e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e5
Official Journal of the European Paediatric Neurology Society
Case study
Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature5 David F.G.J. Wolthuis a,b,c,e, Ellyze van Asbeck a,b,c,e, Miski Mohamed a,b,c, Thatjana Gardeitchik a,b,c, Elizabeth R. Lim-Melia d, Ron A. Wevers b, Eva Morava a,c,* a
Hayward Genetics Center, Tulane University Medical School, 1430 Tulane Ave, New Orleans, LA 70112, USA Laboratory of Genetic, Metabolic and Endocrine Diseases, Radboud University Medical Centre Nijmegen, The Netherlands c Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands d Regional Medical Genetics Center, N.Y. Medical College, Valhalla, USA b
article info
abstract
Article history:
Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by
Received 7 July 2013
wrinkled, inelastic skin, frequently associated with a neurologic involvement and
Received in revised form
multisystem disease. Next generation sequencing was performed in genetically unsolved
12 January 2014
patients with progeroid features, neurological and eye involvement to assess the un-
Accepted 19 January 2014
derlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all re-
Keywords:
ported P5CS patients.
Cutis laxa
So far 10 patients were described with mutations in ALDH18A1. Features of our patient
ALDH18A1
that have been described in literature included cutis laxa on hands and feet, visible veins
Abnormal fat distribution
on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and
Retinopathy
severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly. ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
5
The authors are all in agreement with the publication. * Corresponding author. Tel.: þ1 504 9885101. E-mail address: [email protected] (E. Morava). e Contributed equally. http://dx.doi.org/10.1016/j.ejpn.2014.01.003 1090-3798/ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e5
Introduction
Patients with metabolic cutis laxa generally present at birth with loose, sagging skin, associated with neurologic disease. These symptoms can be caused by genetic defects in proteins of the extracellular matrix, but many defects in metabolic pathways have been identified in these cutis laxa syndromes.1,2 Mutations in different enzymes with an essential role in proline synthesis have been associated with metabolic cutis laxa.1 Autosomal Recessive Cutis Laxa type IIB (ARCL2B; MIM 612940) as well as type IIIA (ARCL3A; MIM 219150) and IIIB (ARCL3B; MIM 614438), also known as De Barsy syndrome have been associated with mutations in genes that play a crucial role in proline metabolism.3 De Barsy syndrome was first described in 1968, but it was not until 2008 that a genetic cause was identified, leading to a new nomenclature in cutis laxa syndromes and the discovery of new cases.4 ARCL3A is associated with mutations in the ALDH18A1 gene.5 Mutations in PYCR1, another gene involved in proline synthesis, can result in both ARCL2B and ARCL3B.3,6 These two genes, both leading to cutis laxa syndromes with high phenotypic overlap and are clinically difficult to distinguish. Characteristic symptoms include wrinkly, parchment-like skin with progeroid appearance and visible veins, ophthalmologic abnormalities, especially cataract and corneal abnormalities, suggestive facial features, central nervous system involvement, distal contractures, and failure to thrive.3,6,7 ALDH18A1 encodes for D1pyrroline-5-carboxylate synthase (P5CS), a mitochondrial enzyme catalyzing the reduction of glutamate to D1-pyrroline5-carboxylate (P5C). This substrate then undergoes reduction to be metabolized to proline or it is converted to ornithine by ornithine aminotransferase to enter the urea cycle.8,9 Alternative splicing of P5CS results in two isoforms, of which the long isoform is necessary for the synthesis of proline from glutamate, whereas the short isoform particularly plays a role in the gut.9,10 Moreover, the short isoform is inhibited by ornithine, while the long isoform remains insensitive to this regulatory mechanism.10 The two catalytic sites of P5CS consist of a glutamate kinase (GK) domain which works in an ATP-dependent matter and the NADPH-dependent g-glutamyl phosphate reductase domain.9 Ten patients with proven defects in P5CS have been described so far.3,5,7,11,12 Overlapping clinical features include thin, parchment-like skin with visible veins, hypotonia, wasting of distal muscle bulk, brisk reflexes, cataract and frequent distal contractures. Some cases showed spontaneous improvement over time, while others developed hypertonia and progression of neurological symptoms. Interestingly, both hypoelasticity as well as hyperelasticity of the skin has been described.5,7,11e13 Biochemical parameters are typically not significantly altered and levels of proline, arginine and ornithine are decreased in 3/6 cases with reported levels.5,12,13
2.
Case study
We present a two-year-old male patient, who was born from consanguineous parents after 38 weeks of gestation via
normal vaginal delivery. Pregnancy was complicated by intrauterine growth retardation. Birth weight was 1980 g. At presentation, this patient showed severely wrinkled skin on thorax and abdomen with visible veins. Bilateral hip dislocations were found in combination with bilateral hip dysplasia as well as contractures of the wrists and adducted thumbs. Furthermore, the patient showed kyphosis, and feet in calcaneo-valgus position. Patient was known with seizures and developed spasticity. Other symptoms included large anterior fontanel, microcephaly, high arched palate, dysmorphic ears, right inguinal hernia, undescended testes, abnormal fat pads on buttocks and upper thighs and blue sclerae. Growth delay and failure to thrive were noted. Abnormal pigmentation in the periphery and salt and pepper fundus were found upon ophthalmology examination. Cerebral MRI showed a diffusely thinned corpus callosum and mild enlargement of the temporal horns. Biochemical analysis showed normal levels of ammonia, serum amino acids, ceruloplasmin, copper and lactic acid. Urine organic acids were normal. Our patient did not show any metabolic abnormality, which has been observed in a few patients (variable degree of hyperammonemia, hypoprolinaemia and a deficiency of urea cycle intermediates, Supp Table 1).1 Transferrin iso-electric focussing (TIEF) was normal. Based on the severe skin wrinkling, neurologic involvement and abnormal fat distribution, in spite of normal TIEF, we suspected the diagnosis of ARCL2A or COG7-CDG. DNA was isolated from EDTA blood or leucocytes by standard procedures. Genetic analysis of ATP6V0A2, COG7, GORAB and PYCR1 did not show any mutations. ARCL3 was not suspected originally based on the severe generalized skin wrinkling, fat pads, retinopathy and normal metabolic studies. We performed next generation sequencing on the exome (w21,000 genes) of the patient by using the SureSelect Human All Exon 50Mb Kit (Agilent, Santa Clara, CA, USA) and multiplexed analysis on a SOLiD 4 System sequencing slide (Life Technologies, Carlsbad, CA, USA). This revealed a c.2339T>C (p.Tyr780Cys/ alternate transcript p.Tyr782Cys) missense mutation in exon 18 of the ALDH18A1 gene. The mutation was not found in any of the over 6000 publicly available exomes (Exome Variant Server, NHLBI Exome Sequencing Project [ESP], Seattle) nor in our in house database with over 2800 exomes. The mutation was absent in 100 ethnically matched healthy controls. SIFT22 and PolyPhen23 predicted that the p.Tyr780Cys (p.Tyr782Cys) missense mutation identified in our patient is deleterious and probably damaging.14,15 Additional sequence analysis of this gene was performed by standard methods using Sanger sequencing in the patient, and the mutation was confirmed. Unfortunately the parents were lost for follow-up.
3.
Discussion
Here we describe a new patient with autosomal recessive cutis laxa syndrome diagnosed with ARCL3A due to homozygous ALDH18A1 mutations. The patient presented with unique features, including abnormal fat distribution and retinopathy; symptoms, which have never been described in this syndrome. Additionally, our patient had very severe generalized
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e5
different, because no excessive fat was present in his arms, while abnormal fat pads on his buttocks were remarkable. Most of the clinical features of our patient, including lax skin, congenital hip dislocations, distal joint contractures, blue sclerae, large anterior fontanel, undescended testes and corpus callosum abnormalities, have been described in association with PYCR1 mutations, which was molecularly ruled out in our patient. Both ALDH18A1 and PYCR1 mutations have been associated with De Barsy Syndrome. Our patient shows symptoms overlapping both phenotypes, thus closing the gap between the two. The enzymes PYCR1 and P5CS play a role in the same pathway of proline synthesis (Fig. 1), which could explain the high phenotypic overlap in PYCR1 and P5CS deficient patients. The most common eye involvement associated with ARCL3A and ARCL3B is corneal clouding or cataract, but none of the patients with P5CS deficiency has been observed with either retinopathy or retinitis pigmentosa. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is highly variable, but always associated with neurologic symptoms. We suggest genetic testing for possible ALDH18A1 and PYCR1 mutations in patients with wrinkled skin or any sign of progeria, when presented in association with seizures, hypotonia, FTT, microcephaly, or any eye abnor
cutis laxa, with sagging, inelastic texture, and some visible veins on his thorax, but not the parchment-like, wrinkled skin described in most patients with ARCL3A before.7,11,12 Also, he had blue sclera but no signs of cataract, which is common in patients with ALDH18A1 mutations.7,11,12 Excessive skin wrinkling in combination with abnormal fat distribution and late closing fontanel, or failure to thrive, white matter disease and adducted thumbs were more comparable to the cutis laxa phenotypes seen in congenital glycosylation defects (CDG). However, ATP6V0A2-CDG (ARCL2A; MIM 2199200) and COG7-CDG (MIM 608779)16e19 were ruled out on a molecular and biochemical basis.20 So far 10 patients were described (Table 1) with mutations in ALDH18A1. Typical features included failure to thrive, short stature, visible veins on thorax and abdomen with cutis laxa on hands and feet, microcephaly, developmental delay, spasticity, and joint laxity. Unique features included IUGR, corneal clouding, scoliosis, tremor, and dystonia.7,11e13 Our patient is unique due to his retinal abnormalities, undescended testis, late closing fontanel and adducted thumbs. Abnormal fat distribution was never reported in other patients, although the picture in patient 7 showed abnormal fat distribution in his arms.7 However, the distribution in our patient was markedly
Table 1 e Comparison of clinical features of 11 ALDH18A1 patients. Characteristic
Baumgartner et al., 2000/2005
Patient 1 Skin Abnormalities Lax skin þ Hyperelastic skin þ Visible veins NA Joint abnormalities Lax joints þ Hip dislocation þ Adducted thumbs NA Abnormal fat distribution NA Cardiac abnormalities NA Neurological/muscular abnormalities Microcephaly Macrocephaly Brisk reflexes/spasticity þ Seizures (neonatal) NA White matter abnormalities NA Hypotonia þ Dystonia þ Distal wasting muscle bulk þ Contractures NA Development/growth IUGR NA Failure to thrive þ Developmental delay þ Late closing fontanel NA Undescended testes NA Inability to walk þ Absent speech Inguinal hernia NA Eye abnormalities Cataract þ Corneal clouding NA Blue Sclerae NA Retinitis Pigmentosa NA
Bicknell et al., 2008
Skidmore et al. 20111
Martinelli et al., 2012
Zampatti et al., 2012
Current patient
2
3
4
5
6
7
8
9
10
11
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ NA ?
þ NA þ
þ þ
þ þ NA NA
þ NA NA NA
þ þ NA NA NA
þ þ NA NA NA
þ þ NA NA NA
NA NA NA þ þ
þ NA þ NA
þ NA þ NA NA
þ NA þ NA NA
þ þ þ þ
þ þ þ þ NA þ þ
þ þ * NA þ NA þ NA
þ þ * þ þ NA þ NA
þ þ * NA þ NA þ NA
þ þ * NA þ NA þ NA
þ NA þ NA þ NA NA NA
þ NA þ NA þ NA NA þ
NA NA NA NA NA NA þ NA NA
NA NA NA NA NA NA þ NA NA
þ þ þ þ þ þ þ
þ þ NA NA þ NA
þ þ NA NA þ
þ þ NA NA þ þ þ
þ þ NA NA þ
þ þ NA NA þ þ
þ þ þ NA NA NA NA þ
NA þ þ NA NA NA NA þ
þ þ þ NA NA NA þ þ
þ þ þ NA NA NA þ NA
þ þ þ þ þ NA NA þ
þ NA NA NA
NA NA NA
þ NA NA NA
NA NA NA
NA NA NA
NA þ NA NA
þ NA þ
þ NA NA NA
þ NA NA NA
þ þ
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
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Fig. 1 e Our patient at 18 weeks of age. A: severe generalized wrinkling of the skin. It’s parchment-like on the thorax, with visible veins. The patient has adducted thumbs and slightly posteriorly rotated, cupped ears. B: High arched palate and long fingers are clearly visible. C and D: Abnormal fat distribution. Inguinal hernia. E: Overview of D1-pyrroline-5-carboxylate metabolism. P5C deficiency leads to only a mild decrease in proline, arginine and ornithine concentrations.
malities (cataract, retinopathy or corneal clouding), especially when distal contractures or white matter abnormalities are present.
Conflict of interest The authors disclose any financial conflict of interest.
Ethical approval The authors disclose any ethical conflict.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejpn.2014.01.003.
references
1. Mohamed M, Kouwenberg D, Gardeitchik T, et al. Metabolic cutis laxa syndromes. J Inherit Metab Dis 2011;34:907e16. 2. Okanishi T, Saito Y, Yuasa I, et al. Cutis laxa with frontoparietal cortical malformation: a novel type of congenital disorder of glycosylation. Eur J Paediatr Neurol 2008;12:262e5. 3. Zampatti S, Castori M, Fischer B, et al. De Barsy Syndrome: a genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction. Am J Med Genet A 2012;158A:927e31. 4. Kivuva EC, Parker MJ, Cohen MC, Wagner BE, Sobey G. De Barsy syndrome: a review of the phenotype. Clin Dysmorphol 2008;17:99e107. 5. Baumgartner MR, Hu CA, Almashanu S, et al. Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5carboxylate synthase. Hum Mol Genet 2000;9:2853e8.
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
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6. Lin DS, Chang JH, Liu HL, et al. Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome. Am J Med Genet A 2011;155A:3095e9. 7. Skidmore DL, Chitayat D, Morgan T, et al. Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Delta(1)-pyrroline-5-carboxylate synthase (P5CS). Am J Med Genet A 2011;155A:1848e56. 8. Phang JMYG, Scriver CR. Disorders of proline and hydroxyproline metabolism. In: Scriver CR BA, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw Hill; 1995. pp. 1125e46. 9. Valle DSO. The hyperornithemias. In: Scriver CRB, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw Hill; 1995. pp. 1147e85. 10. Hu CA, Lin WW, Obie C, Valle D. Molecular enzymology of mammalian Delta1-pyrroline-5-carboxylate synthase. Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition. J Biol Chem 1999;274:6754e62. 11. Baumgartner MR, Rabier D, Nassogne MC, et al. Delta1pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline. Eur J Pediatr 2005;164:31e6. 12. Bicknell LS, Pitt J, Aftimos S, et al. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome. Eur J Hum Genet 2008;16:1176e86.
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13. Martinelli D, Haberle J, Rubio V, et al. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structurebased analysis, and novel therapy with arginine. J Inherit Metab Dis 2012;35:761e76. 14. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31:3812e4. 15. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013;7:20. Chapter 7:Unit7 20. 16. Morava E, Zeevaert R, Korsch E, et al. A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. Eur J Hum Genet 2007;15:638e45. 17. Ng BG, Kranz C, Hagebeuk EE, et al. Molecular and clinical characterization of a Moroccan Cog7 deficient patient. Mol Genet Metab 2007;91:201e4. 18. Wu X, Steet RA, Bohorov O, et al. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med 2004;10:518e23. 19. Spaapen LJ, Bakker JA, van der Meer SB, et al. Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder. J Inherit Metab Dis 2005;28:707e14. 20. Fischer B, Dimopoulou A, Egerer J, et al. Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum Genet 2012;131:1761e73.
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
Official Journal of the European Paediatric Neurology Society
Case study
Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature5 David F.G.J. Wolthuis a,b,c,e, Ellyze van Asbeck a,b,c,e, Miski Mohamed a,b,c, Thatjana Gardeitchik a,b,c, Elizabeth R. Lim-Melia d, Ron A. Wevers b, Eva Morava a,c,* a
Hayward Genetics Center, Tulane University Medical School, 1430 Tulane Ave, New Orleans, LA 70112, USA Laboratory of Genetic, Metabolic and Endocrine Diseases, Radboud University Medical Centre Nijmegen, The Netherlands c Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands d Regional Medical Genetics Center, N.Y. Medical College, Valhalla, USA b
article info
abstract
Article history:
Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by
Received 7 July 2013
wrinkled, inelastic skin, frequently associated with a neurologic involvement and
Received in revised form
multisystem disease. Next generation sequencing was performed in genetically unsolved
12 January 2014
patients with progeroid features, neurological and eye involvement to assess the un-
Accepted 19 January 2014
derlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all re-
Keywords:
ported P5CS patients.
Cutis laxa
So far 10 patients were described with mutations in ALDH18A1. Features of our patient
ALDH18A1
that have been described in literature included cutis laxa on hands and feet, visible veins
Abnormal fat distribution
on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and
Retinopathy
severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly. ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
5
The authors are all in agreement with the publication. * Corresponding author. Tel.: þ1 504 9885101. E-mail address: [email protected] (E. Morava). e Contributed equally. http://dx.doi.org/10.1016/j.ejpn.2014.01.003 1090-3798/ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
2
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e5
Introduction
Patients with metabolic cutis laxa generally present at birth with loose, sagging skin, associated with neurologic disease. These symptoms can be caused by genetic defects in proteins of the extracellular matrix, but many defects in metabolic pathways have been identified in these cutis laxa syndromes.1,2 Mutations in different enzymes with an essential role in proline synthesis have been associated with metabolic cutis laxa.1 Autosomal Recessive Cutis Laxa type IIB (ARCL2B; MIM 612940) as well as type IIIA (ARCL3A; MIM 219150) and IIIB (ARCL3B; MIM 614438), also known as De Barsy syndrome have been associated with mutations in genes that play a crucial role in proline metabolism.3 De Barsy syndrome was first described in 1968, but it was not until 2008 that a genetic cause was identified, leading to a new nomenclature in cutis laxa syndromes and the discovery of new cases.4 ARCL3A is associated with mutations in the ALDH18A1 gene.5 Mutations in PYCR1, another gene involved in proline synthesis, can result in both ARCL2B and ARCL3B.3,6 These two genes, both leading to cutis laxa syndromes with high phenotypic overlap and are clinically difficult to distinguish. Characteristic symptoms include wrinkly, parchment-like skin with progeroid appearance and visible veins, ophthalmologic abnormalities, especially cataract and corneal abnormalities, suggestive facial features, central nervous system involvement, distal contractures, and failure to thrive.3,6,7 ALDH18A1 encodes for D1pyrroline-5-carboxylate synthase (P5CS), a mitochondrial enzyme catalyzing the reduction of glutamate to D1-pyrroline5-carboxylate (P5C). This substrate then undergoes reduction to be metabolized to proline or it is converted to ornithine by ornithine aminotransferase to enter the urea cycle.8,9 Alternative splicing of P5CS results in two isoforms, of which the long isoform is necessary for the synthesis of proline from glutamate, whereas the short isoform particularly plays a role in the gut.9,10 Moreover, the short isoform is inhibited by ornithine, while the long isoform remains insensitive to this regulatory mechanism.10 The two catalytic sites of P5CS consist of a glutamate kinase (GK) domain which works in an ATP-dependent matter and the NADPH-dependent g-glutamyl phosphate reductase domain.9 Ten patients with proven defects in P5CS have been described so far.3,5,7,11,12 Overlapping clinical features include thin, parchment-like skin with visible veins, hypotonia, wasting of distal muscle bulk, brisk reflexes, cataract and frequent distal contractures. Some cases showed spontaneous improvement over time, while others developed hypertonia and progression of neurological symptoms. Interestingly, both hypoelasticity as well as hyperelasticity of the skin has been described.5,7,11e13 Biochemical parameters are typically not significantly altered and levels of proline, arginine and ornithine are decreased in 3/6 cases with reported levels.5,12,13
2.
Case study
We present a two-year-old male patient, who was born from consanguineous parents after 38 weeks of gestation via
normal vaginal delivery. Pregnancy was complicated by intrauterine growth retardation. Birth weight was 1980 g. At presentation, this patient showed severely wrinkled skin on thorax and abdomen with visible veins. Bilateral hip dislocations were found in combination with bilateral hip dysplasia as well as contractures of the wrists and adducted thumbs. Furthermore, the patient showed kyphosis, and feet in calcaneo-valgus position. Patient was known with seizures and developed spasticity. Other symptoms included large anterior fontanel, microcephaly, high arched palate, dysmorphic ears, right inguinal hernia, undescended testes, abnormal fat pads on buttocks and upper thighs and blue sclerae. Growth delay and failure to thrive were noted. Abnormal pigmentation in the periphery and salt and pepper fundus were found upon ophthalmology examination. Cerebral MRI showed a diffusely thinned corpus callosum and mild enlargement of the temporal horns. Biochemical analysis showed normal levels of ammonia, serum amino acids, ceruloplasmin, copper and lactic acid. Urine organic acids were normal. Our patient did not show any metabolic abnormality, which has been observed in a few patients (variable degree of hyperammonemia, hypoprolinaemia and a deficiency of urea cycle intermediates, Supp Table 1).1 Transferrin iso-electric focussing (TIEF) was normal. Based on the severe skin wrinkling, neurologic involvement and abnormal fat distribution, in spite of normal TIEF, we suspected the diagnosis of ARCL2A or COG7-CDG. DNA was isolated from EDTA blood or leucocytes by standard procedures. Genetic analysis of ATP6V0A2, COG7, GORAB and PYCR1 did not show any mutations. ARCL3 was not suspected originally based on the severe generalized skin wrinkling, fat pads, retinopathy and normal metabolic studies. We performed next generation sequencing on the exome (w21,000 genes) of the patient by using the SureSelect Human All Exon 50Mb Kit (Agilent, Santa Clara, CA, USA) and multiplexed analysis on a SOLiD 4 System sequencing slide (Life Technologies, Carlsbad, CA, USA). This revealed a c.2339T>C (p.Tyr780Cys/ alternate transcript p.Tyr782Cys) missense mutation in exon 18 of the ALDH18A1 gene. The mutation was not found in any of the over 6000 publicly available exomes (Exome Variant Server, NHLBI Exome Sequencing Project [ESP], Seattle) nor in our in house database with over 2800 exomes. The mutation was absent in 100 ethnically matched healthy controls. SIFT22 and PolyPhen23 predicted that the p.Tyr780Cys (p.Tyr782Cys) missense mutation identified in our patient is deleterious and probably damaging.14,15 Additional sequence analysis of this gene was performed by standard methods using Sanger sequencing in the patient, and the mutation was confirmed. Unfortunately the parents were lost for follow-up.
3.
Discussion
Here we describe a new patient with autosomal recessive cutis laxa syndrome diagnosed with ARCL3A due to homozygous ALDH18A1 mutations. The patient presented with unique features, including abnormal fat distribution and retinopathy; symptoms, which have never been described in this syndrome. Additionally, our patient had very severe generalized
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
3
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different, because no excessive fat was present in his arms, while abnormal fat pads on his buttocks were remarkable. Most of the clinical features of our patient, including lax skin, congenital hip dislocations, distal joint contractures, blue sclerae, large anterior fontanel, undescended testes and corpus callosum abnormalities, have been described in association with PYCR1 mutations, which was molecularly ruled out in our patient. Both ALDH18A1 and PYCR1 mutations have been associated with De Barsy Syndrome. Our patient shows symptoms overlapping both phenotypes, thus closing the gap between the two. The enzymes PYCR1 and P5CS play a role in the same pathway of proline synthesis (Fig. 1), which could explain the high phenotypic overlap in PYCR1 and P5CS deficient patients. The most common eye involvement associated with ARCL3A and ARCL3B is corneal clouding or cataract, but none of the patients with P5CS deficiency has been observed with either retinopathy or retinitis pigmentosa. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is highly variable, but always associated with neurologic symptoms. We suggest genetic testing for possible ALDH18A1 and PYCR1 mutations in patients with wrinkled skin or any sign of progeria, when presented in association with seizures, hypotonia, FTT, microcephaly, or any eye abnor
cutis laxa, with sagging, inelastic texture, and some visible veins on his thorax, but not the parchment-like, wrinkled skin described in most patients with ARCL3A before.7,11,12 Also, he had blue sclera but no signs of cataract, which is common in patients with ALDH18A1 mutations.7,11,12 Excessive skin wrinkling in combination with abnormal fat distribution and late closing fontanel, or failure to thrive, white matter disease and adducted thumbs were more comparable to the cutis laxa phenotypes seen in congenital glycosylation defects (CDG). However, ATP6V0A2-CDG (ARCL2A; MIM 2199200) and COG7-CDG (MIM 608779)16e19 were ruled out on a molecular and biochemical basis.20 So far 10 patients were described (Table 1) with mutations in ALDH18A1. Typical features included failure to thrive, short stature, visible veins on thorax and abdomen with cutis laxa on hands and feet, microcephaly, developmental delay, spasticity, and joint laxity. Unique features included IUGR, corneal clouding, scoliosis, tremor, and dystonia.7,11e13 Our patient is unique due to his retinal abnormalities, undescended testis, late closing fontanel and adducted thumbs. Abnormal fat distribution was never reported in other patients, although the picture in patient 7 showed abnormal fat distribution in his arms.7 However, the distribution in our patient was markedly
Table 1 e Comparison of clinical features of 11 ALDH18A1 patients. Characteristic
Baumgartner et al., 2000/2005
Patient 1 Skin Abnormalities Lax skin þ Hyperelastic skin þ Visible veins NA Joint abnormalities Lax joints þ Hip dislocation þ Adducted thumbs NA Abnormal fat distribution NA Cardiac abnormalities NA Neurological/muscular abnormalities Microcephaly Macrocephaly Brisk reflexes/spasticity þ Seizures (neonatal) NA White matter abnormalities NA Hypotonia þ Dystonia þ Distal wasting muscle bulk þ Contractures NA Development/growth IUGR NA Failure to thrive þ Developmental delay þ Late closing fontanel NA Undescended testes NA Inability to walk þ Absent speech Inguinal hernia NA Eye abnormalities Cataract þ Corneal clouding NA Blue Sclerae NA Retinitis Pigmentosa NA
Bicknell et al., 2008
Skidmore et al. 20111
Martinelli et al., 2012
Zampatti et al., 2012
Current patient
2
3
4
5
6
7
8
9
10
11
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ NA ?
þ NA þ
þ þ
þ þ NA NA
þ NA NA NA
þ þ NA NA NA
þ þ NA NA NA
þ þ NA NA NA
NA NA NA þ þ
þ NA þ NA
þ NA þ NA NA
þ NA þ NA NA
þ þ þ þ
þ þ þ þ NA þ þ
þ þ * NA þ NA þ NA
þ þ * þ þ NA þ NA
þ þ * NA þ NA þ NA
þ þ * NA þ NA þ NA
þ NA þ NA þ NA NA NA
þ NA þ NA þ NA NA þ
NA NA NA NA NA NA þ NA NA
NA NA NA NA NA NA þ NA NA
þ þ þ þ þ þ þ
þ þ NA NA þ NA
þ þ NA NA þ
þ þ NA NA þ þ þ
þ þ NA NA þ
þ þ NA NA þ þ
þ þ þ NA NA NA NA þ
NA þ þ NA NA NA NA þ
þ þ þ NA NA NA þ þ
þ þ þ NA NA NA þ NA
þ þ þ þ þ NA NA þ
þ NA NA NA
NA NA NA
þ NA NA NA
NA NA NA
NA NA NA
NA þ NA NA
þ NA þ
þ NA NA NA
þ NA NA NA
þ þ
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e5
Fig. 1 e Our patient at 18 weeks of age. A: severe generalized wrinkling of the skin. It’s parchment-like on the thorax, with visible veins. The patient has adducted thumbs and slightly posteriorly rotated, cupped ears. B: High arched palate and long fingers are clearly visible. C and D: Abnormal fat distribution. Inguinal hernia. E: Overview of D1-pyrroline-5-carboxylate metabolism. P5C deficiency leads to only a mild decrease in proline, arginine and ornithine concentrations.
malities (cataract, retinopathy or corneal clouding), especially when distal contractures or white matter abnormalities are present.
Conflict of interest The authors disclose any financial conflict of interest.
Ethical approval The authors disclose any ethical conflict.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejpn.2014.01.003.
references
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13. Martinelli D, Haberle J, Rubio V, et al. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structurebased analysis, and novel therapy with arginine. J Inherit Metab Dis 2012;35:761e76. 14. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31:3812e4. 15. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013;7:20. Chapter 7:Unit7 20. 16. Morava E, Zeevaert R, Korsch E, et al. A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. Eur J Hum Genet 2007;15:638e45. 17. Ng BG, Kranz C, Hagebeuk EE, et al. Molecular and clinical characterization of a Moroccan Cog7 deficient patient. Mol Genet Metab 2007;91:201e4. 18. Wu X, Steet RA, Bohorov O, et al. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med 2004;10:518e23. 19. Spaapen LJ, Bakker JA, van der Meer SB, et al. Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder. J Inherit Metab Dis 2005;28:707e14. 20. Fischer B, Dimopoulou A, Egerer J, et al. Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum Genet 2012;131:1761e73.
Please cite this article in press as: Wolthuis DFGJ, et al., Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.01.003
