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Pontocerebellar Hypoplasia Type 3 With Severe Vitamin A Deficiency
Pontocerebellar Hypoplasia Type 3 With Severe Vitamin A Deficiency Francois D. Jacob, MD, Simona Hasal, MD, and Helly R. Goez, MD Pontocerebellar hypoplasia consists of a rare heterogenous group of congenital neurodevelopmental disorders. It is characterized by hypoplasia and atrophy of the cerebellar cortex, dentate nuclei, pontine nuclei, and inferior olives. We present an 18-month-old infant with pontocerebellar hypoplasia type 3 and severe vitamin A deficiency. This case emphasizes the significance of vitamin A in the proper formation of the hindbrain. The authors conclude that vitamin A screening should be considered in maternal and newborn metabolic screening. Ó 2011 Elsevier Inc. All rights reserved. Jacob FD, Hasal S, Goez HR. Pontocerebellar hypoplasia type 3 with severe vitamin A deficiency. Pediatr Neurol 2011;44:147-149.
Introduction Pontocerebellar hypoplasia is the collective term for a rare group of congenital neurodevelopmental disorders that appear to have an autosomal recessive genetic etiology, and that compromise the cerebellar cortex, dentate nuclei, pontine nuclei, and inferior olives [1]. Other disorders associated with pontocerebellar hypoplasia include lissencephaly, congenital disorder of glycosylation, and mitochondrial disorders [2]. Initially, pontocerebellar hypoplasia was classified into two categories: type 1, which is characterized by a loss of spinal motor
neurons, similar to that in Werdnig-Hoffman disease; and type 2, which is characterized by the preservation of spinal motor neurons and the presence of chorea and dystonia. Since then, numerous other types have been described: type 3, which is characterized by cerebellar atrophy with progressive microcephaly and in some cases optic atrophy; type 4, which is characterized by severe neonatal encephalopathy associated with microcephaly, myoclonus, and muscular hypertonia; type 5, which is characterized by severe olivopontocerebellar hypoplasia and degeneration with fetal seizure-like activity; and type 6, which is characterized by fatal infantile encephalopathy [1,3-5]. We report on an 18-month-old infant with pontocerebellar hypoplasia type 3 and severe vitamin A deficiency. Case Report A 14-month-old boy was referred to our center for evaluation of his developmental delay. He was born at term to healthy nonconsanguineous parents after an unremarkable pregnancy and delivery. No history of maternal alcohol, tobacco, drug, or medication use was reported. An antenatal ultrasound at 18 weeks of gestation revealed right talipes equinovarus. The Apgar scores were 4, 6, and 8 at 1, 5, and 10 minutes, respectively. He briefly required positive pressure ventilation. His birth weight was 3420 g (50th percentile), and his head circumference was 34 cm (40th percentile). His neonatal course was complicated by hyperbilirubinemia (maximum level of 18.8 mg/dL; normal range, up to 18 mg/ dL), treated with phototherapy, and right talipes equinovarus, treated with casting. Developmentally, at age 6 months he displayed significant motor delay, and was unable to roll over. At age 14 months, he was able to roll over, but could not sit independently. His fine motor skills were also delayed, i.e., he had started to reach for objects and had an immature grasp. He was a social child who smiled and had started to make sounds, but he did not have any words. He demonstrated no history of developmental regression or seizures. Other medical issues included gastroesophageal reflux and chronic constipation. His family history included autism in a paternal first cousin, talipes equinovarus in two distant maternal and paternal cousins, and a mental and physical handicap of unclear etiology in a maternal first cousin. Upon examination at age 14 months, his head circumference was 40.5 cm (below the 2nd percentile), his weight was 5.9 kg (below the 5th percentile), and his height was 68 cm (below the 5th percentile). He exhibited no dysmorphic features. A cranial nerve examination revealed symmetrical pupils with a minimal reaction to light. He was unable to track objects. No nystagmus or roving eye movements were evident. A funduscopic examination revealed small, pale optic discs with attenuation of retinal vessels, in keeping with optic atrophy. He exhibited decreased axial tone and a head lag. His peripheral tone was increased in the upper and lower extremities. His hands were fisted, with cortical
From the Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Communications should be addressed to: Dr. Goez; Division of Pediatric Neurology, Department of Pediatrics; Stollery Children’s Hospital; #7319A Aberhart Centre 1; 11402 University Avenue NW; Edmonton, Alberta T6G 2J3, Canada. E-mail: [email protected] Received July 4, 2010; accepted September 10, 2010.
Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.09.002 0887-8994/$ - see front matter
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thumbs. He moved all four limbs symmetrically. His deep tendon reflexes were brisk bilaterally with spread, and sustained clonus at the right ankle. His plantar response was extensor bilaterally. A Galant reflex was present, but no parachute reflex was evident. Magnetic resonance imaging of the head and orbits (Fig 1) at age 15 months revealed pontocerebellar hypoplasia with optic chiasm atrophy. Laboratory investigations indicated normal liver function, and normal findings for serum lactate, ammonia, creatine kinase, thyroid stimulating hormone, and a metabolic screen, including a urinary organic acid profile. A screen for congenital disorders of glycosylation was unrevealing. A karyotype revealed 46 XY chromosomes. As part of the investigation of failure to thrive, serum vitamin levels were tested and revealed a severely low level of vitamin A (17.2 ng/mL; normal range, 28.7-71.6 ng/mL), with normal levels of vitamins D and E. A dietary assessment by a dietician determined that the infant’s intake of vitamin A was appropriate, excluding a nutritional deficit. No extra-central nervous system malformations, which are described in the literature in cases of maternal vitamin A deficiency, were evident in our patient. An electroencephalogram, performed at age 17 months, revealed a generalized slow background, with one focal epileptiform discharge from the left frontocentral head region, and a few generalized epileptiform bursts associated with drowsiness. No clinical correlation was observed.
Discussion Six categories of pontocerebellar hypoplasia have been defined. However, new and unique variants continue to be described in the literature. Reports have included forms with microcephaly, hypotonia, severe developmental delay, and seizures before age 1 year, combined with optic atrophy. Genetic testing revealed evidence for a linkage of this latter form to chromosome 7q11-q21 [6]. Another noteworthy variant presents with visual impairment without dyskinesia [7]. Because no clinical evidence existed of motor neuron loss or of a movement disorder such as dystonia or chorea, the present patient does not fit with the diagnostic classification of pontocerebellar hypoplasia types 1 or 2. Rather, the presence of optic atrophy is more consistent with cases of pontocerebellar hypoplasia type 3. Further diagnostic considerations of disorders combining pontocerebellar hypoplasia and optic atrophy include the progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy syndrome and cerebellar ataxia with mental retardation, optic atrophy, and skin abnormalities [8,9]. The present case shares many clinical features with these conditions. However, the distinguishing features of our patient include a lack of seizures, hypsarrhythmia, edema, or skin changes. In our patient, investigation revealed a normal karyotype and basic metabolic screen. However, a severely low level of vitamin A at age 14 months was identified, with otherwise normal levels of vitamin D and E. Acquired vitamin A deficiency is reported in children with chronic disease or malabsorption disorders. Its clinical signs include xerophthalmia, dry skin, dry hair, broken fingernails, and decreased resistance to infection. However, our patient presented no evidence of a malabsorption disorder, and his intake of vitamin A was appropriate. In utero retinoids are transferred to the embryo from the maternal circulation. The patient’s
148 PEDIATRIC NEUROLOGY Vol. 44 No. 2
mother presented no clinical evidence of vitamin A deficiency, and she maintained a well-balanced diet. We hypothesize that the low level of vitamin A may have contributed to the infant’s neurologic malformations. Animal studies indicate that the development of the cerebellum and of hindbrain patterning is significantly influenced by the vitamin A derivative retinoic acid [10]. Animal models of maternal vitamin A depletion described congenital malformations of the genitourinary tract, kidneys, diaphragm, lungs, aortic arch, heart, and central nervous system. Specific abnormalities of the central nervous system include hindbrain malformation, hydrocephalus, and spina bifida, but these abnormalities rarely appear without other organ abnormalities [11]. Gavrilova et al. [12] described a neonate with the syndrome of pulmonary or pulmonary artery hypoplasia, agonadism, omphalocele/diaphragmatic defect, and dextrocardia, as well as low levels of vitamin A. They hypothesized that a disturbance in the early stages of embryonic development, secondary to vitamin A deficiency, might have been responsible for some of the clinical features, because many similarities with the vitamin A deficiency syndrome were evident [12]. None of the extracentral nervous system signs described in the literature as characteristic of hypovitaminosis A was detected in our patient. The brainstem and cerebellum arise in the embryo from the hindbrain. Animal studies indicate that retinoic acid is responsible for hindbrain patterning. The developing spinal cord generates a gradient of retinoic acid, which is responsible for the organization of the posterior rhombomeres. In retinoic acid-deficient quail embryos, the posterior segments (R4-R7) of the hindbrain were completely missing [13]. Retinaldehyde dehydrogenase II is a retinoic acid-producing enzyme located in the spinal cord, and is responsible for the production of the retinoic acid gradient. In the retinaldehyde dehydrogenase II null mutant mouse, the caudal rhombomeres are missing [14]. The meninges overlying the anterior hindbrain, which were demonstrated to influence neuronal development in the cerebellum, also express retinaldehyde dehydrogenase II, and provide an extraneural source of retinoic acid [15,16]. Because the substrate of the retinaldehyde dehydrogenase II enzyme for producing retinoic acid is vitamin A, a state of low systemic vitamin A levels would cause a decrease in the activity of this enzyme. In addition to its hindbrainpatterning effects, retinoic acid induces neural differentiation in progenitors, as well as promote neurite outgrowth, which are necessary for the neural migration of these neurons [13,17]. Therefore, a low level of vitamin A in utero could lead to malformations of the posterior fossa and brainstem, and could contribute to the clinical phenotype of pontocerebellar hypoplasia. In conclusion, we present a patient with pontocerebellar hypoplasia type 3 associated with a severely low systemic level of vitamin A. This patient helps further define the phenotype of this rare congenital abnormality. We also suggest a possible connection between deficiency of vitamin A
Figure 1. Magnetic resonance imaging indicates pontocerebellar hypoplasia with otherwise normal brain structures and appropriate myelination for age. (A) T1 sagittal; (B) T2 coronal; (C) magnetization prepared rapid acquisition gradient echo axial magnetic resonance image.
and the formation of this brain anomaly. The association between low levels of vitamin A and malformations of the hindbrain is an intriguing concept that requires further elucidation, including studies of maternal vitamin A levels during pregnancy in afflicted fetuses and neonates. References [1] Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 1993;15:411-22. [2] Durmaz B, Wollnik B, Cogulu O, et al. Pontocerebellar hypoplasia type III (CLAM): Extended phenotype and novel molecular findings. J Neurol 2009;256:416-9. [3] Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol (Berl) 1993;85:394-9. [4] Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet [A] 2006;140:594-603. [5] Edvardson S, Shaag A, Kolesnikova O, et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 2007;81:857-62. [6] Rajab A, Mochida GH, Hill A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003;60: 1664-7. [7] Zelnik N, Dobyns WB, Forem SL, Kolodny EH. Congenital pontocerebellar atrophy in three patients: Clinical, radiologic and etiologic considerations. Neuroradiology 1996;38:684-7.
[8] Salonen R, Somer M, Haltia M, Lorentz M, Norio R. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome). Clin Genet 1991;39:287-93. [9] Megarbane A, Delague V, Ruchoux MM, et al. New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 2001;101:135-41. [10] McCaffery PJ, Adams J, Maden M, Rosa-Molinar E. Too much of a good thing: Retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci 2003;18:457-72. [11] Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr 2002;22: 347-81. [12] Gavrilova R, Babovic N, Lteif A, et al. Vitamin A deficiency in an infant with PAGOD syndrome. Am J Med Genet [A] 2009;149A: 2241-7. [13] McCaffery P, Drager UC. Regulation of retinoic acid signaling in the embryonic nervous system: A master differentiation factor. Cytokine Growth Factor Rev 2000;11:233-49. [14] Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 2000;127:75-85. [15] Niederreither K, McCaffery P, Drager UC, Chambon P, Dolle P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev 1997;62:67-78. [16] Sievers J, Pehlemann FW. Influences of meningeal cells on brain development. Findings and hypothesis. Naturwissenschaften 1986;73: 188-94. [17] Maden M. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci 2002;3:843-53.
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Introduction Pontocerebellar hypoplasia is the collective term for a rare group of congenital neurodevelopmental disorders that appear to have an autosomal recessive genetic etiology, and that compromise the cerebellar cortex, dentate nuclei, pontine nuclei, and inferior olives [1]. Other disorders associated with pontocerebellar hypoplasia include lissencephaly, congenital disorder of glycosylation, and mitochondrial disorders [2]. Initially, pontocerebellar hypoplasia was classified into two categories: type 1, which is characterized by a loss of spinal motor
neurons, similar to that in Werdnig-Hoffman disease; and type 2, which is characterized by the preservation of spinal motor neurons and the presence of chorea and dystonia. Since then, numerous other types have been described: type 3, which is characterized by cerebellar atrophy with progressive microcephaly and in some cases optic atrophy; type 4, which is characterized by severe neonatal encephalopathy associated with microcephaly, myoclonus, and muscular hypertonia; type 5, which is characterized by severe olivopontocerebellar hypoplasia and degeneration with fetal seizure-like activity; and type 6, which is characterized by fatal infantile encephalopathy [1,3-5]. We report on an 18-month-old infant with pontocerebellar hypoplasia type 3 and severe vitamin A deficiency. Case Report A 14-month-old boy was referred to our center for evaluation of his developmental delay. He was born at term to healthy nonconsanguineous parents after an unremarkable pregnancy and delivery. No history of maternal alcohol, tobacco, drug, or medication use was reported. An antenatal ultrasound at 18 weeks of gestation revealed right talipes equinovarus. The Apgar scores were 4, 6, and 8 at 1, 5, and 10 minutes, respectively. He briefly required positive pressure ventilation. His birth weight was 3420 g (50th percentile), and his head circumference was 34 cm (40th percentile). His neonatal course was complicated by hyperbilirubinemia (maximum level of 18.8 mg/dL; normal range, up to 18 mg/ dL), treated with phototherapy, and right talipes equinovarus, treated with casting. Developmentally, at age 6 months he displayed significant motor delay, and was unable to roll over. At age 14 months, he was able to roll over, but could not sit independently. His fine motor skills were also delayed, i.e., he had started to reach for objects and had an immature grasp. He was a social child who smiled and had started to make sounds, but he did not have any words. He demonstrated no history of developmental regression or seizures. Other medical issues included gastroesophageal reflux and chronic constipation. His family history included autism in a paternal first cousin, talipes equinovarus in two distant maternal and paternal cousins, and a mental and physical handicap of unclear etiology in a maternal first cousin. Upon examination at age 14 months, his head circumference was 40.5 cm (below the 2nd percentile), his weight was 5.9 kg (below the 5th percentile), and his height was 68 cm (below the 5th percentile). He exhibited no dysmorphic features. A cranial nerve examination revealed symmetrical pupils with a minimal reaction to light. He was unable to track objects. No nystagmus or roving eye movements were evident. A funduscopic examination revealed small, pale optic discs with attenuation of retinal vessels, in keeping with optic atrophy. He exhibited decreased axial tone and a head lag. His peripheral tone was increased in the upper and lower extremities. His hands were fisted, with cortical
From the Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Communications should be addressed to: Dr. Goez; Division of Pediatric Neurology, Department of Pediatrics; Stollery Children’s Hospital; #7319A Aberhart Centre 1; 11402 University Avenue NW; Edmonton, Alberta T6G 2J3, Canada. E-mail: [email protected] Received July 4, 2010; accepted September 10, 2010.
Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.09.002 0887-8994/$ - see front matter
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thumbs. He moved all four limbs symmetrically. His deep tendon reflexes were brisk bilaterally with spread, and sustained clonus at the right ankle. His plantar response was extensor bilaterally. A Galant reflex was present, but no parachute reflex was evident. Magnetic resonance imaging of the head and orbits (Fig 1) at age 15 months revealed pontocerebellar hypoplasia with optic chiasm atrophy. Laboratory investigations indicated normal liver function, and normal findings for serum lactate, ammonia, creatine kinase, thyroid stimulating hormone, and a metabolic screen, including a urinary organic acid profile. A screen for congenital disorders of glycosylation was unrevealing. A karyotype revealed 46 XY chromosomes. As part of the investigation of failure to thrive, serum vitamin levels were tested and revealed a severely low level of vitamin A (17.2 ng/mL; normal range, 28.7-71.6 ng/mL), with normal levels of vitamins D and E. A dietary assessment by a dietician determined that the infant’s intake of vitamin A was appropriate, excluding a nutritional deficit. No extra-central nervous system malformations, which are described in the literature in cases of maternal vitamin A deficiency, were evident in our patient. An electroencephalogram, performed at age 17 months, revealed a generalized slow background, with one focal epileptiform discharge from the left frontocentral head region, and a few generalized epileptiform bursts associated with drowsiness. No clinical correlation was observed.
Discussion Six categories of pontocerebellar hypoplasia have been defined. However, new and unique variants continue to be described in the literature. Reports have included forms with microcephaly, hypotonia, severe developmental delay, and seizures before age 1 year, combined with optic atrophy. Genetic testing revealed evidence for a linkage of this latter form to chromosome 7q11-q21 [6]. Another noteworthy variant presents with visual impairment without dyskinesia [7]. Because no clinical evidence existed of motor neuron loss or of a movement disorder such as dystonia or chorea, the present patient does not fit with the diagnostic classification of pontocerebellar hypoplasia types 1 or 2. Rather, the presence of optic atrophy is more consistent with cases of pontocerebellar hypoplasia type 3. Further diagnostic considerations of disorders combining pontocerebellar hypoplasia and optic atrophy include the progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy syndrome and cerebellar ataxia with mental retardation, optic atrophy, and skin abnormalities [8,9]. The present case shares many clinical features with these conditions. However, the distinguishing features of our patient include a lack of seizures, hypsarrhythmia, edema, or skin changes. In our patient, investigation revealed a normal karyotype and basic metabolic screen. However, a severely low level of vitamin A at age 14 months was identified, with otherwise normal levels of vitamin D and E. Acquired vitamin A deficiency is reported in children with chronic disease or malabsorption disorders. Its clinical signs include xerophthalmia, dry skin, dry hair, broken fingernails, and decreased resistance to infection. However, our patient presented no evidence of a malabsorption disorder, and his intake of vitamin A was appropriate. In utero retinoids are transferred to the embryo from the maternal circulation. The patient’s
148 PEDIATRIC NEUROLOGY Vol. 44 No. 2
mother presented no clinical evidence of vitamin A deficiency, and she maintained a well-balanced diet. We hypothesize that the low level of vitamin A may have contributed to the infant’s neurologic malformations. Animal studies indicate that the development of the cerebellum and of hindbrain patterning is significantly influenced by the vitamin A derivative retinoic acid [10]. Animal models of maternal vitamin A depletion described congenital malformations of the genitourinary tract, kidneys, diaphragm, lungs, aortic arch, heart, and central nervous system. Specific abnormalities of the central nervous system include hindbrain malformation, hydrocephalus, and spina bifida, but these abnormalities rarely appear without other organ abnormalities [11]. Gavrilova et al. [12] described a neonate with the syndrome of pulmonary or pulmonary artery hypoplasia, agonadism, omphalocele/diaphragmatic defect, and dextrocardia, as well as low levels of vitamin A. They hypothesized that a disturbance in the early stages of embryonic development, secondary to vitamin A deficiency, might have been responsible for some of the clinical features, because many similarities with the vitamin A deficiency syndrome were evident [12]. None of the extracentral nervous system signs described in the literature as characteristic of hypovitaminosis A was detected in our patient. The brainstem and cerebellum arise in the embryo from the hindbrain. Animal studies indicate that retinoic acid is responsible for hindbrain patterning. The developing spinal cord generates a gradient of retinoic acid, which is responsible for the organization of the posterior rhombomeres. In retinoic acid-deficient quail embryos, the posterior segments (R4-R7) of the hindbrain were completely missing [13]. Retinaldehyde dehydrogenase II is a retinoic acid-producing enzyme located in the spinal cord, and is responsible for the production of the retinoic acid gradient. In the retinaldehyde dehydrogenase II null mutant mouse, the caudal rhombomeres are missing [14]. The meninges overlying the anterior hindbrain, which were demonstrated to influence neuronal development in the cerebellum, also express retinaldehyde dehydrogenase II, and provide an extraneural source of retinoic acid [15,16]. Because the substrate of the retinaldehyde dehydrogenase II enzyme for producing retinoic acid is vitamin A, a state of low systemic vitamin A levels would cause a decrease in the activity of this enzyme. In addition to its hindbrainpatterning effects, retinoic acid induces neural differentiation in progenitors, as well as promote neurite outgrowth, which are necessary for the neural migration of these neurons [13,17]. Therefore, a low level of vitamin A in utero could lead to malformations of the posterior fossa and brainstem, and could contribute to the clinical phenotype of pontocerebellar hypoplasia. In conclusion, we present a patient with pontocerebellar hypoplasia type 3 associated with a severely low systemic level of vitamin A. This patient helps further define the phenotype of this rare congenital abnormality. We also suggest a possible connection between deficiency of vitamin A
Figure 1. Magnetic resonance imaging indicates pontocerebellar hypoplasia with otherwise normal brain structures and appropriate myelination for age. (A) T1 sagittal; (B) T2 coronal; (C) magnetization prepared rapid acquisition gradient echo axial magnetic resonance image.
and the formation of this brain anomaly. The association between low levels of vitamin A and malformations of the hindbrain is an intriguing concept that requires further elucidation, including studies of maternal vitamin A levels during pregnancy in afflicted fetuses and neonates. References [1] Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 1993;15:411-22. [2] Durmaz B, Wollnik B, Cogulu O, et al. Pontocerebellar hypoplasia type III (CLAM): Extended phenotype and novel molecular findings. J Neurol 2009;256:416-9. [3] Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol (Berl) 1993;85:394-9. [4] Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet [A] 2006;140:594-603. [5] Edvardson S, Shaag A, Kolesnikova O, et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 2007;81:857-62. [6] Rajab A, Mochida GH, Hill A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003;60: 1664-7. [7] Zelnik N, Dobyns WB, Forem SL, Kolodny EH. Congenital pontocerebellar atrophy in three patients: Clinical, radiologic and etiologic considerations. Neuroradiology 1996;38:684-7.
[8] Salonen R, Somer M, Haltia M, Lorentz M, Norio R. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome). Clin Genet 1991;39:287-93. [9] Megarbane A, Delague V, Ruchoux MM, et al. New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 2001;101:135-41. [10] McCaffery PJ, Adams J, Maden M, Rosa-Molinar E. Too much of a good thing: Retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci 2003;18:457-72. [11] Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr 2002;22: 347-81. [12] Gavrilova R, Babovic N, Lteif A, et al. Vitamin A deficiency in an infant with PAGOD syndrome. Am J Med Genet [A] 2009;149A: 2241-7. [13] McCaffery P, Drager UC. Regulation of retinoic acid signaling in the embryonic nervous system: A master differentiation factor. Cytokine Growth Factor Rev 2000;11:233-49. [14] Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 2000;127:75-85. [15] Niederreither K, McCaffery P, Drager UC, Chambon P, Dolle P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev 1997;62:67-78. [16] Sievers J, Pehlemann FW. Influences of meningeal cells on brain development. Findings and hypothesis. Naturwissenschaften 1986;73: 188-94. [17] Maden M. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci 2002;3:843-53.
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