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Lissencephaly associated with congenital hypomyelinating and axonal neuropathy
Lissencephaly Associated With Congenital Hypomyelinating and Axonal Neuropathy Andreea Nissenkorn, MD*, Shlomo Weintraub, MD†, Menachem Sadeh, MD‡, and Tally Lerman-Sagie, MD* The authors describe an 11-year-old male with severe mental retardation, hypotonia, and arthrogryposis, with both type I lissencephaly and a congenital peripheral neuropathy, probably hypomyelinating with axonal involvement. To the best of the authors’ knowledge, this is the first report involving the co-occurrence of these two developmental disorders. A viral, metabolic, or nutritional insult acting throughout the period of migration and myelination or a contiguous gene linkage are possible explanations for this disorder. © 1998 by Elsevier Science Inc. All rights reserved. Nissenkorn A, Weintraub S, Sadeh M, Lerman-Sagie T. Lissencephaly associated with congenital hypomyelinating and axonal neuropathy. Pediatr Neurol 1998;19:313316.
Introduction Central hypotonia in utero resulting from neuronal migration disorders may cause arthrogryposis. However, arthrogryposis in these disorders also has been described as neurogenic or myopathic [1]. Type I lissencephaly is defined as a smooth four-layered cortex, with a figureeight appearance on neuroimaging and associated anomalies of the corpus callosum [1,2]. Peripheral nervous
From the *Pediatric Neurology Unit; Pediatrics Department; Wolfson Medical Center; Holon; †Pediatric Orthopedics Department; Dana Children’s Hospital; Tel-Aviv Medical Center; and ‡Neurology Department, Wolfson Medical Center; Holon; Sackler Medical School; Tel-Aviv University; Tel-Aviv, Israel.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00063-0 ● 0887-8994/98/$19.00
system involvement is not described. Type II lissencephaly is defined as a disarrayed cobblestone-like cortex associated with hydrocephalus, abnormal white matter, and a small brainstem and cerebellum [1,2]. It often is associated with a congenital muscular dystrophy (e.g., Fukuyama muscular dystrophy) [3]. Neurogenic arthrogryposis also has been reported in patients with pachygyria or polymicrogyria [1,4-7]. The authors report a child with type I lissencephaly, associated with both an axonal and hypomyelinating congenital neuropathy. To the best of the authors’ knowledge the co-occurrence of type I lissencephaly and peripheral nervous system involvement has not been reported previously. Case Report The patient, an 11-year-old male, was referred for neurologic evaluation by his orthopedic surgeon. He weighed 2,820 gm at birth after an uneventful pregnancy and term delivery. Apgar scores were 10 and 10 at 1 and 5 minutes, respectively. His parents are healthy, nonconsanguineous Ashkenazi Jews who have two other healthy children. At birth, he was diagnosed as having bilateral developmental dislocation of the hip, bilateral clubfeet, congenital arthrogryposis, and anal hypotonia. Severe psychomotor retardation became evident during his first year. He underwent several corrective orthopedic operations. In his second year, he was admitted to the pediatric intensive care unit multiple times for febrile status epilepticus. He was treated with antiepileptic drugs for several years; thereafter, the medication was withdrawn, and there was no recurrence. At 11 years of age, he is retarded severely, has no language, is confined to a wheelchair, and has gained no control over his sphincters. There never has been a developmental regression. The physical examination revealed a well-nourished child, with prominent microcephaly (head circumference 48 cm), bitemporal narrowing, and a high arched palate (Fig 1). His hips were deformed severely because of posterior dislocation. Cranial nerves were normal. There was severe muscle atrophy and weakness of both the upper and lower limbs. The feet were small, cold, and purple with cutis marmorata. He was hyposensitive to sensory stimuli. However, deep tendon reflexes were brisk. A computed tomography myelogram at birth was normal. The metabolic evaluation, including blood and urine pH, serum lactate and ammonia, plasma amino acids, and urine organic acids was unremarkable. An electroencephalogram, indirect funduscopic examination, and karyotype at 14 months of age were normal. Cranial computed tomography performed twice (last time at 5 years of age) revealed diffuse brain atrophy and enlargement of the ventricles. An electromyogram and a muscle biopsy performed at 2 years of age revealed denervation. The nerve conduction velocity (NCV) study was consistent with both a hypomyelinating and axonal neuropathy. Both the electromyogram and NCV study were performed again at 14 years of age. The electromyogram of the proximal and distal lower limb muscles
Communications should be addressed to: Dr. Lerman-Sagie; Pediatric Neurology Unit; Wolfson Medical Center; POB 5, Holon 58100; Israel. Received August 7, 1997; accepted April 29, 1998.
Nissenkorn et al: Lissencephaly and Congenital Neuropathy 313
Figure 1. Patient at 11 years of age, with microcephaly, bitemporal hollowing, deep set eyes, irregular teeth, and prognathism.
revealed no spontaneous activity at rest. During voluntary movement, some of the motor units had an above normal amplitude. During maximal motor activity there was a full recruitment pattern in only a part of the motor units. The NCV study revealed markedly prolonged distal latencies and velocities with highly decreased amplitudes in the motor nerves of the lower limbs and no elicitable responses in the sensory nerves, consistent with a de/hypomyelinating neuropathy with secondary axonopathy. The changes in the upper limbs were mild (Table 1). A brain magnetic resonance image revealed type I lissencephaly/ pachygyria (Fig 2) and a thin corpus callosum. Magnetic resonance
Table 1.
PEDIATRIC NEUROLOGY
imaging of the spine was normal. Deletions at the 17p13.3 locus for the Miller-Dieker gene were not detected by fluorescent in situ hybridization.
Discussion The authors describe a child who presented at birth with arthrogryposis and the association of a congenital neuropathy and lissencephaly type I. NCV studies were consis-
Nerve conduction studies performed at the age of 14
Motor nerves Median Ulnar Tibialis posterior Common peroneal Sensory nerves Median Ulnar Tibialis posterior Common peroneal
314
Figure 2. Axial T1-weighted magnetic resonance imaging (IR 2,100/25) at ventricle level reveals a smooth lissencephalic brain with primitive sulcation and enlarged ventricles.
Vol. 19 No. 4
Distal latency (ms) [Normal Values]
Amplitude (mV) [Normal Values]
Conduction Velocity (m/s) [Normal Values]
4.7 [,4.0] 3.5 [,3.4] 17.9 [,5.0] 9.0 [,5.0]
3.6 [.5.0] 5.3 [.5.0] 0.1 [.3.0] 0.2 [.1.5]
40.7 [.50] 36.2 [.50.0] 18.9 [.45.0] 19.4 [.45]
4.0 [,4.0] 4.5 [,3.7] Not elicited Not elicited
51 [.15] 41 [.15] Not elicited Not elicited
48 [.52] 51 [.52] Not elicited Not elicited
tent with both abnormal myelination and an axonal process. The authors do not have nerve biopsy results to confirm that the underlying abnormality was indeed hypomyelination and not dysmyelination or demyelination. However, the early presentation, the clinical picture, and the lack of progression (as seen by two NCV studies performed 9 years apart) are typical of hypomyelinating neuropathy, a congenital disorder of myelin formation [8-10]. Interestingly, on physical evaluation he had brisk tendon reflexes, although suffering from a congenital neuropathy, probably resulting from pyramidal involvement of the brain dysgenesis. Neuronal migration is the process by which postmitotic immature neurons in the subependymal layer climb to their final position in the cortex or elsewhere. This process takes place during the third and the fourth month of gestation. The most common types of neuronal migration disorders are lissencephaly (agyria-pachygyria spectrum), polymicrogyria, and focal subcortical heterotopias [2]. Dobyns and Truvit [2] define two types of lissencephaly: classical (type I) and cobblestone (type II). Classical lissencephaly comprises a wide spectrum of abnormalities according to the severity. It is manifested by a smooth cerebral surface, an abnormally thick four-layered cortex with widespread neuronal heterotopias, enlarged ventricles, a figure-eight appearance on magnetic resonance imaging, and often agenesis or malformations of the corpus callosum. Classical lissencephaly often is associated with the Miller-Dieker syndrome, which is due to deletions or other rearrangements on chromosome 17p13.3 [2]. Cobblestone lissencephaly consists of a cobblestonelike cortex, abnormal white matter, enlarged ventricles, and small brainstem and cerebellum and often is associated with eye malformations and congenital muscular dystrophy [1,2]. Neuronal migration disorders can often present at birth with arthrogryposis resulting from fetal hypotonia resulting from brain malformations or lower motor neuron dysfunction. The association of neuronal migration disorders with neurogenic arthrogryposis is the subject of several recent articles [4-7]. The most common cause of neurogenic arthrogryposis is anterior horn cell dysgenesis [1]. In most cases the cortical gray matter is intact; however, because the spinal cord and the cortex are both derived from the neural plate and both undergo the same process of proliferation, migration, and differentiation, an early insult can result in a gross disturbance of the cytoarchitecture diffusely along the neural axis and cause both a cortical and spinal neuronal migration disorder [1]. In all cases of neurogenic arthrogryposis and abnormal neuronal migration [4-7], there was involvement of the spinal motor neuron but not of the peripheral nerves. A prenatal viral infection or a genetic defect affecting the neural axis was speculated as the etiology of this association. Congenital hypomyelinating neuropathy [8-10] is a rare cause of neurogenic arthrogryposis. It presents from birth
with marked hypotonia, areflexia, predominantly distal weakness, and swallowing and respiratory difficulties. In severe cases, life expectancy is less than 2 years, but there also may be a milder form resulting in a significant motor disability. Usually the patients demonstrate only minimal clinical improvement. The peripheral nerve abnormality [8,9] is characterized by a profound absence of the myelin sheaths, especially those surrounding the large axons. Classic “onion bulbs” are absent, but occasionally one can see atypical “onion bulbs” consisting of basal membrane. There are no signs of inflammation or myelin degradation; therefore the defect must be in the synthesis of myelin, probably in the promyelin stage. In addition to the overall thinness of the myelin sheath, loss of large axons has been reported [11], suggesting that additional axonal abnormalities may be an intrinsic part of the disease. Congenital hypomyelinating neuropathy usually involves just the peripheral nervous system, but there are a few reports of associated central nervous system abnormalities. Takada et al. [12] report on an infant with Pena-Shokeir I syndrome who had congenital hypomyelinating neuropathy, dysplasia of the inferior olivary and dentate nuclei, and leptomeningeal heterotopia. Kimura et al. [13] report on an infant with type II lissencephaly (Walker-Warburg syndrome) and congenital peripheral nerve dysmyelination. Lissencephaly has its origins in the third to fourth month of gestation; myelination is a perinatal process. Thus the reason for their occurrence together is obscure. Barkovich et al. [14] found no delay in central nervous system myelination in 10 patients with lissencephaly. They conclude that the brain insult that produces the neuronal migration disorder does not involve the ventricular or subventricular zones of the germinal matrix or the glial cells that are destined to differentiate into oligodendrocytes. A viral insult during gestation (e.g., Cytomegalovirus) has been demonstrated to result in congenital lissencephaly [15]. It is possible that an infection active throughout the whole period of migration and myelination could result in the association of a neuronal migration disorder with a congenital hypomyelinating neuropathy; unfortunately, serologic tests after birth had not been performed in the authors’ patient. Because the neuroepithelial embryonic cells lining the cerebral ventricles are the precursors of both neurons and glial cells, an insult during neurogenesis because of intrinsic defects in neurotransmitters (e.g., gamma-aminobutyric acid or glutamate receptor activators), signaling factors (e.g., neurotropins and brain-derived neurotropic factors), or apoptosis [16], as well as an early extrinsic viral or ischemic insult, could result in a global defect of neuronal migration and myelin formation. However, this cannot explain the involvement of only the peripheral and not the central myelin in the authors’ patient. Syndromes with lissencephaly are often caused by deletions or rearrangements of contiguous genes, for example, the Miller-Dieker and isolated lissencephaly
Nissenkorn et al: Lissencephaly and Congenital Neuropathy 315
sequence, which is caused by deletions on chromosome 17p13, and Fukuyama muscular dystrophy, which has been mapped to the 9q31-33 locus [2]. Therefore, another tentative explanation is a gene linkage involving genes responsible for both neuronal migration and formation of peripheral myelin. References [1] Banker BQ. Arthrogryposis multiplex congenita: Spectrum of pathological changes. Hum Pathol 1986;17:656-72. [2] Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: An 1995 update. Neuropediatrics 1995;26:13247. [3] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type— clinical, genetic and pathological considerations. Brain Dev 1981;3:1-29. [4] Brodkorb E, Tobrgsen T, Nakken KO, Anderson K, Gimse R, Sjaastad O. Epileptic seizures, arthrogryposis, and migrational brain disorders: A syndrome? Acta Neurol Scand 1994;90:232-40. [5] Fedrizzi E, Botteon G, Inverno M, Ciceri E, D’Incerti L, Dworzak F. Neurogenic arthrogryposis multiplex congenita: Clinical and MRI findings. Pediatr Neurol 1993;9:343-8. [6] Hageman G, Hoogenraad TU, Prevo RL. The association of cortical dysplasia and anterior horn arthrogryposis: A case report. Brain Dev 1994;16:463-6. [7] Baker EM, Ghazavi Khorasgani M, Gardner-Medwin D,
316
PEDIATRIC NEUROLOGY
Vol. 19 No. 4
Gholkar A, Griffiths PD. Arthrogryposis multiplex congenita and bilateral parietal polymicrogyria in association with the intrauterine death of a twin. Neuropediatrics 1996;27:54-6. [8] Guzzetta F, Ferriere G, Lyon G. Congenital hypomyelination polyneuropathy: Pathological findings compared with polyneuropathies starting later in life. Brain 1982;105:395-416. [9] Harati Y, Butler IJ. Congenital hypomyelinating neuropathy. J Neurol Neurosurg Psychiatry 1985;48:1269-76. [10] Boylan KB, Ferriero DM, Greco CM, Sheldon RA, Dew M. Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita. Ann Neurol 1992;31:337-40. [11] Landrieu P, Selva J, Cau D, Barre M, Metral S, Leonard C. Schwann cells pathology and axonal reduction in one case of congenital neuropathy with hypomyelinisation. Arch Pediatr 1985;42:497-502. [12] Takada E, Koyama N, Ogawa Y, Itoyama S, Takashima S. Neuropathology of infant with Pena-Shokeir I syndrome. Pediatr Neurol 1994;10:241-3. [13] Kimura S, Kobayashi T, Sasaki Y, et al. Congenital polyneuropathy in Walker-Walburg syndrome. Neuropediatrics 1992;23:14-7. [14] Barkovich JA, Thomas KK, Clark CL. The spectrum of lissencephaly: Report of ten patients analysed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. [15] Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA. Lissencephaly-pachygyria associated with congenital cytomegalovirus infection. J Child Neurol 1991;6:109-14. [16] Kriegstein AR. Cortical neurogenesis and its disorders. Curr Opin Neurol 1996;9:113-17.
Introduction Central hypotonia in utero resulting from neuronal migration disorders may cause arthrogryposis. However, arthrogryposis in these disorders also has been described as neurogenic or myopathic [1]. Type I lissencephaly is defined as a smooth four-layered cortex, with a figureeight appearance on neuroimaging and associated anomalies of the corpus callosum [1,2]. Peripheral nervous
From the *Pediatric Neurology Unit; Pediatrics Department; Wolfson Medical Center; Holon; †Pediatric Orthopedics Department; Dana Children’s Hospital; Tel-Aviv Medical Center; and ‡Neurology Department, Wolfson Medical Center; Holon; Sackler Medical School; Tel-Aviv University; Tel-Aviv, Israel.
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00063-0 ● 0887-8994/98/$19.00
system involvement is not described. Type II lissencephaly is defined as a disarrayed cobblestone-like cortex associated with hydrocephalus, abnormal white matter, and a small brainstem and cerebellum [1,2]. It often is associated with a congenital muscular dystrophy (e.g., Fukuyama muscular dystrophy) [3]. Neurogenic arthrogryposis also has been reported in patients with pachygyria or polymicrogyria [1,4-7]. The authors report a child with type I lissencephaly, associated with both an axonal and hypomyelinating congenital neuropathy. To the best of the authors’ knowledge the co-occurrence of type I lissencephaly and peripheral nervous system involvement has not been reported previously. Case Report The patient, an 11-year-old male, was referred for neurologic evaluation by his orthopedic surgeon. He weighed 2,820 gm at birth after an uneventful pregnancy and term delivery. Apgar scores were 10 and 10 at 1 and 5 minutes, respectively. His parents are healthy, nonconsanguineous Ashkenazi Jews who have two other healthy children. At birth, he was diagnosed as having bilateral developmental dislocation of the hip, bilateral clubfeet, congenital arthrogryposis, and anal hypotonia. Severe psychomotor retardation became evident during his first year. He underwent several corrective orthopedic operations. In his second year, he was admitted to the pediatric intensive care unit multiple times for febrile status epilepticus. He was treated with antiepileptic drugs for several years; thereafter, the medication was withdrawn, and there was no recurrence. At 11 years of age, he is retarded severely, has no language, is confined to a wheelchair, and has gained no control over his sphincters. There never has been a developmental regression. The physical examination revealed a well-nourished child, with prominent microcephaly (head circumference 48 cm), bitemporal narrowing, and a high arched palate (Fig 1). His hips were deformed severely because of posterior dislocation. Cranial nerves were normal. There was severe muscle atrophy and weakness of both the upper and lower limbs. The feet were small, cold, and purple with cutis marmorata. He was hyposensitive to sensory stimuli. However, deep tendon reflexes were brisk. A computed tomography myelogram at birth was normal. The metabolic evaluation, including blood and urine pH, serum lactate and ammonia, plasma amino acids, and urine organic acids was unremarkable. An electroencephalogram, indirect funduscopic examination, and karyotype at 14 months of age were normal. Cranial computed tomography performed twice (last time at 5 years of age) revealed diffuse brain atrophy and enlargement of the ventricles. An electromyogram and a muscle biopsy performed at 2 years of age revealed denervation. The nerve conduction velocity (NCV) study was consistent with both a hypomyelinating and axonal neuropathy. Both the electromyogram and NCV study were performed again at 14 years of age. The electromyogram of the proximal and distal lower limb muscles
Communications should be addressed to: Dr. Lerman-Sagie; Pediatric Neurology Unit; Wolfson Medical Center; POB 5, Holon 58100; Israel. Received August 7, 1997; accepted April 29, 1998.
Nissenkorn et al: Lissencephaly and Congenital Neuropathy 313
Figure 1. Patient at 11 years of age, with microcephaly, bitemporal hollowing, deep set eyes, irregular teeth, and prognathism.
revealed no spontaneous activity at rest. During voluntary movement, some of the motor units had an above normal amplitude. During maximal motor activity there was a full recruitment pattern in only a part of the motor units. The NCV study revealed markedly prolonged distal latencies and velocities with highly decreased amplitudes in the motor nerves of the lower limbs and no elicitable responses in the sensory nerves, consistent with a de/hypomyelinating neuropathy with secondary axonopathy. The changes in the upper limbs were mild (Table 1). A brain magnetic resonance image revealed type I lissencephaly/ pachygyria (Fig 2) and a thin corpus callosum. Magnetic resonance
Table 1.
PEDIATRIC NEUROLOGY
imaging of the spine was normal. Deletions at the 17p13.3 locus for the Miller-Dieker gene were not detected by fluorescent in situ hybridization.
Discussion The authors describe a child who presented at birth with arthrogryposis and the association of a congenital neuropathy and lissencephaly type I. NCV studies were consis-
Nerve conduction studies performed at the age of 14
Motor nerves Median Ulnar Tibialis posterior Common peroneal Sensory nerves Median Ulnar Tibialis posterior Common peroneal
314
Figure 2. Axial T1-weighted magnetic resonance imaging (IR 2,100/25) at ventricle level reveals a smooth lissencephalic brain with primitive sulcation and enlarged ventricles.
Vol. 19 No. 4
Distal latency (ms) [Normal Values]
Amplitude (mV) [Normal Values]
Conduction Velocity (m/s) [Normal Values]
4.7 [,4.0] 3.5 [,3.4] 17.9 [,5.0] 9.0 [,5.0]
3.6 [.5.0] 5.3 [.5.0] 0.1 [.3.0] 0.2 [.1.5]
40.7 [.50] 36.2 [.50.0] 18.9 [.45.0] 19.4 [.45]
4.0 [,4.0] 4.5 [,3.7] Not elicited Not elicited
51 [.15] 41 [.15] Not elicited Not elicited
48 [.52] 51 [.52] Not elicited Not elicited
tent with both abnormal myelination and an axonal process. The authors do not have nerve biopsy results to confirm that the underlying abnormality was indeed hypomyelination and not dysmyelination or demyelination. However, the early presentation, the clinical picture, and the lack of progression (as seen by two NCV studies performed 9 years apart) are typical of hypomyelinating neuropathy, a congenital disorder of myelin formation [8-10]. Interestingly, on physical evaluation he had brisk tendon reflexes, although suffering from a congenital neuropathy, probably resulting from pyramidal involvement of the brain dysgenesis. Neuronal migration is the process by which postmitotic immature neurons in the subependymal layer climb to their final position in the cortex or elsewhere. This process takes place during the third and the fourth month of gestation. The most common types of neuronal migration disorders are lissencephaly (agyria-pachygyria spectrum), polymicrogyria, and focal subcortical heterotopias [2]. Dobyns and Truvit [2] define two types of lissencephaly: classical (type I) and cobblestone (type II). Classical lissencephaly comprises a wide spectrum of abnormalities according to the severity. It is manifested by a smooth cerebral surface, an abnormally thick four-layered cortex with widespread neuronal heterotopias, enlarged ventricles, a figure-eight appearance on magnetic resonance imaging, and often agenesis or malformations of the corpus callosum. Classical lissencephaly often is associated with the Miller-Dieker syndrome, which is due to deletions or other rearrangements on chromosome 17p13.3 [2]. Cobblestone lissencephaly consists of a cobblestonelike cortex, abnormal white matter, enlarged ventricles, and small brainstem and cerebellum and often is associated with eye malformations and congenital muscular dystrophy [1,2]. Neuronal migration disorders can often present at birth with arthrogryposis resulting from fetal hypotonia resulting from brain malformations or lower motor neuron dysfunction. The association of neuronal migration disorders with neurogenic arthrogryposis is the subject of several recent articles [4-7]. The most common cause of neurogenic arthrogryposis is anterior horn cell dysgenesis [1]. In most cases the cortical gray matter is intact; however, because the spinal cord and the cortex are both derived from the neural plate and both undergo the same process of proliferation, migration, and differentiation, an early insult can result in a gross disturbance of the cytoarchitecture diffusely along the neural axis and cause both a cortical and spinal neuronal migration disorder [1]. In all cases of neurogenic arthrogryposis and abnormal neuronal migration [4-7], there was involvement of the spinal motor neuron but not of the peripheral nerves. A prenatal viral infection or a genetic defect affecting the neural axis was speculated as the etiology of this association. Congenital hypomyelinating neuropathy [8-10] is a rare cause of neurogenic arthrogryposis. It presents from birth
with marked hypotonia, areflexia, predominantly distal weakness, and swallowing and respiratory difficulties. In severe cases, life expectancy is less than 2 years, but there also may be a milder form resulting in a significant motor disability. Usually the patients demonstrate only minimal clinical improvement. The peripheral nerve abnormality [8,9] is characterized by a profound absence of the myelin sheaths, especially those surrounding the large axons. Classic “onion bulbs” are absent, but occasionally one can see atypical “onion bulbs” consisting of basal membrane. There are no signs of inflammation or myelin degradation; therefore the defect must be in the synthesis of myelin, probably in the promyelin stage. In addition to the overall thinness of the myelin sheath, loss of large axons has been reported [11], suggesting that additional axonal abnormalities may be an intrinsic part of the disease. Congenital hypomyelinating neuropathy usually involves just the peripheral nervous system, but there are a few reports of associated central nervous system abnormalities. Takada et al. [12] report on an infant with Pena-Shokeir I syndrome who had congenital hypomyelinating neuropathy, dysplasia of the inferior olivary and dentate nuclei, and leptomeningeal heterotopia. Kimura et al. [13] report on an infant with type II lissencephaly (Walker-Warburg syndrome) and congenital peripheral nerve dysmyelination. Lissencephaly has its origins in the third to fourth month of gestation; myelination is a perinatal process. Thus the reason for their occurrence together is obscure. Barkovich et al. [14] found no delay in central nervous system myelination in 10 patients with lissencephaly. They conclude that the brain insult that produces the neuronal migration disorder does not involve the ventricular or subventricular zones of the germinal matrix or the glial cells that are destined to differentiate into oligodendrocytes. A viral insult during gestation (e.g., Cytomegalovirus) has been demonstrated to result in congenital lissencephaly [15]. It is possible that an infection active throughout the whole period of migration and myelination could result in the association of a neuronal migration disorder with a congenital hypomyelinating neuropathy; unfortunately, serologic tests after birth had not been performed in the authors’ patient. Because the neuroepithelial embryonic cells lining the cerebral ventricles are the precursors of both neurons and glial cells, an insult during neurogenesis because of intrinsic defects in neurotransmitters (e.g., gamma-aminobutyric acid or glutamate receptor activators), signaling factors (e.g., neurotropins and brain-derived neurotropic factors), or apoptosis [16], as well as an early extrinsic viral or ischemic insult, could result in a global defect of neuronal migration and myelin formation. However, this cannot explain the involvement of only the peripheral and not the central myelin in the authors’ patient. Syndromes with lissencephaly are often caused by deletions or rearrangements of contiguous genes, for example, the Miller-Dieker and isolated lissencephaly
Nissenkorn et al: Lissencephaly and Congenital Neuropathy 315
sequence, which is caused by deletions on chromosome 17p13, and Fukuyama muscular dystrophy, which has been mapped to the 9q31-33 locus [2]. Therefore, another tentative explanation is a gene linkage involving genes responsible for both neuronal migration and formation of peripheral myelin. References [1] Banker BQ. Arthrogryposis multiplex congenita: Spectrum of pathological changes. Hum Pathol 1986;17:656-72. [2] Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: An 1995 update. Neuropediatrics 1995;26:13247. [3] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type— clinical, genetic and pathological considerations. Brain Dev 1981;3:1-29. [4] Brodkorb E, Tobrgsen T, Nakken KO, Anderson K, Gimse R, Sjaastad O. Epileptic seizures, arthrogryposis, and migrational brain disorders: A syndrome? Acta Neurol Scand 1994;90:232-40. [5] Fedrizzi E, Botteon G, Inverno M, Ciceri E, D’Incerti L, Dworzak F. Neurogenic arthrogryposis multiplex congenita: Clinical and MRI findings. Pediatr Neurol 1993;9:343-8. [6] Hageman G, Hoogenraad TU, Prevo RL. The association of cortical dysplasia and anterior horn arthrogryposis: A case report. Brain Dev 1994;16:463-6. [7] Baker EM, Ghazavi Khorasgani M, Gardner-Medwin D,
316
PEDIATRIC NEUROLOGY
Vol. 19 No. 4
Gholkar A, Griffiths PD. Arthrogryposis multiplex congenita and bilateral parietal polymicrogyria in association with the intrauterine death of a twin. Neuropediatrics 1996;27:54-6. [8] Guzzetta F, Ferriere G, Lyon G. Congenital hypomyelination polyneuropathy: Pathological findings compared with polyneuropathies starting later in life. Brain 1982;105:395-416. [9] Harati Y, Butler IJ. Congenital hypomyelinating neuropathy. J Neurol Neurosurg Psychiatry 1985;48:1269-76. [10] Boylan KB, Ferriero DM, Greco CM, Sheldon RA, Dew M. Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita. Ann Neurol 1992;31:337-40. [11] Landrieu P, Selva J, Cau D, Barre M, Metral S, Leonard C. Schwann cells pathology and axonal reduction in one case of congenital neuropathy with hypomyelinisation. Arch Pediatr 1985;42:497-502. [12] Takada E, Koyama N, Ogawa Y, Itoyama S, Takashima S. Neuropathology of infant with Pena-Shokeir I syndrome. Pediatr Neurol 1994;10:241-3. [13] Kimura S, Kobayashi T, Sasaki Y, et al. Congenital polyneuropathy in Walker-Walburg syndrome. Neuropediatrics 1992;23:14-7. [14] Barkovich JA, Thomas KK, Clark CL. The spectrum of lissencephaly: Report of ten patients analysed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. [15] Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA. Lissencephaly-pachygyria associated with congenital cytomegalovirus infection. J Child Neurol 1991;6:109-14. [16] Kriegstein AR. Cortical neurogenesis and its disorders. Curr Opin Neurol 1996;9:113-17.