Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Case report
An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases Yumi Okoshi a,b, Masaharu Hayashi a,⇑, Sachiko Kanda c, Toshiyuki Yamamoto d a
Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan b Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for the Disabled, Tokyo, Japan c Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan d Tokyo Women’s Medical University, Institute for Integrated Medical Sciences, Tokyo, Japan Received 24 October 2013; received in revised form 25 November 2013; accepted 29 November 2013
Abstract We reported a 64-year-old autopsy case, showing a unique combination of disorders in visceral organs and brain. She had developmental delay, microencephaly, and facial dysmorphism. She developed sick sinus syndrome and liver cirrhosis. There were no abnormalities in laboratory tests for congenital metabolic errors or anomaly syndromes, including activities of lysosomal enzymes, isoelectric focusing of serum transferrin or array comparative genomic hybridization. She died of cardiorespiratory failure. At autopsy she showed liver cirrhosis and mesangial proliferation. The brain weighed 710 g. Bizarre putaminal changes were found, in which the size of area of putamen in coronal sections was small, aberrant fiber running was increased, and immunoreactivity for tyrosine hydroxylase was reduced. Loss of Purkinje cells was found throughout the cerebellar cortex. She had unreported combination of developmental delay, facial dysmorphism, small brain, bizarre putaminal lesion, cerebellar atrophy, cardiac disease, liver cirrhosis and renal disease. Although the exact cause of disease still remains to be investigated, it will be a clue for the establishment of new disease entity to accumulate subjects having the similar phenotype. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Facial dysmorphism; Microencephaly; Putamen; Cerebellum; Sick sinus syndrome; Liver cirrhosis
1. Introduction Constellation of various abnormalities in the brain may coexist with structural changes in other visceral organs in anomaly syndromes, chromosomal anomalies and congenital metabolic errors such as mucopolysaccharidosis (MPS) and congenital disorders of glycosylation (CDG) [1,2]. Combined involvement of the central nervous system (CNS) and visceral organs may possibly suggest a specific pathological condition, and in order to neglect the mere coexistence, the detailed examinations, ⇑ Corresponding author. Tel.: +81 3 6834 2334; fax: +81 3 5316 3150. E-mail address: [email protected] (M. Hayashi).
such as tests for metabolic errors, genetic analysis for anomaly syndromes and autopsy, are requiring. Recently, whole-exome sequencing in several patients has been performed to identify the causative gene for rare diseases, but that is not applicable in a single patient, unless the simultaneous analysis was done in the parent [3]. Recently we demonstrated specific immunohistochemical changes in the putamen in an autopsy case of Segawa disease, which seemed to be related to the dysfunction of the basal ganglia and the generation of levodopa-responsive dystonia [4]. Herein, we report a 64-year-old autopsy case, showing a clinico-pathological combination of cardiac disease, liver cirrhosis, microencephaly, and cerebellar
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.010
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
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Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
atrophy, in addition to the fine structural changes in the putamen like those in Segawa disease. 2. Case report The proband was born to a non-consanguineous and healthy parent at full term without asphyxia, with a birth weight of 2700 g. There was no family history of neuromuscular disorders or congenital metabolic errors. She had psychomotor retardation, and she achieved uttering words at 4 years, and independent walking at 6 years. She developed generalized tonic and clonic seizures in early infancy, lasting until the age of 60 years, regardless of anticonvulsant treatment. At 39 years, she was admitted to our center, and she showed voluntary movements in the upper extremities but not in the legs, and she was diagnosed as spastic paraplegia. She had no involuntary movements. She demonstrated microencephaly, facial dysmorphism such as coarse feature, hypertelorism, thick lip, retrognathia, and joint contractures. Chromosomal G-banding analysis was normal 46XX. There were no abnormal findings in urinary and plasma amino acid analysis, activities of lysosomal enzymes in leukocytes, organic acid profiles or isoelectric focusing of serum transferrin. At 40 years, she developed bouts of bradycardia, and she received implantation of cardiac pacemaker under the diagnosis of sick sinus syndrome. At 59 years, she was diagnosed as having liver cirrhosis, although hepatitis virus antigens and antibodies were negative. Brain magnetic resonance imaging (MRI) was not done due to the implantation of cardiac pacemaker. At 64 years, she died of heart failure subsequent to respiratory failure. Autopsy was granted by her family. Array comparative genomic hybridization (CGH) failed to show copy number variation, using autopsy liver samples. Whole-exome sequencing was not done, because the parents passed away several years before the patient’s death. At autopsy, she showed bronchopneumonia, liver cirrhosis, renal calculus and segmental mesangial proliferation. There was no steatohepatitis. The heart, including specialized cardiac muscle cells in the conducting system, had no morphological changes. The brain was small, weighing 710 g, but there seemed to be no dysplasticor destructive lesions in the surface of brain. In coronal section, the area of the cerebral hemisphere and cerebellum was small (Fig. 1), but there were no neuronal loss, ballooning of cells or gliosis in the cerebral cortex, amygdaloid body, hippocampus, or the cerebral white matter including internal capsule. The size of putamen was proportionally small. Pencil fibers in the putamen tend to run from the dorsolateral part to the ventromedial part, whereas those in the case were fragmented and seemed run randomly. We measured the area of the whole putamen (WP), and part of aberrant fiber running (PAF) in the section of right cerebrum at
Fig. 1. Coronal section in the cerebrum and cerebellum. The area of the cerebral hemisphere was small in the case (A), being compared with that in a 69-year-old control (B). The cerebellar vermis was small in the case (C), being compared with that in a 65-year-old control (D). Klu¨ver–Barrera staining.
the level of anterior commissure, using a Leica DMD 108 digital microimaging device (Leica Microsystems CMS GmbH, Wetzler, Germany) in our case and two controls, a 65-year-old male having oculopharyngeal muscular dystrophy and a 69-year-old female having cor pulmonale, both of which showed no changes in the brain. The WP value was 59.4 mm2 in our case, whereas those in two controls were 113.4 and 110.0 mm2, respectively. The PAF value was 52.7% in our case, whereas those in controls were 24.0% and 12.0%, respectively (Fig. 2A and B). In immunohistochemistry for tyrosine hydroxylase (TH) (monoclonal antibody at dilution of 1:400) (Affinity Bioreagents, CO, USA), the putamen showed reduced immunoreactivity, although that was comparatively preserved in the caudate (Fig. 2C and D). The medial and lateral segments in the globus pallidus demonstrated immunoreactivity for substance P (polyclonal antibody at dilution of 1:100) (Zymed Laboratories, Foster City, CA, USA), and methionine-enkephalin (polyclonal antibody at dilution of 1:1000) (Chemicon International, Inc., Temecula, CA, USA), respectively. Grumose foamy spheroid bodies (GFSBs) were increased in the medial segment of globus pallidus and in the substantia nigra pars reticularis (Fig. 3A). GFSB were stained by periodic acid Schiff and silver methods, and immunoreactive for ubiquitin (polyclonal antibody at dilution of 1:100) (Dako A/S, Glostrup, Denmark). There was no neuronal loss,
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 2. The area encircled by dots designated the part of aberrant fiber running in the right putamen at the level of anterior commissure in a 65-yearold control (A) and the case (B), in which the latter was larger than the former. Bar = 5 mm, Klu¨ver–Barrera staining. Immunoreactivity for tyrosine hydroxylase was comparatively well preserved in the right putamen in a65-year-old control (C), and in the caudate in the case (asterisk) (D), whereas that was reduced in the putamen in the case (D). Bar = 5 mm.
Fig. 3. Grumose foamy spheroid body in the left substantia nigra pars reticulata in the case, Bar = 50 lm, hematoxylin eosin staining (A). Loss of Purkinje cells in the cerebellar cortex, Bar = 100 lm, hematoxylin eosin staining (B).
ballooning of cells orgliosis in the basal ganglia, thalamus and substantia nigra. In the cerebellum, loss of Purkinje cells was found throughout the cerebellar cortex except in the tuber and folium in the vermis (Fig. 3B), and there was fibrillary gliosis in the intrafolial white matter and hilum of dentate nucleus. In the brainstem, there was no neuronal loss, ballooning of cells, reduction of myelinated fibers or gliosis. Neurofibrillary tangles and senile plaques were absent throughout the CNS. 3. Discussion This case showed the combination of anomalies and degeneration in the visceral organs and CNS. Facial dysmorphism, microencephaly and bizarre putaminal lesion were anomalous, while the changes in the heart, liver, kidney and cerebellum were speculated to be degenerative. Such combination was found in congenital malformation syndrome, chromosomal anomalies [5],
and congenital metabolic errors such as lysosomal diseases, mucopolysaccharidosis (MPS) and congenital disorders of glycosylation (CDG) [1,2]. Our case showed no abnormal data in either of array CGH, activities of lysosomal enzymes or isoelectric focusing of serum transferrin, and the neurons and glial cells lacked ballooning in the brain. Hence she did not fit the typical phenotypes of chromosomal anomalies, copy number variation, MPS or CDG, although normal patterns in serum transferrin isoelectric focusing cannot exclude the possibility of subtle types of CDG completely [6]. Patients with Cockayne syndrome (CS) have microencephaly, developmental delay, kidney disease, liver cirrhosis, basal ganglia lesion and cerebellar atrophy. However our case did not reveal photosensitivity, progeroid features, hypomyelination or intracerebral calcification, all of which are observed in most CS patients [7]. The constellation of developmental delay, sick sinus syndrome, liver cirrhosis and cerebellar atrophy may occur in mitochondrial disorders, but prolonged slow
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
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Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
course and facial dysmorphism were not in accordance with such disorders. Accordingly, we speculated that clinicopathological phenotype in our case is unique and has not been reported. Intriguingly, our case demonstrated bizarre structural changes in the putamen. Irregular running of pencil fiber may be anomalous, although the pathological significance was not clear. Rather the dissociative reduction of TH immunoreactivity in the putamen and caudate seemed to be more important, leading to the possible basal ganglia dysfunction. It should be noted that the putaminal lesion in our case was fine and not identified by brain MRI. Recently, we reported that the partial reduction of TH immunohistochemistry in the putamen may be involved in the generation of levodopa-responsive dystonia in the brain of Segawa disease [4]. On the other hand, regardless of the putaminal lesion, our case did not show any involuntary movements or rigidity except spastic paraplegia. Anomalous character in the putaminal lesion and/or complication of cerebellar lesion may be involved in absence of typical movement disorders. It is well known that GFSBs appear in the globus pallidus and substantia nigra in adult and child-onset neurodegenerative disorders, including CS [8,9]. The medial segment of the globus pallidus and substantia nigra pars reticularis consist of the striatal output pathway [10], and the occurrence of GFSBs may suggest the dysfunction of basal ganglia. In our case, GFSBs may be related to the selective paucity of TH-immunopositive fibers in the putamen. The combination of dysmorphic features in the face and brain, and degenerative changes in several organs is unique, and has not been reported within our knowledge. We believe that it will be a clue for the establishment of new disease entities to accumulate similar cases. Accumulation of subjects may enable the future exome analysis. Even in cases of developmental disorders, the functional evaluation of basal ganglia lesion should be implemented, using immunohistochemical analysis, in order to discuss the interrelationships
between movement disorders and the fine structural changes in the striatum and/or globus pallidus.
Acknowledgments The authors thank Dr. I. Yuasa, Division of Legal Medicine, Tottori University School of Medicine, for performing isoelectric focusing of serum transferrin. References [1] Gordon N. Carbohydrate-deficient glycoprotein syndromes. Postgrad Med J 2000;76:145–9. [2] Thomas JA, Beck M, Clarke JTR, Cox GF. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. J Inherit Metab Dis 2010;33:421–7. [3] Okumura A, Hayashi M, Shimojima K, Ikeno M, Uchida T, Takanashi J, et al. Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia. Neuropathology 2013;33:553–60. [4] Segawa M, Nomura Y, Hayashi M. Dopa-responsive dystonia is caused by particular impairment of nigrostriatal dopamine neurons different from those involved in Parkinson disease: evidence observed in studies on Segawa disease. Neuropediatrics 2013;44:61–6. [5] Speleman F, Craen M, Leroy J. De novo terminal deletion 7q22.1-pter in a child without craniosynostosis. J Med Genet 1989;26:528–32. [6] Jaeken J. Congenital disorders of glycosylation (CDG). J Inherit Met 2003;26:99–118. [7] Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992;42:68–84. [8] Arai N. Grumose or foamy spheroid bodies involving astrocytes in the human brain. Neuropathol Appl Neurobiol 1995;21:238–45. [9] Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawa K, et al. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 1999;21:326–33. [10] Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R, Tamagawa K. Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. J Neuropathol Exp Neurol 2004;63:1048–57.
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
Case report
An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases Yumi Okoshi a,b, Masaharu Hayashi a,⇑, Sachiko Kanda c, Toshiyuki Yamamoto d a
Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan b Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for the Disabled, Tokyo, Japan c Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan d Tokyo Women’s Medical University, Institute for Integrated Medical Sciences, Tokyo, Japan Received 24 October 2013; received in revised form 25 November 2013; accepted 29 November 2013
Abstract We reported a 64-year-old autopsy case, showing a unique combination of disorders in visceral organs and brain. She had developmental delay, microencephaly, and facial dysmorphism. She developed sick sinus syndrome and liver cirrhosis. There were no abnormalities in laboratory tests for congenital metabolic errors or anomaly syndromes, including activities of lysosomal enzymes, isoelectric focusing of serum transferrin or array comparative genomic hybridization. She died of cardiorespiratory failure. At autopsy she showed liver cirrhosis and mesangial proliferation. The brain weighed 710 g. Bizarre putaminal changes were found, in which the size of area of putamen in coronal sections was small, aberrant fiber running was increased, and immunoreactivity for tyrosine hydroxylase was reduced. Loss of Purkinje cells was found throughout the cerebellar cortex. She had unreported combination of developmental delay, facial dysmorphism, small brain, bizarre putaminal lesion, cerebellar atrophy, cardiac disease, liver cirrhosis and renal disease. Although the exact cause of disease still remains to be investigated, it will be a clue for the establishment of new disease entity to accumulate subjects having the similar phenotype. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Facial dysmorphism; Microencephaly; Putamen; Cerebellum; Sick sinus syndrome; Liver cirrhosis
1. Introduction Constellation of various abnormalities in the brain may coexist with structural changes in other visceral organs in anomaly syndromes, chromosomal anomalies and congenital metabolic errors such as mucopolysaccharidosis (MPS) and congenital disorders of glycosylation (CDG) [1,2]. Combined involvement of the central nervous system (CNS) and visceral organs may possibly suggest a specific pathological condition, and in order to neglect the mere coexistence, the detailed examinations, ⇑ Corresponding author. Tel.: +81 3 6834 2334; fax: +81 3 5316 3150. E-mail address: [email protected] (M. Hayashi).
such as tests for metabolic errors, genetic analysis for anomaly syndromes and autopsy, are requiring. Recently, whole-exome sequencing in several patients has been performed to identify the causative gene for rare diseases, but that is not applicable in a single patient, unless the simultaneous analysis was done in the parent [3]. Recently we demonstrated specific immunohistochemical changes in the putamen in an autopsy case of Segawa disease, which seemed to be related to the dysfunction of the basal ganglia and the generation of levodopa-responsive dystonia [4]. Herein, we report a 64-year-old autopsy case, showing a clinico-pathological combination of cardiac disease, liver cirrhosis, microencephaly, and cerebellar
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.010
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
2
Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
atrophy, in addition to the fine structural changes in the putamen like those in Segawa disease. 2. Case report The proband was born to a non-consanguineous and healthy parent at full term without asphyxia, with a birth weight of 2700 g. There was no family history of neuromuscular disorders or congenital metabolic errors. She had psychomotor retardation, and she achieved uttering words at 4 years, and independent walking at 6 years. She developed generalized tonic and clonic seizures in early infancy, lasting until the age of 60 years, regardless of anticonvulsant treatment. At 39 years, she was admitted to our center, and she showed voluntary movements in the upper extremities but not in the legs, and she was diagnosed as spastic paraplegia. She had no involuntary movements. She demonstrated microencephaly, facial dysmorphism such as coarse feature, hypertelorism, thick lip, retrognathia, and joint contractures. Chromosomal G-banding analysis was normal 46XX. There were no abnormal findings in urinary and plasma amino acid analysis, activities of lysosomal enzymes in leukocytes, organic acid profiles or isoelectric focusing of serum transferrin. At 40 years, she developed bouts of bradycardia, and she received implantation of cardiac pacemaker under the diagnosis of sick sinus syndrome. At 59 years, she was diagnosed as having liver cirrhosis, although hepatitis virus antigens and antibodies were negative. Brain magnetic resonance imaging (MRI) was not done due to the implantation of cardiac pacemaker. At 64 years, she died of heart failure subsequent to respiratory failure. Autopsy was granted by her family. Array comparative genomic hybridization (CGH) failed to show copy number variation, using autopsy liver samples. Whole-exome sequencing was not done, because the parents passed away several years before the patient’s death. At autopsy, she showed bronchopneumonia, liver cirrhosis, renal calculus and segmental mesangial proliferation. There was no steatohepatitis. The heart, including specialized cardiac muscle cells in the conducting system, had no morphological changes. The brain was small, weighing 710 g, but there seemed to be no dysplasticor destructive lesions in the surface of brain. In coronal section, the area of the cerebral hemisphere and cerebellum was small (Fig. 1), but there were no neuronal loss, ballooning of cells or gliosis in the cerebral cortex, amygdaloid body, hippocampus, or the cerebral white matter including internal capsule. The size of putamen was proportionally small. Pencil fibers in the putamen tend to run from the dorsolateral part to the ventromedial part, whereas those in the case were fragmented and seemed run randomly. We measured the area of the whole putamen (WP), and part of aberrant fiber running (PAF) in the section of right cerebrum at
Fig. 1. Coronal section in the cerebrum and cerebellum. The area of the cerebral hemisphere was small in the case (A), being compared with that in a 69-year-old control (B). The cerebellar vermis was small in the case (C), being compared with that in a 65-year-old control (D). Klu¨ver–Barrera staining.
the level of anterior commissure, using a Leica DMD 108 digital microimaging device (Leica Microsystems CMS GmbH, Wetzler, Germany) in our case and two controls, a 65-year-old male having oculopharyngeal muscular dystrophy and a 69-year-old female having cor pulmonale, both of which showed no changes in the brain. The WP value was 59.4 mm2 in our case, whereas those in two controls were 113.4 and 110.0 mm2, respectively. The PAF value was 52.7% in our case, whereas those in controls were 24.0% and 12.0%, respectively (Fig. 2A and B). In immunohistochemistry for tyrosine hydroxylase (TH) (monoclonal antibody at dilution of 1:400) (Affinity Bioreagents, CO, USA), the putamen showed reduced immunoreactivity, although that was comparatively preserved in the caudate (Fig. 2C and D). The medial and lateral segments in the globus pallidus demonstrated immunoreactivity for substance P (polyclonal antibody at dilution of 1:100) (Zymed Laboratories, Foster City, CA, USA), and methionine-enkephalin (polyclonal antibody at dilution of 1:1000) (Chemicon International, Inc., Temecula, CA, USA), respectively. Grumose foamy spheroid bodies (GFSBs) were increased in the medial segment of globus pallidus and in the substantia nigra pars reticularis (Fig. 3A). GFSB were stained by periodic acid Schiff and silver methods, and immunoreactive for ubiquitin (polyclonal antibody at dilution of 1:100) (Dako A/S, Glostrup, Denmark). There was no neuronal loss,
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
3
Fig. 2. The area encircled by dots designated the part of aberrant fiber running in the right putamen at the level of anterior commissure in a 65-yearold control (A) and the case (B), in which the latter was larger than the former. Bar = 5 mm, Klu¨ver–Barrera staining. Immunoreactivity for tyrosine hydroxylase was comparatively well preserved in the right putamen in a65-year-old control (C), and in the caudate in the case (asterisk) (D), whereas that was reduced in the putamen in the case (D). Bar = 5 mm.
Fig. 3. Grumose foamy spheroid body in the left substantia nigra pars reticulata in the case, Bar = 50 lm, hematoxylin eosin staining (A). Loss of Purkinje cells in the cerebellar cortex, Bar = 100 lm, hematoxylin eosin staining (B).
ballooning of cells orgliosis in the basal ganglia, thalamus and substantia nigra. In the cerebellum, loss of Purkinje cells was found throughout the cerebellar cortex except in the tuber and folium in the vermis (Fig. 3B), and there was fibrillary gliosis in the intrafolial white matter and hilum of dentate nucleus. In the brainstem, there was no neuronal loss, ballooning of cells, reduction of myelinated fibers or gliosis. Neurofibrillary tangles and senile plaques were absent throughout the CNS. 3. Discussion This case showed the combination of anomalies and degeneration in the visceral organs and CNS. Facial dysmorphism, microencephaly and bizarre putaminal lesion were anomalous, while the changes in the heart, liver, kidney and cerebellum were speculated to be degenerative. Such combination was found in congenital malformation syndrome, chromosomal anomalies [5],
and congenital metabolic errors such as lysosomal diseases, mucopolysaccharidosis (MPS) and congenital disorders of glycosylation (CDG) [1,2]. Our case showed no abnormal data in either of array CGH, activities of lysosomal enzymes or isoelectric focusing of serum transferrin, and the neurons and glial cells lacked ballooning in the brain. Hence she did not fit the typical phenotypes of chromosomal anomalies, copy number variation, MPS or CDG, although normal patterns in serum transferrin isoelectric focusing cannot exclude the possibility of subtle types of CDG completely [6]. Patients with Cockayne syndrome (CS) have microencephaly, developmental delay, kidney disease, liver cirrhosis, basal ganglia lesion and cerebellar atrophy. However our case did not reveal photosensitivity, progeroid features, hypomyelination or intracerebral calcification, all of which are observed in most CS patients [7]. The constellation of developmental delay, sick sinus syndrome, liver cirrhosis and cerebellar atrophy may occur in mitochondrial disorders, but prolonged slow
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
4
Y. Okoshi et al. / Brain & Development xxx (2014) xxx–xxx
course and facial dysmorphism were not in accordance with such disorders. Accordingly, we speculated that clinicopathological phenotype in our case is unique and has not been reported. Intriguingly, our case demonstrated bizarre structural changes in the putamen. Irregular running of pencil fiber may be anomalous, although the pathological significance was not clear. Rather the dissociative reduction of TH immunoreactivity in the putamen and caudate seemed to be more important, leading to the possible basal ganglia dysfunction. It should be noted that the putaminal lesion in our case was fine and not identified by brain MRI. Recently, we reported that the partial reduction of TH immunohistochemistry in the putamen may be involved in the generation of levodopa-responsive dystonia in the brain of Segawa disease [4]. On the other hand, regardless of the putaminal lesion, our case did not show any involuntary movements or rigidity except spastic paraplegia. Anomalous character in the putaminal lesion and/or complication of cerebellar lesion may be involved in absence of typical movement disorders. It is well known that GFSBs appear in the globus pallidus and substantia nigra in adult and child-onset neurodegenerative disorders, including CS [8,9]. The medial segment of the globus pallidus and substantia nigra pars reticularis consist of the striatal output pathway [10], and the occurrence of GFSBs may suggest the dysfunction of basal ganglia. In our case, GFSBs may be related to the selective paucity of TH-immunopositive fibers in the putamen. The combination of dysmorphic features in the face and brain, and degenerative changes in several organs is unique, and has not been reported within our knowledge. We believe that it will be a clue for the establishment of new disease entities to accumulate similar cases. Accumulation of subjects may enable the future exome analysis. Even in cases of developmental disorders, the functional evaluation of basal ganglia lesion should be implemented, using immunohistochemical analysis, in order to discuss the interrelationships
between movement disorders and the fine structural changes in the striatum and/or globus pallidus.
Acknowledgments The authors thank Dr. I. Yuasa, Division of Legal Medicine, Tottori University School of Medicine, for performing isoelectric focusing of serum transferrin. References [1] Gordon N. Carbohydrate-deficient glycoprotein syndromes. Postgrad Med J 2000;76:145–9. [2] Thomas JA, Beck M, Clarke JTR, Cox GF. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. J Inherit Metab Dis 2010;33:421–7. [3] Okumura A, Hayashi M, Shimojima K, Ikeno M, Uchida T, Takanashi J, et al. Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia. Neuropathology 2013;33:553–60. [4] Segawa M, Nomura Y, Hayashi M. Dopa-responsive dystonia is caused by particular impairment of nigrostriatal dopamine neurons different from those involved in Parkinson disease: evidence observed in studies on Segawa disease. Neuropediatrics 2013;44:61–6. [5] Speleman F, Craen M, Leroy J. De novo terminal deletion 7q22.1-pter in a child without craniosynostosis. J Med Genet 1989;26:528–32. [6] Jaeken J. Congenital disorders of glycosylation (CDG). J Inherit Met 2003;26:99–118. [7] Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992;42:68–84. [8] Arai N. Grumose or foamy spheroid bodies involving astrocytes in the human brain. Neuropathol Appl Neurobiol 1995;21:238–45. [9] Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawa K, et al. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 1999;21:326–33. [10] Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R, Tamagawa K. Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. J Neuropathol Exp Neurol 2004;63:1048–57.
Please cite this article in press as: Okoshi Y et al. An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2013.11.010
