.
Data about the prevalence of the different neuromuscular disorders are scarce, due to inadequate registration and dispute on diagnostic criteria. In the Dutch population the prevalence of congenital neuromuscular disease is 1/1000---l 500 for males and l/2500-3000 for females. Although there is a rapid progress in genetic research, chmcal and histopathological investigations still are the most important tools for correct diagnosis. Observation of spontaneous motor activity like respiration, ocular motility, crying and swallowing, antigravity movements of neck muscles and arms and kicking of the legs gives an impression of the distibution of muscle power. Testing of infantile reflexes, posturing in different positions and passive joint movements may reveal peripheral hypotonia and contractures. Palpation of muscle bulks gives information about muscle atrophy or pseudohypertrophy. Electromyography in young children is difficult to perform and results may be contradictory. Normal findings never exclude neuromuscular disease. Muscle biopsy not always reveals specific changes and focal distribution of pathology has to be taken into account. Careful selection of biopsy sites is indicated and sometimes repeated biopsy is necessary.
6.
diagnosis of Differential chronic demyelinating polyneuropathies - J.E. Hoogendijk, PA. Bolhuis and M. de Visser, Department of Neurology, Academic Medical Centel: Amsterdam, The Netherlands
If a child is found to have a chronic demyelinating polyneuropathy without other abnormalities, the differential diagnosis is as follows: (1) hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1); (2) HMSN type III (Dejerine-Sottas disease); (3) congenital neuropathies, often with amyelination or severe hypomyelination; (4) acquired polyneuropathies, usually chronic inflammatory demyelinating polyneuropathy (CIDP). By far the most frequent of these is HMSN I. Diagnosing this (mostly) autosomal dominant disorder is easy if one of the parents is affected, but if not, the distinction with recessive HMSN I, and with other polyneuropathies may be cumbersome. Recently, it was shown that autosomal dominant HMSN I is most frequently caused by a DNAduplication on chromosome 17. This finding makes it possible to diagnose the disease in individual patients. The diagnostic test is relatively easy and highly reliable, and by its use we have shown that most isolated HMSN I patients have this duplication as a de novo mutation. This refutes previous assumptions that sporadic patients are autosomal recessive. We have also found the duplication in several severely affected patients with a prior diagnosis of HMSN III, and in a child with lymphocytic infiltrates in a nerve biopsy. In conclusion, testing for the chromosome 17~ DNAduplication may be helpful with regard to differential diagnosis of chronic demyelinating polyneuropathies in childhood.
329
CLINEU 00318
Society Proceedings
-.-
Netherlands Society of Child Neurology Amsterdam,The Ne~erlands,
Secretariat: Netherlands
4 December
1992
Society of Child Neurology
Division ofPaediatric Neumbgv, Universify Hospital Amstenfam, Ah&II,Meibeqdreef9, iI OSAZ (Received for publication
1. Inborn errors of GABA metabolism - J. Jaeken, Deyartrnent of Pediatrics, Metabolic Diseases, Wniversitair Ziekenhuis Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Three genetic and ~iinically impo~ant diseases due to a defect in the brain GABA me~bolism have been reported: py~doxine-~sponsive convulsions considered to be the consequence of a GABA-synthesis defect (glutamate decarboxylase deficiency) and two defects in the GABA catabolism. One is GABA transaminase deficiency and the other succinic semialdehyde dehydrogenase deficiency. GABA transaminase deficiency, in the one family reported, was associated with severe psychomotor retardation, hypotonia, hyperreflexia, minor convulsions, and growth acceleration. No efficient therapy was found. The key biochemical feature was grossly elevated free and conjugated GABA in the CSF. Succinic semialdehyde dehydrogenase deficiency is clinically characterized by mild to marked psychomotor retardation, hypotonia, nonprogressive ataxia and sometimes convulsions. More than 30 patients have been identified. The organic acid y-hy~oxybu~rate accumulates in body fluids, including urine, of these patients. It is suggested that in all children and adults with unexplained brain disease CSF should be obtained for GABA and homocarnosine determination, and urine for organic acid analysis. A trial with pyridoxine is indicated in unexplained convulsions up to the age of about 2 years.
2.
Neurofibromatosis type I: clinicaf and genetic aspects W.C.G. Ove~eg-Plandsoena, C.J. van Asperenb, “Pediatric ~e~~ro~o~~, and ‘~~i~~cal Genetics, and the ~nterd~sc~p~inu~J ~e~4ro~bromatos~s Workgrol~~, Academic Medical Center; Amsterdam, The Netherlands
According
to NIH (1988) criteria, NF I is present when a patient
exhibits: 6 or more cafe-au-lait spots (2 0.5 cm below 6 years, 2 1 cm 6-12 years, 2 1.5 cm over 12 years); axillar or generalized freckling; two or more Lisch nodules; bilateral optic pathway glioma; > 2 neurotibromata; 1 plexiform neurotibroma; a specific osseous defect; a first degree relative affected by NF I. In the Amsterdam multidisciplinary NF clinic, 190 individuals between 6 months and 65 years have been investigated since 1985. 94 were over 18 years, 96 below 18 years. A definite diagnosis of NFI was made in 162. Specific diagnostic and therapeutic
10 September,
Amsterdam. The Netherlunds
1993)
problems in children with NFI are discussed, such as macrocephaly, hypertelorism, tumors, polyneuropathy, learning disabilities, kyphoscoliosis, specific osseous defects, hypertension, results of brain imaging and associated disorders especially Noonan and Weaver syndrome. In 1987, the gene for NFI was mapped to chromosome 17qll.2. Subsequently, closely linked and intragenic markers became available for diagnostic procedures. In addition, the gene product has been identified as a 250 kDa protein, named ‘neurofibromin’. The absence of this tumor suppressor protein in NFI appears to facilitate cellular transformation by a ras proto-oncogene product. The practical application of the new diagnostic possibilities are discussed. 3.
MRI of white matter disorders in children - E. BoltshauseP, C. Kiinzle*, S. SchefeP, W. Wichma~b, A. Valavanisb, departments of “Pediatrics and ‘~euroradiolo~, ~n~versi~ ofZiirich, Z&i& ~wi~er~and
MRI, particularly T2 weighted images, is a sensitive method to visualize abnormal myelination of the white matter. From a didactic point of view, one can distinguish between disorders of primary myelin formation (dysmyelination) and those with secondary loss of normally formed myelin (demyelination, leukodystrophies in the strict sense). Typical examples of the first group are PelizaeusMerzbacher disease, Cockayne syndrome and Alexander’s disease, the second group includes metachromatic and adrenoleukodystrophy. Systematic analysis of the MRI findings (evaluation of dist~bution of lesions, involvement of subcortical fibers, calcification, cerebellar involvement?) may allow to recognize a pattern which might suggest the possibility of a particular disorder. However, depending on the stage of the condition, many individual cases cannot be clearly attributed to a specific pattern, and it is not even always possible to distinguish between dys- and demyelination. Similar white matter changes can occur in cases of Leigh’s disease, aminoaciduria and organic aciduria, as well as in some peroxisomal and mitochondrial disorders. Differentiation of genetically determined dysmyelination from “acquired” gliosis may not always be possible in infants. To complicate the matter even further, marked white matter changes have been found incidentally in apparently healthy individuals. The MRI results have to be interpreted in the context of clinical findings and other additional investi8atioi~s.
330 4.
Peroxisomai disorders - P.G. Bartha*b, R.J.A. Wanders”, R.B.H. Schutgens”, B.M. van GeePb, E.B. HaverkorY and J. Assie&, Departments of “Pediatrics, bNeuroloo, ‘Dietetics and dEndocrinology, Academic Medical Center: Amsterdam, The Netherlands
Peroxisomes are organelles bounded by a single membrane, present in all vertebrate cells (except red blood cells). Their relevance to human genetic disease was discovered by their apparent absence on routine electronmicroscopy in patients with the cerebrohepatorenal (Zellweger) syndrome, later also in infantile Refsum syndrome and neonatal adrenoleukodystrophy. This triad is now collectively known as disorders of peroxisomal assembly: group I. In these disorders an inherited defect in peroxisomal assembly, and hence in multiple peroxisomal pathways exists. In group II, mostly confined to rhizomelic chondrodysplasia calcilicans punctata, peroxisomes are morphologically present and at least two peroxisoma1 metabolic pathways are clinically affected. In group III only one peroxisomal enzyme is deficient and the peroxisomes are morphologically well preserved. The latter group includes the important X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex (XALD/AMN) as well as a number of isolated peroxisoma1 P-oxidation defects. Complementation analysis has revealed that at least 8 genes control peroxisomal assembly. This has also proven the close (allelic) relationship between mild and severe generalized peroxisomal disorders. Recently, a mild variant of rhizomelic chondrodysplasia calcilicans punctata (group 11) has been discovered. The wealth of peroxisomal pathology is exemplified by abnormalities in neuronal migration, dysmyelination, leukodystrophy, as retinal degeneration, cataract, bone dysplasias or liver disease. Further research will bear relevance to the importance of peroxisomal metabolism for development and maintenance of the central nervous system, and in this regard “rare cases” add precious material to our understanding of brain functioning before and after birth. Diagnosis of genetic peroxisomal disorders is clinically important because of the feasibility of prenatal diagnosis in all the disorders presently known. Therapeutic interest is focused on measures intended to decrease the storage of very long chain fatty acids (> C22) in adrenoleukodystrophy, and more recently, on the ill-understood long chain fatty acid deficiency (C22:6n-~3, docosahexaenoic acid) in generalized peroxisomal disorders that may be amenable to therapy. In the Netherlands, coordination of therapeutic trials aimed at XALDiAMN has been through the Dutch XALD/AMN Workgroup. 5.
achieved
Congenital muscle disease - L.M.E. Smit, Department of Pediatric Neurology, Free University Hospital, Amsterdam, The NetherIan&
Neonatal paresis, often in combination with congenital contractures, has its own differential diagnosis. More frequently hypotonia and slow motor development become graduatly apparent and diagnosis is delayed until paresis and exercise intolerance become obvious in infancy or in later childhood.
Data about the prevalence of the different neuromuscular disorders are scarce, due to inadequate registration and dispute on diagnostic criteria. In the Dutch population the prevalence of congenital neuromuscular disease is 1/1000---l 500 for males and l/2500-3000 for females. Although there is a rapid progress in genetic research, chmcal and histopathological investigations still are the most important tools for correct diagnosis. Observation of spontaneous motor activity like respiration, ocular motility, crying and swallowing, antigravity movements of neck muscles and arms and kicking of the legs gives an impression of the distibution of muscle power. Testing of infantile reflexes, posturing in different positions and passive joint movements may reveal peripheral hypotonia and contractures. Palpation of muscle bulks gives information about muscle atrophy or pseudohypertrophy. Electromyography in young children is difficult to perform and results may be contradictory. Normal findings never exclude neuromuscular disease. Muscle biopsy not always reveals specific changes and focal distribution of pathology has to be taken into account. Careful selection of biopsy sites is indicated and sometimes repeated biopsy is necessary.
6.
diagnosis of Differential chronic demyelinating polyneuropathies - J.E. Hoogendijk, PA. Bolhuis and M. de Visser, Department of Neurology, Academic Medical Centel: Amsterdam, The Netherlands
If a child is found to have a chronic demyelinating polyneuropathy without other abnormalities, the differential diagnosis is as follows: (1) hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1); (2) HMSN type III (Dejerine-Sottas disease); (3) congenital neuropathies, often with amyelination or severe hypomyelination; (4) acquired polyneuropathies, usually chronic inflammatory demyelinating polyneuropathy (CIDP). By far the most frequent of these is HMSN I. Diagnosing this (mostly) autosomal dominant disorder is easy if one of the parents is affected, but if not, the distinction with recessive HMSN I, and with other polyneuropathies may be cumbersome. Recently, it was shown that autosomal dominant HMSN I is most frequently caused by a DNAduplication on chromosome 17. This finding makes it possible to diagnose the disease in individual patients. The diagnostic test is relatively easy and highly reliable, and by its use we have shown that most isolated HMSN I patients have this duplication as a de novo mutation. This refutes previous assumptions that sporadic patients are autosomal recessive. We have also found the duplication in several severely affected patients with a prior diagnosis of HMSN III, and in a child with lymphocytic infiltrates in a nerve biopsy. In conclusion, testing for the chromosome 17~ DNAduplication may be helpful with regard to differential diagnosis of chronic demyelinating polyneuropathies in childhood.