- Email: [email protected]
Congenital disorder of glycosylation type 1a: Three siblings with a mild neurological phenotype
668
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
9. Ricchiuti VS, Seftel AD. Iatrogenic pneumocephalus after laparoscopic renal biopsy. J Urol 2001;166:982015–8. 10. Chhabra R, Pathak A, Ray P. Fatal posterior fossa pneumocephalus due to hydrogen peroxide irrigation of lumbar wound. Br J Neurosurg 2000;14:549–51.
11. Schwarz G, Tritthart H. Pneumocephalus–a possible cause of postoperative convulsions following cervical laminectomy (in German). Anasth Intensivther Notfallmed 1987;22:239–41. 12. Black PM, Davis JM, Kjellberg RN, et al. Tension pneumocephalus of the cranial subdural space: a case report. Neurosurgery 1979;5:368–70.
doi:10.1016/j.jocn.2006.02.021
Congenital disorder of glycosylation type 1a: Three siblings with a mild neurological phenotype D. Coman
a,d
, J. McGill a,d, R. MacDonald c, D. Morris d, S. Klingberg d, J. Jaeken e, D. Appleton b,*
a
b
Department of Metabolic Medicine, The Royal Children’s Hospital, Brisbane, Queensland, Australia Department of Neurology, The Royal Children’s Hospital, Herston Road, Brisbane 4029, Queensland, Australia c Department of Psychology, The Royal Children’s Hospital, Brisbane, Queensland, Australia d The Queensland Health Pathology Service, Brisbane, Queensland, Australia e Department of Pediatrics, Centre for Metabolic Disease, University Hospital, Gasthuisberg, Leuven, Belgium Received 24 November 2005; accepted 12 April 2006
Abstract We report 3 siblings (1 male and 2 female) recently diagnosed with congenital disorder of glycosylation type Ia (CDG-Ia) in their mid20s. They experience mild mental retardation but manage to function independently in society. Their professions are library assistant, professional artistic painter and secretarial work. All three siblings have cerebellar hypoplasia and ataxia, but are able to ambulate easily. Two of the siblings have required strabismus surgical repairs. All have antithrombin III deficiency, osteoporosis, and mild dysmorphic features. Hypergonadotrophic hypogonadism was a feature of the two female siblings. A type 1 sialotransferrin pattern and phosphomannomutase (PMM) deficiency have been demonstrated. They are compound heterozygotes for R141H and L32R mutations in the PMM2 gene. While there is clinical heterogeneity in CDG-Ia, we believe that our patients are among the mildest of intellectually affected CDG-Ia patients reported to date. 2006 Published by Elsevier Ltd. Keywords: Congenital disorder of glycosylation type 1a; Phosphomannomutase; Transferrin isoforms
1. Introduction The congenital disorders of glycosylation are autosomal recessive disorders with defects in the synthesis or processing of N-glycans.1 The most common sub-type is congenital disorder of glycosylation (CDG) type Ia, with over 500 reported cases worldwide.2 There is marked clinical heterogeneity in CDG-Ia, and multi-organ pathology is typical. Major clinical features include mental retardation, cerebellar hypoplasia, peripheral neuropathy, growth retardation, hepatic dysfunction, stroke-like episodes, haemorrhagic episodes and seizures.3 Mortality resulting from severe infections, liver insufficiency or cardiomyopathy is reported
*
Corresponding author. Tel.: +61 7 3636 8111; fax: +61 7 3636 1860. E-mail address: [email protected] (D. Appleton).
in approximately 20% of cases in the first year of life.4 Most of the reported cases thus far have been children; however milder clinical phenotypes are being recognised that may have escaped diagnosis during the paediatric phase of life; thus highlighting the importance of increased awareness of CDG-1a for the neurologist dealing with adults. CDG-Ia is secondary to a deficiency in the enzyme phosphomannomutase (PMM),1 which was discovered some 15 years after Jaeken’s first clinical description. Phosphomannomutase is a cytosolic enzyme that isomerises mannose6-phosphate to mannose-1-phosphate.4 PMM deficiency decreases the supply of intracellular GDP-mannose and limits the amount of lipid-linked oligosaccharide precursor available for protein glycosylation.5 We describe three siblings diagnosed in adulthood, who display a remarkably mild intellectual phenotype despite significant multi-organ pathology.
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
2. Combined patient summary Tables 1 and 2 provide summary of the patients’ clinical and neuropsychological features. Their parents are nonconsanguineous. All three children had presented to their paediatrician and neurologist by 18 months of age due to maternal concerns regarding global developmental delay, in particular affecting gross motor aspects. Common clinical features displayed by the siblings during childhood included cerebellar hypoplasia (affecting the Table 1 Wechsler Adult Intelligence Scale – third edition (Australian adaptation)
Verbal IQ Performance IQ Full scale IQ Verbal comprehension Perceptual organisation Working memory index Processing speed Profession and function
Patient 1 Score
Patient 2 Score Patient 3 Score
65 60 60 67
58 54 52 61
MI MI MI MI
MOI MOI MOI MI
72 63 65 76
B MI MI B
50 MOI
54 MOI
69 MI
71 B
53 MOI
78 B
57 MOI Library assistant, lives independently
57 MOI Professional artist lives with parents.
50 MOI Secretarial work, lives independently
MI mild impairment, MOI moderate impairment, B borderline.
669
entire cerebellum as identified on CT scanning), mild ataxia and mild global developmental delay. Subtle dysmorphic features were present in all three siblings, which included slightly larger ears than other family members. Inverted nipples and subcutaneous fat pads were not present. Patients 1 and 2 required strabismus surgery. During adolescence and adulthood, common clinical manifestations included antithrombin III deficiency and osteoporosis. Only patient 1 has experienced deep venous thromboses and fractures. Both the female siblings have displayed hypergonadotrophic hypogonadism requiring estrogen supplementation for pubertal development. All siblings have followed the 50–75 percentile growth parameters for height, weight and head circumference throughout their life. Clinical examination by their neurologist has not elucidated any progressive neurological features of CDG1a, in that their ataxia and cognitive abilities have not deteriorated and there are no signs of a peripheral neuropathy on clinical examination. The combination of cerebellar pathology (Fig. 1), prothrombotic tendencies, osteoporosis, and hypergonadotrophic hypogonadism led their paediatric neurologist to consider CDG-Ia as a possible diagnosis. A type 1 transferrin isoform pattern (Fig. 2), decreased PMM activity in leucocytes and subsequently the demonstration of compound heterozygous mutations in the PMM2 gene, confirmed the
Table 2 Summary of clinical features
Age at diagnosis Sex Cerebellar hypoplasia Peripheral neuropathy Level of function Eye Antithrombin III level (80–120) Thrombotic events Orthopaedic
Puberty
Dysmorphic Transferrin Isoform patterna TBG (11–35 mg/L) PMM (WBC assay)b (0.3–1.6 u/g protein) Genotypec a
Patient 1
Patient 2
Patient 3
28 Female Present Absent Library assistant, lives independently Strabismus. Surgery 2 years old
24 Male Present Absent Artist
20 Female Present Absent Secretarial work, lives independently Nil
42% Right leg DVT Warfarin Osteoporosis Z Score –2.88 T Score –2.99 Fractured clavicle Hypergonadotrophic hypogonadism LH 61 U/L (1–12) FSH 269 U/L (1–8) Oestradol <35 pmol/L (80–1300) Prolactin 6 mU/L (<500) Large ears Type 1 pattern TBG 15 mg/L 0.1 R141H/L32R
Strabismus. Surgery 2 years old 71% No DVT Aspirin Osteopenia Z Score –1.8 T Score –2.0 Normal
45% No DVT Aspirin Osteoporosis Z Score –4 T Score –2.1
Large ears Type1 pattern TBG 10 mg/L
Hypergonadotrophic hypogonadism LH 45 U/L (1–12) FSH 92 U/L (1–8) Oestradol <35 pmol/L (80–1300) Prolactin 185 mU/L (<500) Large ears Type 1 pattern TBG 15 mg/L
0.08 R141H/L32R
<0.1 R141H/L32R
Isoelectric focusing (IEF) analysis of transferrin was performed by standard methods,15 TBG = thyroxine binding globule, DVT = deep vein thrombosis, LH = luteinizing hormone, FSH = follicle stimulating hormone, PMM = phosphomannomutase, WBC = white blood cell. b PMM activities were determined as previously described.15 c PMM2 Genotype determined using previously described techniques for cDNA analysis and genomic DNA analysis15 (performed by G Matthijs, Belgium).
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Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
Fig. 3. ‘‘Seascape’’ (with permission of the artist).
Fig. 1. MRI Scan; 3-year-old child with CDG1a and global cerebellar hypoplasia.
Fig. 4. ‘‘Windmill’’ (with permission of the artist).
Fig. 2. Transferrin Isoforms: Transferrin normally contains two complex carbohydrate side chains consisting of four different carbohydrates (Nacetylglucosamine, mannose, galactose and sialic acid). Sialic acid is the only charged carbohydrate; it is always positioned terminally, and 0–6 or more residues may be present, resulting in variations in isoelectric point (pI) of 0.1 pH per residue. The main transferrin isoform has a pI of 5.4 and four sialic acid residues (tetrasialotransferrin), two on each carbohydrate side chain. Minor isoforms with lower pI (penta- and hexasialotransferrin) and higher pI values (tri- and disialotransferrin) are normally present in decreasing amounts. Disialo- (pI 5.7), monosialo- (pI 5.8) and asialotransferrin (pI 5.9) are the ‘carbohydrate-deficient’ isoforms seen in congenital disorders of glycosylation syndromes (CDG). CDG type I results in transferrin isoform patterns with increased amounts of asialoand disialotransferrin bands. The disialotransferrin isoform in Type I CDGS is of equal or greater intensity (concentration) than the tetrasialotransferrin, which is usually the predominating isoform. CDG QC, known CDG1a patient quality control.
diagnosis of CDG-1a in our patients. Their ages at the time of diagnosis ranged from 20–28 years of age. All three siblings are capable of independent living, functioning and employment. Patient 1 experiences more functional cognitive difficulties compared to her siblings. She works as a library assistant in a semi-supervised capacity and her activities mainly involve stock maintenance rather than journal cataloguing; patient 2 is a professional
artist (see Figs. 3 and 4 for examples of this artwork). Patient 3 works as a secretary in a local real estate agency. She writes short stories and screen plays in her spare time, none of which have been published to date. 3. Discussion In CDG, hypoglycosylation of different glycoproteins and occasionally of other glycoconjugates leads to a variety of symptoms affecting multiple systems,6 reflecting the important role glycosylation has in the function of numerous proteins and hence reflecting the multi-system nature of the clinical features observed. Some authors have described three clinical stages/phases for CDG-Ia: infantile multisystem stage; late infantile and childhood ataxia–mental retardation stage; and adult disability stage. However, many affected individuals, including most of the mildly affected ones, do not follow that clinical pattern. Approximately 20% of CDG-Ia infants do not survive the infantile period, with death occurring secondary to hepatic insufficiency, cardiomyopathy, pericardial effusion, sepsis and multiorgan failure.4 Features such as facial dysmorphism (high nasal bridge, prominent jaw and large ears), strabismus and unusual fat pads are also observed.7 The childhood ataxia and mental retardation stage is highlighted by hypotonia, ataxia (from cere-
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
bellar hypoplasia and/or atrophy), retinitis pigmentosa and joint contractures. Acute deteriorations during this phase occur due to stroke-like events. Hypergonadotrophic hypogonadism, stroke-like events, progressive retinitis pigmentosa, and peripheral neuropathy are important clinical features during the adult stable phase. Mental cognitive capabilities are stable during this phase. Central and peripheral nervous system involvement are predominant features of CDG-Ia. Central involvement includes generalised cerebellar hypoplasia/atrophy, hypotonia, mental retardation, developmental delay, and acute neurological events.8,9 Both epilepsy and strokes have been reported in 50% of patients.10 Stroke-like events may be triggered by intercurrent infections with variable outcomes. Decreased antithrombin III and protein C have been reported and may play a role in the aetiology of these stroke-like events.9 Peripheral neuropathy develops and exacerbates the ataxia caused by cerebellar involvement. Our patients differ from the majority of the CDG-Ia patients reported in the literature, who display moderate-severe psychomotor delay.11 Unsupported walking is attained in a small minority of CDG-Ia patients.12,13 Mental retardation, memory impairment, and perceptual difficulties can create significant learning difficulty.10 The average intellectual quotient (IQ) commonly reported is in the 40–60 range.4,8,12 Other cases of CDG-Ia with mild intellectual impairment have been reported previously,1,12–14 with their receptive language and cognitive ability being stronger than motor abilities.15–17 An intriguing aspect of our patient’s phenotype is their ability to perform above weaknesses identified on Wechsler Intelligence Scale for Children (WISC) testing. Patient 1 suffers the most significant functional difficulties and works in a semi-supervised environment as a library assistant. Patent 2 has exhibited moderate impairment in perceptual skills but is a capable and skilful professional artist. Patient 3 displayed borderline IQ and comprehension but manages to work successfully and without supervision in a real estate agency. The results of our patients’ WISC testing has perhaps not done them justice, and may reflect under-performance during the testing period. Reported endocrine features include euthyroidism, hyperprolactinaemia,18 postnatal growth failure,19 hyperinsulinaemic hypoglycaemia,20 and hypergonadotrophic hypogonadism.21 Treatment of the osteopenia and hypogonadotrophic hypogonadism with estrogens can increase the risk of thrombotic events in predisposed female patients. Bisphosphonates might be beneficial in patients with recurrent fractures.22 CDG commonly exhibits an unusual subcutaneous fat distribution pattern over the buttocks and the suprapubic area. The cause for this lipodystrophy is unknown and the pattern of lipodystrophy appears to be distinct from that created by lamin A/C gene defects. Ophthalmic manifestations are frequent in CDG-Ia, with congenital esotropia, delayed visual maturation, and retinitis pigmentosa being the most frequent abnormalities noted.6 The PMM2 gene maps to chromosome 16p13, consists of eight exons and spans at least 17 kb of genomic DNA
671
and to date over 50 mutations have been described.20,23 The R141H mutation accounts for 40% of disease alleles in CDG-Ia patients, with a carrier frequency of 1/70 in the general population.2 Our patients were found to be compound heterozygous for the R141H mutation and the L32R mutation. L32R in combination with R141H has been reported to have residual PMM activity of 30–50%,5 perhaps accounting for the milder clinical patients reported with these mutations. Giurgea et al. describes two remarkable patients with normal intelligence, mild neurological signs and PMM2 mutations of C241S/R141H and V44F, and Q37H/R141H respectively.24 For the most part, no correlation can be drawn between genotype and phenotype,15 although some mild functional mutations have been reported, involved with a milder neurological phenotype. C9Y, C241S,5 E151G,8 T18S and V67G,25 are examples of such mild mutations. Patient 3 expressed the mildest neurological phenotype but has a PMM activity usually seen in more severely affected patients. This observation and the interfamilial variation in clinical and biochemical phenotype are difficult to explain. Perhaps there are other factors influencing disease expression in our patients, for example modifier genes or environmental factors affecting glycosylation. An example of a polymorphism amplifying the disease expression in severe cases of CDG-Ia is the F304S polymorphism in the ALG6 gene. This polymorphism places further stress on an already defective glycosylation system.26 Pathogenic mutations in the ALG6 gene are responsible for CDG1c.26 Our patients have mild global developmental delay but manage to live and work independently as well as display abstract and creative thought. We believe that our patients are among the mildest of CDG-Ia neurological phenotypes reported thus far. Acknowledgement Dr Coman is supported by the Royal Children’s Hospital Foundation, Cressbrook Committee. Mutation analysis was kindly preformed by Professor Matthijs and Dr Els Schollen. Patient 2 (LK) has kindly given permission for the use of Figs. 1 and 2. References 1. Mader I, Dobler-Neumann M, KuKer W, et al. Congenital disorder of glycosylation type 1a: benign clinical course in a new genetic variant. Childs Nerv Syst 2002;18:77–80. 2. Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003;162:359–79. 3. Mizughishi K, Yamanaka K, Kuwajima K, et al. Missense mutations in the phosphomannomutase 2 gene of two Japanese siblings with carbohydrate-deficient glycoprotein syndrome type I. Brain Dev 1999;21:223–8. 4. Drouin-Garraud V, Belgrand M, Grunewald S, et al. Neurological presentation of a congenital disorder of glycosylation CDG-Ia:
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5.
6.
7. 8.
9.
10. 11.
12.
13. 14.
15.
Case reports / Journal of Clinical Neuroscience 14 (2007) 672–675 Implications for diagnosis and genetic counselling. Am J Med Genet 2001;101:46–9. Westphal V, Peterson S, Patterson M, et al. Functional significance of PMM2 mutations in mildly affected patients with congenital disorder of glycosylation Ia. Genet Med 2001;3:393–8. Jensen H, Kjaergaard S, Klie F, et al. Ophthalmic mainfestations of congenital disorder of glycosylation type Ia. Ophthal Genet 2003;24: 81–8. Gene Reviews (Online). 2005 August; Available from: URL: http:// www.genetests.org/ (Accessed 14 March 2006). Miossec-Chauvet E, Mikaeloff Y, Heron D, et al. Neurological presentations in pediatric patients with congenital disorder of glycosylation type Ia. Neuropediatrics 2003;34:1–6. Jensen PR, Hansen FJ, Skovby F. Cerebellar hypoplasia in children with the carbohydrate-deficient glycoprotein syndrome. Neuroradiology 1995;37:328–30. Pearl P, Krasnewich D. Neurologic course of congenital disorders of glycosylation. J Child Neurol 2001;16:409–13. Barone R, Pavone L, Fiumara A, et al. Developmental patterns and neuropsychological assesment in patients with carbohydrate-deficient glycoconjugate syndrome type Ia (phosphomannomutase deficiency). Brain Dev 1999;21:260–3. Van Ommenn C, Peters M, Barth P, et al. Carbohydrate-deficient glycoprotein syndrome type Ia: A variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances. J Pediatr 2000;136:400–3. Jaeken J, Carchon H. What’s new in congenital disorders of glycosylation? Eur J Pediatr Neurol 2000;4:163–7. deLonay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a serries of 26 cases. J Med Genet 2001;38:14–9. Stibler H, Blennow G, Kristiansson B, et al. Carbohydrate-deficient glycoprotein syndrome: clinical expression in adults with a new metabolic disease. J Neurol Neurosurg Psychiatry 1994;57:552–6.
16. Westphal V, Enns GM, McCracken MF, et al. Functional analysis of novel mutations in a congenital disorder of glycosylation ia patient with mixed Asian ancestry. Mol Genet Metab 2001;73:71–6. 17. Briones P, Vilaseca MA, Schollen E, et al. Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia. J Inherit Metab Dis 2002;25:635–46. 18. De Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type i from birth through adolescence. Pediatr Res 1995;37:395–401. 19. Kjaergaard S, Muller J, Skovby F. Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia). Arch Dis Child 2002;87:324–7. 20. Matthijs G, Schollen E, Bjursell C. Mutations in PMM2 that cause congenital disorders if glycosylation, type Ia (CDG-Ia). Hum Mutat 2000;16:386–94. 21. Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: A review. Pediatr Res 2002;52:618–24. 22. Jaeken J. Congenital disorders of glycosylation (CDG): It’s all in it! J Inherit Metab Dis 2003;26:99–118. 23. Enn G, Steiner R, Bruist N, et al. Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins. J Pediatr 2002;141:695–700. 24. Giurgea I, Michel A, Le Merrer M, et al. Under diagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol 2005;32:121–3. 25. Coman D, Klingberg S, Morris D, et al. Congenital disorder of glycosylation type Ia in a 6-year-old girl with a mild intellectual phenotype: Two novel PMM2 mutations. J Inherit Metab Dis 2005;28:1189–90. 26. Westphal V, Kjaergaard S, Schollen E, et al. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum Molec Genet 2002;11: 599–604.
doi:10.1016/j.jocn.2006.04.008
Intraventricular rhabdoid meningioma Jacqueline McMaster *, Thomas Ng, Mark Dexter Westmead Hospital, Department of Neurosurgery, PO Box 533, Wentworthville, New South Wales, 2145, Australia Received 19 December 2005; accepted 22 February 2006
Abstract Rhabdoid meningioma is a rare variant of meningioma, often found in tumour recurrences. We report a 55-year-old woman with a history of intraventricular fibroblastic meningioma, who developed headache and tinnitus 5 years after complete resection of the initial tumour. Imaging confirmed a recurrent tumour in the intraventricular location. Histological analysis revealed rhabdoid meningioma. We reviewed the literature and were unable to find any previously reported cases of intraventricular rhabdoid meningioma. 2006 Elsevier Ltd. All rights reserved. Keywords: Meningioma; Rhabdoid; Intraventricular; Recurrence
*
Corresponding author. E-mail address: [email protected] (J. McMaster).
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
9. Ricchiuti VS, Seftel AD. Iatrogenic pneumocephalus after laparoscopic renal biopsy. J Urol 2001;166:982015–8. 10. Chhabra R, Pathak A, Ray P. Fatal posterior fossa pneumocephalus due to hydrogen peroxide irrigation of lumbar wound. Br J Neurosurg 2000;14:549–51.
11. Schwarz G, Tritthart H. Pneumocephalus–a possible cause of postoperative convulsions following cervical laminectomy (in German). Anasth Intensivther Notfallmed 1987;22:239–41. 12. Black PM, Davis JM, Kjellberg RN, et al. Tension pneumocephalus of the cranial subdural space: a case report. Neurosurgery 1979;5:368–70.
doi:10.1016/j.jocn.2006.02.021
Congenital disorder of glycosylation type 1a: Three siblings with a mild neurological phenotype D. Coman
a,d
, J. McGill a,d, R. MacDonald c, D. Morris d, S. Klingberg d, J. Jaeken e, D. Appleton b,*
a
b
Department of Metabolic Medicine, The Royal Children’s Hospital, Brisbane, Queensland, Australia Department of Neurology, The Royal Children’s Hospital, Herston Road, Brisbane 4029, Queensland, Australia c Department of Psychology, The Royal Children’s Hospital, Brisbane, Queensland, Australia d The Queensland Health Pathology Service, Brisbane, Queensland, Australia e Department of Pediatrics, Centre for Metabolic Disease, University Hospital, Gasthuisberg, Leuven, Belgium Received 24 November 2005; accepted 12 April 2006
Abstract We report 3 siblings (1 male and 2 female) recently diagnosed with congenital disorder of glycosylation type Ia (CDG-Ia) in their mid20s. They experience mild mental retardation but manage to function independently in society. Their professions are library assistant, professional artistic painter and secretarial work. All three siblings have cerebellar hypoplasia and ataxia, but are able to ambulate easily. Two of the siblings have required strabismus surgical repairs. All have antithrombin III deficiency, osteoporosis, and mild dysmorphic features. Hypergonadotrophic hypogonadism was a feature of the two female siblings. A type 1 sialotransferrin pattern and phosphomannomutase (PMM) deficiency have been demonstrated. They are compound heterozygotes for R141H and L32R mutations in the PMM2 gene. While there is clinical heterogeneity in CDG-Ia, we believe that our patients are among the mildest of intellectually affected CDG-Ia patients reported to date. 2006 Published by Elsevier Ltd. Keywords: Congenital disorder of glycosylation type 1a; Phosphomannomutase; Transferrin isoforms
1. Introduction The congenital disorders of glycosylation are autosomal recessive disorders with defects in the synthesis or processing of N-glycans.1 The most common sub-type is congenital disorder of glycosylation (CDG) type Ia, with over 500 reported cases worldwide.2 There is marked clinical heterogeneity in CDG-Ia, and multi-organ pathology is typical. Major clinical features include mental retardation, cerebellar hypoplasia, peripheral neuropathy, growth retardation, hepatic dysfunction, stroke-like episodes, haemorrhagic episodes and seizures.3 Mortality resulting from severe infections, liver insufficiency or cardiomyopathy is reported
*
Corresponding author. Tel.: +61 7 3636 8111; fax: +61 7 3636 1860. E-mail address: [email protected] (D. Appleton).
in approximately 20% of cases in the first year of life.4 Most of the reported cases thus far have been children; however milder clinical phenotypes are being recognised that may have escaped diagnosis during the paediatric phase of life; thus highlighting the importance of increased awareness of CDG-1a for the neurologist dealing with adults. CDG-Ia is secondary to a deficiency in the enzyme phosphomannomutase (PMM),1 which was discovered some 15 years after Jaeken’s first clinical description. Phosphomannomutase is a cytosolic enzyme that isomerises mannose6-phosphate to mannose-1-phosphate.4 PMM deficiency decreases the supply of intracellular GDP-mannose and limits the amount of lipid-linked oligosaccharide precursor available for protein glycosylation.5 We describe three siblings diagnosed in adulthood, who display a remarkably mild intellectual phenotype despite significant multi-organ pathology.
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
2. Combined patient summary Tables 1 and 2 provide summary of the patients’ clinical and neuropsychological features. Their parents are nonconsanguineous. All three children had presented to their paediatrician and neurologist by 18 months of age due to maternal concerns regarding global developmental delay, in particular affecting gross motor aspects. Common clinical features displayed by the siblings during childhood included cerebellar hypoplasia (affecting the Table 1 Wechsler Adult Intelligence Scale – third edition (Australian adaptation)
Verbal IQ Performance IQ Full scale IQ Verbal comprehension Perceptual organisation Working memory index Processing speed Profession and function
Patient 1 Score
Patient 2 Score Patient 3 Score
65 60 60 67
58 54 52 61
MI MI MI MI
MOI MOI MOI MI
72 63 65 76
B MI MI B
50 MOI
54 MOI
69 MI
71 B
53 MOI
78 B
57 MOI Library assistant, lives independently
57 MOI Professional artist lives with parents.
50 MOI Secretarial work, lives independently
MI mild impairment, MOI moderate impairment, B borderline.
669
entire cerebellum as identified on CT scanning), mild ataxia and mild global developmental delay. Subtle dysmorphic features were present in all three siblings, which included slightly larger ears than other family members. Inverted nipples and subcutaneous fat pads were not present. Patients 1 and 2 required strabismus surgery. During adolescence and adulthood, common clinical manifestations included antithrombin III deficiency and osteoporosis. Only patient 1 has experienced deep venous thromboses and fractures. Both the female siblings have displayed hypergonadotrophic hypogonadism requiring estrogen supplementation for pubertal development. All siblings have followed the 50–75 percentile growth parameters for height, weight and head circumference throughout their life. Clinical examination by their neurologist has not elucidated any progressive neurological features of CDG1a, in that their ataxia and cognitive abilities have not deteriorated and there are no signs of a peripheral neuropathy on clinical examination. The combination of cerebellar pathology (Fig. 1), prothrombotic tendencies, osteoporosis, and hypergonadotrophic hypogonadism led their paediatric neurologist to consider CDG-Ia as a possible diagnosis. A type 1 transferrin isoform pattern (Fig. 2), decreased PMM activity in leucocytes and subsequently the demonstration of compound heterozygous mutations in the PMM2 gene, confirmed the
Table 2 Summary of clinical features
Age at diagnosis Sex Cerebellar hypoplasia Peripheral neuropathy Level of function Eye Antithrombin III level (80–120) Thrombotic events Orthopaedic
Puberty
Dysmorphic Transferrin Isoform patterna TBG (11–35 mg/L) PMM (WBC assay)b (0.3–1.6 u/g protein) Genotypec a
Patient 1
Patient 2
Patient 3
28 Female Present Absent Library assistant, lives independently Strabismus. Surgery 2 years old
24 Male Present Absent Artist
20 Female Present Absent Secretarial work, lives independently Nil
42% Right leg DVT Warfarin Osteoporosis Z Score –2.88 T Score –2.99 Fractured clavicle Hypergonadotrophic hypogonadism LH 61 U/L (1–12) FSH 269 U/L (1–8) Oestradol <35 pmol/L (80–1300) Prolactin 6 mU/L (<500) Large ears Type 1 pattern TBG 15 mg/L 0.1 R141H/L32R
Strabismus. Surgery 2 years old 71% No DVT Aspirin Osteopenia Z Score –1.8 T Score –2.0 Normal
45% No DVT Aspirin Osteoporosis Z Score –4 T Score –2.1
Large ears Type1 pattern TBG 10 mg/L
Hypergonadotrophic hypogonadism LH 45 U/L (1–12) FSH 92 U/L (1–8) Oestradol <35 pmol/L (80–1300) Prolactin 185 mU/L (<500) Large ears Type 1 pattern TBG 15 mg/L
0.08 R141H/L32R
<0.1 R141H/L32R
Isoelectric focusing (IEF) analysis of transferrin was performed by standard methods,15 TBG = thyroxine binding globule, DVT = deep vein thrombosis, LH = luteinizing hormone, FSH = follicle stimulating hormone, PMM = phosphomannomutase, WBC = white blood cell. b PMM activities were determined as previously described.15 c PMM2 Genotype determined using previously described techniques for cDNA analysis and genomic DNA analysis15 (performed by G Matthijs, Belgium).
670
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
Fig. 3. ‘‘Seascape’’ (with permission of the artist).
Fig. 1. MRI Scan; 3-year-old child with CDG1a and global cerebellar hypoplasia.
Fig. 4. ‘‘Windmill’’ (with permission of the artist).
Fig. 2. Transferrin Isoforms: Transferrin normally contains two complex carbohydrate side chains consisting of four different carbohydrates (Nacetylglucosamine, mannose, galactose and sialic acid). Sialic acid is the only charged carbohydrate; it is always positioned terminally, and 0–6 or more residues may be present, resulting in variations in isoelectric point (pI) of 0.1 pH per residue. The main transferrin isoform has a pI of 5.4 and four sialic acid residues (tetrasialotransferrin), two on each carbohydrate side chain. Minor isoforms with lower pI (penta- and hexasialotransferrin) and higher pI values (tri- and disialotransferrin) are normally present in decreasing amounts. Disialo- (pI 5.7), monosialo- (pI 5.8) and asialotransferrin (pI 5.9) are the ‘carbohydrate-deficient’ isoforms seen in congenital disorders of glycosylation syndromes (CDG). CDG type I results in transferrin isoform patterns with increased amounts of asialoand disialotransferrin bands. The disialotransferrin isoform in Type I CDGS is of equal or greater intensity (concentration) than the tetrasialotransferrin, which is usually the predominating isoform. CDG QC, known CDG1a patient quality control.
diagnosis of CDG-1a in our patients. Their ages at the time of diagnosis ranged from 20–28 years of age. All three siblings are capable of independent living, functioning and employment. Patient 1 experiences more functional cognitive difficulties compared to her siblings. She works as a library assistant in a semi-supervised capacity and her activities mainly involve stock maintenance rather than journal cataloguing; patient 2 is a professional
artist (see Figs. 3 and 4 for examples of this artwork). Patient 3 works as a secretary in a local real estate agency. She writes short stories and screen plays in her spare time, none of which have been published to date. 3. Discussion In CDG, hypoglycosylation of different glycoproteins and occasionally of other glycoconjugates leads to a variety of symptoms affecting multiple systems,6 reflecting the important role glycosylation has in the function of numerous proteins and hence reflecting the multi-system nature of the clinical features observed. Some authors have described three clinical stages/phases for CDG-Ia: infantile multisystem stage; late infantile and childhood ataxia–mental retardation stage; and adult disability stage. However, many affected individuals, including most of the mildly affected ones, do not follow that clinical pattern. Approximately 20% of CDG-Ia infants do not survive the infantile period, with death occurring secondary to hepatic insufficiency, cardiomyopathy, pericardial effusion, sepsis and multiorgan failure.4 Features such as facial dysmorphism (high nasal bridge, prominent jaw and large ears), strabismus and unusual fat pads are also observed.7 The childhood ataxia and mental retardation stage is highlighted by hypotonia, ataxia (from cere-
Case reports / Journal of Clinical Neuroscience 14 (2007) 668–672
bellar hypoplasia and/or atrophy), retinitis pigmentosa and joint contractures. Acute deteriorations during this phase occur due to stroke-like events. Hypergonadotrophic hypogonadism, stroke-like events, progressive retinitis pigmentosa, and peripheral neuropathy are important clinical features during the adult stable phase. Mental cognitive capabilities are stable during this phase. Central and peripheral nervous system involvement are predominant features of CDG-Ia. Central involvement includes generalised cerebellar hypoplasia/atrophy, hypotonia, mental retardation, developmental delay, and acute neurological events.8,9 Both epilepsy and strokes have been reported in 50% of patients.10 Stroke-like events may be triggered by intercurrent infections with variable outcomes. Decreased antithrombin III and protein C have been reported and may play a role in the aetiology of these stroke-like events.9 Peripheral neuropathy develops and exacerbates the ataxia caused by cerebellar involvement. Our patients differ from the majority of the CDG-Ia patients reported in the literature, who display moderate-severe psychomotor delay.11 Unsupported walking is attained in a small minority of CDG-Ia patients.12,13 Mental retardation, memory impairment, and perceptual difficulties can create significant learning difficulty.10 The average intellectual quotient (IQ) commonly reported is in the 40–60 range.4,8,12 Other cases of CDG-Ia with mild intellectual impairment have been reported previously,1,12–14 with their receptive language and cognitive ability being stronger than motor abilities.15–17 An intriguing aspect of our patient’s phenotype is their ability to perform above weaknesses identified on Wechsler Intelligence Scale for Children (WISC) testing. Patient 1 suffers the most significant functional difficulties and works in a semi-supervised environment as a library assistant. Patent 2 has exhibited moderate impairment in perceptual skills but is a capable and skilful professional artist. Patient 3 displayed borderline IQ and comprehension but manages to work successfully and without supervision in a real estate agency. The results of our patients’ WISC testing has perhaps not done them justice, and may reflect under-performance during the testing period. Reported endocrine features include euthyroidism, hyperprolactinaemia,18 postnatal growth failure,19 hyperinsulinaemic hypoglycaemia,20 and hypergonadotrophic hypogonadism.21 Treatment of the osteopenia and hypogonadotrophic hypogonadism with estrogens can increase the risk of thrombotic events in predisposed female patients. Bisphosphonates might be beneficial in patients with recurrent fractures.22 CDG commonly exhibits an unusual subcutaneous fat distribution pattern over the buttocks and the suprapubic area. The cause for this lipodystrophy is unknown and the pattern of lipodystrophy appears to be distinct from that created by lamin A/C gene defects. Ophthalmic manifestations are frequent in CDG-Ia, with congenital esotropia, delayed visual maturation, and retinitis pigmentosa being the most frequent abnormalities noted.6 The PMM2 gene maps to chromosome 16p13, consists of eight exons and spans at least 17 kb of genomic DNA
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and to date over 50 mutations have been described.20,23 The R141H mutation accounts for 40% of disease alleles in CDG-Ia patients, with a carrier frequency of 1/70 in the general population.2 Our patients were found to be compound heterozygous for the R141H mutation and the L32R mutation. L32R in combination with R141H has been reported to have residual PMM activity of 30–50%,5 perhaps accounting for the milder clinical patients reported with these mutations. Giurgea et al. describes two remarkable patients with normal intelligence, mild neurological signs and PMM2 mutations of C241S/R141H and V44F, and Q37H/R141H respectively.24 For the most part, no correlation can be drawn between genotype and phenotype,15 although some mild functional mutations have been reported, involved with a milder neurological phenotype. C9Y, C241S,5 E151G,8 T18S and V67G,25 are examples of such mild mutations. Patient 3 expressed the mildest neurological phenotype but has a PMM activity usually seen in more severely affected patients. This observation and the interfamilial variation in clinical and biochemical phenotype are difficult to explain. Perhaps there are other factors influencing disease expression in our patients, for example modifier genes or environmental factors affecting glycosylation. An example of a polymorphism amplifying the disease expression in severe cases of CDG-Ia is the F304S polymorphism in the ALG6 gene. This polymorphism places further stress on an already defective glycosylation system.26 Pathogenic mutations in the ALG6 gene are responsible for CDG1c.26 Our patients have mild global developmental delay but manage to live and work independently as well as display abstract and creative thought. We believe that our patients are among the mildest of CDG-Ia neurological phenotypes reported thus far. Acknowledgement Dr Coman is supported by the Royal Children’s Hospital Foundation, Cressbrook Committee. Mutation analysis was kindly preformed by Professor Matthijs and Dr Els Schollen. Patient 2 (LK) has kindly given permission for the use of Figs. 1 and 2. References 1. Mader I, Dobler-Neumann M, KuKer W, et al. Congenital disorder of glycosylation type 1a: benign clinical course in a new genetic variant. Childs Nerv Syst 2002;18:77–80. 2. Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003;162:359–79. 3. Mizughishi K, Yamanaka K, Kuwajima K, et al. Missense mutations in the phosphomannomutase 2 gene of two Japanese siblings with carbohydrate-deficient glycoprotein syndrome type I. Brain Dev 1999;21:223–8. 4. Drouin-Garraud V, Belgrand M, Grunewald S, et al. Neurological presentation of a congenital disorder of glycosylation CDG-Ia:
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Case reports / Journal of Clinical Neuroscience 14 (2007) 672–675 Implications for diagnosis and genetic counselling. Am J Med Genet 2001;101:46–9. Westphal V, Peterson S, Patterson M, et al. Functional significance of PMM2 mutations in mildly affected patients with congenital disorder of glycosylation Ia. Genet Med 2001;3:393–8. Jensen H, Kjaergaard S, Klie F, et al. Ophthalmic mainfestations of congenital disorder of glycosylation type Ia. Ophthal Genet 2003;24: 81–8. Gene Reviews (Online). 2005 August; Available from: URL: http:// www.genetests.org/ (Accessed 14 March 2006). Miossec-Chauvet E, Mikaeloff Y, Heron D, et al. Neurological presentations in pediatric patients with congenital disorder of glycosylation type Ia. Neuropediatrics 2003;34:1–6. Jensen PR, Hansen FJ, Skovby F. Cerebellar hypoplasia in children with the carbohydrate-deficient glycoprotein syndrome. Neuroradiology 1995;37:328–30. Pearl P, Krasnewich D. Neurologic course of congenital disorders of glycosylation. J Child Neurol 2001;16:409–13. Barone R, Pavone L, Fiumara A, et al. Developmental patterns and neuropsychological assesment in patients with carbohydrate-deficient glycoconjugate syndrome type Ia (phosphomannomutase deficiency). Brain Dev 1999;21:260–3. Van Ommenn C, Peters M, Barth P, et al. Carbohydrate-deficient glycoprotein syndrome type Ia: A variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances. J Pediatr 2000;136:400–3. Jaeken J, Carchon H. What’s new in congenital disorders of glycosylation? Eur J Pediatr Neurol 2000;4:163–7. deLonay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a serries of 26 cases. J Med Genet 2001;38:14–9. Stibler H, Blennow G, Kristiansson B, et al. Carbohydrate-deficient glycoprotein syndrome: clinical expression in adults with a new metabolic disease. J Neurol Neurosurg Psychiatry 1994;57:552–6.
16. Westphal V, Enns GM, McCracken MF, et al. Functional analysis of novel mutations in a congenital disorder of glycosylation ia patient with mixed Asian ancestry. Mol Genet Metab 2001;73:71–6. 17. Briones P, Vilaseca MA, Schollen E, et al. Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia. J Inherit Metab Dis 2002;25:635–46. 18. De Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type i from birth through adolescence. Pediatr Res 1995;37:395–401. 19. Kjaergaard S, Muller J, Skovby F. Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia). Arch Dis Child 2002;87:324–7. 20. Matthijs G, Schollen E, Bjursell C. Mutations in PMM2 that cause congenital disorders if glycosylation, type Ia (CDG-Ia). Hum Mutat 2000;16:386–94. 21. Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: A review. Pediatr Res 2002;52:618–24. 22. Jaeken J. Congenital disorders of glycosylation (CDG): It’s all in it! J Inherit Metab Dis 2003;26:99–118. 23. Enn G, Steiner R, Bruist N, et al. Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins. J Pediatr 2002;141:695–700. 24. Giurgea I, Michel A, Le Merrer M, et al. Under diagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol 2005;32:121–3. 25. Coman D, Klingberg S, Morris D, et al. Congenital disorder of glycosylation type Ia in a 6-year-old girl with a mild intellectual phenotype: Two novel PMM2 mutations. J Inherit Metab Dis 2005;28:1189–90. 26. Westphal V, Kjaergaard S, Schollen E, et al. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum Molec Genet 2002;11: 599–604.
doi:10.1016/j.jocn.2006.04.008
Intraventricular rhabdoid meningioma Jacqueline McMaster *, Thomas Ng, Mark Dexter Westmead Hospital, Department of Neurosurgery, PO Box 533, Wentworthville, New South Wales, 2145, Australia Received 19 December 2005; accepted 22 February 2006
Abstract Rhabdoid meningioma is a rare variant of meningioma, often found in tumour recurrences. We report a 55-year-old woman with a history of intraventricular fibroblastic meningioma, who developed headache and tinnitus 5 years after complete resection of the initial tumour. Imaging confirmed a recurrent tumour in the intraventricular location. Histological analysis revealed rhabdoid meningioma. We reviewed the literature and were unable to find any previously reported cases of intraventricular rhabdoid meningioma. 2006 Elsevier Ltd. All rights reserved. Keywords: Meningioma; Rhabdoid; Intraventricular; Recurrence
*
Corresponding author. E-mail address: [email protected] (J. McMaster).