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Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation
Brain & Development 30 (2008) 374–377 www.elsevier.com/locate/braindev
Case report
Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation Uluc¸ Yisß a
a,*
, Stefano Pepe b, Semra Hız Kurul a, Andrea Ballabio Maria Pia Cosma b, Eray Dirik a
b,c
,
_ Dokuz Eylu¨l University School of Medicine, Department of Pediatrics, Division of Child Neurology, 35340, Izmir, Turkey b TIGEM, Telethon Institute of Genetics and Medicine, via P. Castellino, 111, 80131, Naples, Italy c Medical Genetics, Department of Pediatrics, Faculty of Medicine, Federico II University, Naples, Italy Received 30 June 2007; received in revised form 25 October 2007; accepted 25 October 2007
Abstract Multiple sulfatase deficiency (MSD) is an inherited lysosomal storage disease that affects post-translational activation of all of the sulfatases. Since biochemical and clinical findings are variable, the diagnosis is difficult in most of the cases. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were found in all of the MSD patients analyzed. Here, we present clinical findings of two consanguineous patients with multiple sulfatase deficiency. They were found to be homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 protein. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Ichtyosis; Child; Psychomotor retardation; SUMF1 protein
1. Introduction Multiple sulfatase deficiency (MSD) is a rare autosomal recessive lysosomal storage disease in which all known sulfatases has defective activity [1]. In the presence of defective activity, sulfated lipids and acid mucopolysaccharides accumulate in the body. Five different types of mucopolysaccharidoses (MPS II, MPS IIIA, MPS IIID, MPS IVA, and MPS VI) metachromatic leukodystrophy (MLD), X-linked ichthyosis (XLI) and Xlinked recessive chondrodysplasia punctata (CDPX) are diseases which are characterized by a single sulfatase deficiency [2]. Patients with multiple sulfatase deficiency carry the phenotypical features of these disorders. Retarded psychomotor development, gargoyle-like features, hepatosplenomegaly, ichtyosis and skeletal find*
Corresponding author. Tel.: +90 232 412 3638; fax: +90 232 259 9723. E-mail address: [email protected] (U. Yisß). 0387-7604/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2007.10.007
ings like scoliosis and dysostosis multiplex are the most common findings of the disease. Severe neonatal, moderate and mild forms of the disease have been described 1. The gene responsible for multiple sulfatase deficiency is SUMF1 and maps on chromosome 3p26. It encodes for a sulfatase modifying factor, which converts a highly conserved cysteine within the sulfatase catalytic domain into Ca-formylglycine [3,4]. This post-translational modification is essential for the enzymatic activity of all sulfatases [5]. Single aminoacid residues of SUMF1 play a functional role. Most of the mutations are clustered in the C-terminal subdomain of the protein and this subdomain is critical for SUMF1 activity. Other mutations are located in the trytophan-rich and N-terminal subdomain [5]. Here, we present clinical findings and mutation analysis of two new patients and describe a novel missense mutation in SUMF1 gene. Patients who carry the combined clinical features of single sulfatase deficiencies should be investigated for MSD. Molecular genetic
U. Yisß et al. / Brain & Development 30 (2008) 374–377
375
studies in these patients are very important in order to give genetic counselling and understand the relationship between the phenotype and genotype of the disease. 2. Subjects and methods 2.1. Subjects Index patient was a four year old girl who was admitted to the hospital for developmental delay and epilepsy. Parents were consanguineous. She was severely mentally retarded and unable to sit and walk. Upper and lower tendon reflexes were brisk and Babinski sign was bilaterally positive. She had spastic quadriplegia. She also had gargoyle like appearance (Fig. 1), hypertrichosis, scoliosis, hepatosplenomegaly and ichtyosis (Fig. 2) which were more apparent in the neck, trunk and legs. Seizures were refractory to antiepileptic drugs and mainly consisted of tonic and myoclonic seizures. Magnetic resonance of the brain revealed cerebral and cerebellar atrophy and hyperintense lesions in the periventricular white matter (Fig. 3). Electroencephalogram demonstrated multifocal epileptiforme activity. Clinical findings suggested multiple sulfatase deficiency and the enzymatic assays of four different sulfatases (Arylsulfatase A, Arylsulfatase B, Arylsulfatase E and Iduronate Sulfatase) revealed very low levels (Table 1). This was also confirmed by DNA analysis and the patient was homozygous for a missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 gene. The second patient was the cousin of index patient. She was an 18 month girl and the primary problem was developmental delay. The parents were also consanguineous. She also had coarse face and hepatosplenomegaly, but the amount of ichtyosis and hypertrichosis was less than the index patient. She was not able to sit
Fig. 2. Ichtyosis of the legs.
Fig. 3. Cortical atrophy and hyperintense lesions in the periventricular white matter (arrow).
and reflexes in four extremities were brisk and Babinski sign was bilaterally positive. Spasticity was prominent in the lower extremities. She did not have epilepsy. Her brother died when he was 5 years old and he also had the same phenotypical findings, severe mental retardation, epilepsy and spastic quadriplegia. Enzymatic assays of four different sulfatases also revealed very low levels of activities (Table 1) and the same homozygous missense mutation was found in the SUMF1 gene. 2.2. Methods
Fig. 1. Gargoyle like appearance of the index patient.
The clinical findings of these two consanguineous patients prompted us to analyse the enzymatic activity
376
U. Yisß et al. / Brain & Development 30 (2008) 374–377
Table 1 Enzymatic assays of four different sulfatases measured in patients Patients
Enzyme activities ARS A (nmol/mg/h)
ARS C (nmol/mg/h)
ARS E (nmol/mg/h)
IDS (nmol/mg/6 h)
Patient 1 Patient 2 Wild-type
0.00118143 0.00090014 0.08101012
0.091132 0.084121 1.792849
0.140203 0.105152 5.757097
0.200991 0.220264 12.22466
of 4 different sulfatases in the lymphoblasts isolated form peripheral blood of the two patients and of two control wild-type individuals. Arylsulfatase A (ARSA), Arylsulfatase B (ARSB), Arylsulfatase E (ARSE) and Iduronate Sulfatase (IDS) were tested as described previously [5]. In the patients lymphoblasts the activities of these four sulfatases were barely detectable with respect to the ones measured in the wild-type control lymphoblasts (Table 1). Thus, we analyzed the sequence of all the exons and splice junctions of the SUMF1 gene in the genomic DNA isolated from the patient peripheral blood and from 50 control individuals (100 alleles), to exclude the presence of sequence polymorphisms. We found that both patients were homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution. 3. Discussion Multiple sulfatase deficiency is a rare autosomal recessive disorder with a prevalence of about 1 in 1.4 million births [6]. A defect of post-translational modification of several sulfatases leads to neurovisceral disorder characterized by tissue accumulation of sulfatides, glycosaminoglycans, and cholesterly sulfate. Although the structure of these proteins is similar, they have different subcellular localisations (mostly lysosomal, endoplasmic reticulum and Golgi apparatus) [7]. The clinical features of the disease is a combination of disorders which are due to combination of single sulfatase deficiencies like early infantile metachromatic leukodystrophy, X-linked ichtyosis and mucopolysaccharidosis. Patients with MSD have mental retardation, seizures, leukodystrophy, tetraplegia, visceromegaly, ichtyosis, gargoyle like features and dysostosis [5]. Early development may be normal following an often rapid clinical progression, with neurodegeneration leading to early death within a few years of clinical onset [1]. Both of our cases had all typical findings of the disease. In the index patient, the rate of neurological impairment, spasticity, seizure frequency, and the amount of ichtyosis increased after two years of age and the second case had less icthyosis, hypertrichosis, spasticity and she had no seizures. In some patients, the course of the disease is different. The neurological progression is slow and there is no hepatosplenomegaly that is typical for
multiple sulfatase deficiency [8]. In Saudi variant of the disease, patients have corneal clouding, macrocephaly, and dysostosis multiplex but there is no ichtyosis and mental retardation is mild [9]. The responsible gene for multiple sulfatase deficiency is SUMF1 and it is located on chromosome 3p26. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were described. Most of these mutations cluster in the C-terminal subdomain of the protein and other mutations are located in the tryptophan-rich and N-terminal subdomains [3,10,11]. SUMF1 mutations have variable effects on the activity of each sulfatase and there is no relationship between the type of molecular defect and the severity of phenotype [5]. New homozygous missense mutation which was detected in our patients may cause severe neurological symptoms like in our patients, but more clinical information about this new homozygous missense mutation is needed in order to clarify this hypothesis. In conclusion, multiple sulfatase deficiency is a rare autosomal recessive disorder and it should be suspected in patients who had the combination of clinical findings that are typical for single sulfatase deficient diseases. Molecular genetic analysis of the SUMF1 gene should be performed to elucidate the disease causing mutation as a prerequisite for precise genetic counselling and prenatal molecular genetic diagnosis in a subsequent pregnancy. References [1] Hopwood JJ, Ballabiao A. Multiple sulfatase deficiency and the nature of the sulfatase family. In: Scriver CR, Baudet AL, Sly WS, editors. The metabolic and molecular basis of inherited disease, 8th ed., vol. III. New York: McGraw-Hill; 2001. p. 3725–32. [2] Ballabiao A, Shapiro LJ. Steroid sulfatase deficiency and X-linked icthyosis. In: Scriver CR, Baudet AL, Sly WS, editors. The metabolic and molecular basis of inherited disease, 8th ed., vol. III. New York: McGraw-Hill; 2001. p. 4241–62. [3] Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, et al. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell 2003;113:445–56. [4] Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell 1995;82:271–8. [5] Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, WadeMartins R, et al. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mut 2004;23:576–81.
U. Yisß et al. / Brain & Development 30 (2008) 374–377 [6] Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249–54. [7] Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson Jr CP. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 2001;293:1663–6. [8] Blanco-Aguirre ME, Kofman-Alfaro SH, Rivera-Vega MR, Medina C, Valdes-Flores M, Rizzo WB, et al. Unusual clinical presentation in two cases of multiple sulfatase deficiency. Pediatr Dermatol 2001;18:388–92.
377
[9] al Aqeel A, Ozand PT, Brismar J, Gascon GG, Brismar G, Nester M, et al. Saudi variant of multiple sulfatase deficiency. J Child Neurol 1992;7:S12–21. [10] Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, et al. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Cell 2003;113:435–44. [11] Schirmer A, Kolter R. Computational analysis of bacterial sulfatases and their modifying enzymes. Chem Biol 1998;5:R181–6.
Case report
Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation Uluc¸ Yisß a
a,*
, Stefano Pepe b, Semra Hız Kurul a, Andrea Ballabio Maria Pia Cosma b, Eray Dirik a
b,c
,
_ Dokuz Eylu¨l University School of Medicine, Department of Pediatrics, Division of Child Neurology, 35340, Izmir, Turkey b TIGEM, Telethon Institute of Genetics and Medicine, via P. Castellino, 111, 80131, Naples, Italy c Medical Genetics, Department of Pediatrics, Faculty of Medicine, Federico II University, Naples, Italy Received 30 June 2007; received in revised form 25 October 2007; accepted 25 October 2007
Abstract Multiple sulfatase deficiency (MSD) is an inherited lysosomal storage disease that affects post-translational activation of all of the sulfatases. Since biochemical and clinical findings are variable, the diagnosis is difficult in most of the cases. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were found in all of the MSD patients analyzed. Here, we present clinical findings of two consanguineous patients with multiple sulfatase deficiency. They were found to be homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 protein. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Ichtyosis; Child; Psychomotor retardation; SUMF1 protein
1. Introduction Multiple sulfatase deficiency (MSD) is a rare autosomal recessive lysosomal storage disease in which all known sulfatases has defective activity [1]. In the presence of defective activity, sulfated lipids and acid mucopolysaccharides accumulate in the body. Five different types of mucopolysaccharidoses (MPS II, MPS IIIA, MPS IIID, MPS IVA, and MPS VI) metachromatic leukodystrophy (MLD), X-linked ichthyosis (XLI) and Xlinked recessive chondrodysplasia punctata (CDPX) are diseases which are characterized by a single sulfatase deficiency [2]. Patients with multiple sulfatase deficiency carry the phenotypical features of these disorders. Retarded psychomotor development, gargoyle-like features, hepatosplenomegaly, ichtyosis and skeletal find*
Corresponding author. Tel.: +90 232 412 3638; fax: +90 232 259 9723. E-mail address: [email protected] (U. Yisß). 0387-7604/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2007.10.007
ings like scoliosis and dysostosis multiplex are the most common findings of the disease. Severe neonatal, moderate and mild forms of the disease have been described 1. The gene responsible for multiple sulfatase deficiency is SUMF1 and maps on chromosome 3p26. It encodes for a sulfatase modifying factor, which converts a highly conserved cysteine within the sulfatase catalytic domain into Ca-formylglycine [3,4]. This post-translational modification is essential for the enzymatic activity of all sulfatases [5]. Single aminoacid residues of SUMF1 play a functional role. Most of the mutations are clustered in the C-terminal subdomain of the protein and this subdomain is critical for SUMF1 activity. Other mutations are located in the trytophan-rich and N-terminal subdomain [5]. Here, we present clinical findings and mutation analysis of two new patients and describe a novel missense mutation in SUMF1 gene. Patients who carry the combined clinical features of single sulfatase deficiencies should be investigated for MSD. Molecular genetic
U. Yisß et al. / Brain & Development 30 (2008) 374–377
375
studies in these patients are very important in order to give genetic counselling and understand the relationship between the phenotype and genotype of the disease. 2. Subjects and methods 2.1. Subjects Index patient was a four year old girl who was admitted to the hospital for developmental delay and epilepsy. Parents were consanguineous. She was severely mentally retarded and unable to sit and walk. Upper and lower tendon reflexes were brisk and Babinski sign was bilaterally positive. She had spastic quadriplegia. She also had gargoyle like appearance (Fig. 1), hypertrichosis, scoliosis, hepatosplenomegaly and ichtyosis (Fig. 2) which were more apparent in the neck, trunk and legs. Seizures were refractory to antiepileptic drugs and mainly consisted of tonic and myoclonic seizures. Magnetic resonance of the brain revealed cerebral and cerebellar atrophy and hyperintense lesions in the periventricular white matter (Fig. 3). Electroencephalogram demonstrated multifocal epileptiforme activity. Clinical findings suggested multiple sulfatase deficiency and the enzymatic assays of four different sulfatases (Arylsulfatase A, Arylsulfatase B, Arylsulfatase E and Iduronate Sulfatase) revealed very low levels (Table 1). This was also confirmed by DNA analysis and the patient was homozygous for a missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 gene. The second patient was the cousin of index patient. She was an 18 month girl and the primary problem was developmental delay. The parents were also consanguineous. She also had coarse face and hepatosplenomegaly, but the amount of ichtyosis and hypertrichosis was less than the index patient. She was not able to sit
Fig. 2. Ichtyosis of the legs.
Fig. 3. Cortical atrophy and hyperintense lesions in the periventricular white matter (arrow).
and reflexes in four extremities were brisk and Babinski sign was bilaterally positive. Spasticity was prominent in the lower extremities. She did not have epilepsy. Her brother died when he was 5 years old and he also had the same phenotypical findings, severe mental retardation, epilepsy and spastic quadriplegia. Enzymatic assays of four different sulfatases also revealed very low levels of activities (Table 1) and the same homozygous missense mutation was found in the SUMF1 gene. 2.2. Methods
Fig. 1. Gargoyle like appearance of the index patient.
The clinical findings of these two consanguineous patients prompted us to analyse the enzymatic activity
376
U. Yisß et al. / Brain & Development 30 (2008) 374–377
Table 1 Enzymatic assays of four different sulfatases measured in patients Patients
Enzyme activities ARS A (nmol/mg/h)
ARS C (nmol/mg/h)
ARS E (nmol/mg/h)
IDS (nmol/mg/6 h)
Patient 1 Patient 2 Wild-type
0.00118143 0.00090014 0.08101012
0.091132 0.084121 1.792849
0.140203 0.105152 5.757097
0.200991 0.220264 12.22466
of 4 different sulfatases in the lymphoblasts isolated form peripheral blood of the two patients and of two control wild-type individuals. Arylsulfatase A (ARSA), Arylsulfatase B (ARSB), Arylsulfatase E (ARSE) and Iduronate Sulfatase (IDS) were tested as described previously [5]. In the patients lymphoblasts the activities of these four sulfatases were barely detectable with respect to the ones measured in the wild-type control lymphoblasts (Table 1). Thus, we analyzed the sequence of all the exons and splice junctions of the SUMF1 gene in the genomic DNA isolated from the patient peripheral blood and from 50 control individuals (100 alleles), to exclude the presence of sequence polymorphisms. We found that both patients were homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution. 3. Discussion Multiple sulfatase deficiency is a rare autosomal recessive disorder with a prevalence of about 1 in 1.4 million births [6]. A defect of post-translational modification of several sulfatases leads to neurovisceral disorder characterized by tissue accumulation of sulfatides, glycosaminoglycans, and cholesterly sulfate. Although the structure of these proteins is similar, they have different subcellular localisations (mostly lysosomal, endoplasmic reticulum and Golgi apparatus) [7]. The clinical features of the disease is a combination of disorders which are due to combination of single sulfatase deficiencies like early infantile metachromatic leukodystrophy, X-linked ichtyosis and mucopolysaccharidosis. Patients with MSD have mental retardation, seizures, leukodystrophy, tetraplegia, visceromegaly, ichtyosis, gargoyle like features and dysostosis [5]. Early development may be normal following an often rapid clinical progression, with neurodegeneration leading to early death within a few years of clinical onset [1]. Both of our cases had all typical findings of the disease. In the index patient, the rate of neurological impairment, spasticity, seizure frequency, and the amount of ichtyosis increased after two years of age and the second case had less icthyosis, hypertrichosis, spasticity and she had no seizures. In some patients, the course of the disease is different. The neurological progression is slow and there is no hepatosplenomegaly that is typical for
multiple sulfatase deficiency [8]. In Saudi variant of the disease, patients have corneal clouding, macrocephaly, and dysostosis multiplex but there is no ichtyosis and mental retardation is mild [9]. The responsible gene for multiple sulfatase deficiency is SUMF1 and it is located on chromosome 3p26. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were described. Most of these mutations cluster in the C-terminal subdomain of the protein and other mutations are located in the tryptophan-rich and N-terminal subdomains [3,10,11]. SUMF1 mutations have variable effects on the activity of each sulfatase and there is no relationship between the type of molecular defect and the severity of phenotype [5]. New homozygous missense mutation which was detected in our patients may cause severe neurological symptoms like in our patients, but more clinical information about this new homozygous missense mutation is needed in order to clarify this hypothesis. In conclusion, multiple sulfatase deficiency is a rare autosomal recessive disorder and it should be suspected in patients who had the combination of clinical findings that are typical for single sulfatase deficient diseases. Molecular genetic analysis of the SUMF1 gene should be performed to elucidate the disease causing mutation as a prerequisite for precise genetic counselling and prenatal molecular genetic diagnosis in a subsequent pregnancy. References [1] Hopwood JJ, Ballabiao A. Multiple sulfatase deficiency and the nature of the sulfatase family. In: Scriver CR, Baudet AL, Sly WS, editors. The metabolic and molecular basis of inherited disease, 8th ed., vol. III. New York: McGraw-Hill; 2001. p. 3725–32. [2] Ballabiao A, Shapiro LJ. Steroid sulfatase deficiency and X-linked icthyosis. In: Scriver CR, Baudet AL, Sly WS, editors. The metabolic and molecular basis of inherited disease, 8th ed., vol. III. New York: McGraw-Hill; 2001. p. 4241–62. [3] Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, et al. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell 2003;113:445–56. [4] Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell 1995;82:271–8. [5] Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, WadeMartins R, et al. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mut 2004;23:576–81.
U. Yisß et al. / Brain & Development 30 (2008) 374–377 [6] Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249–54. [7] Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson Jr CP. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 2001;293:1663–6. [8] Blanco-Aguirre ME, Kofman-Alfaro SH, Rivera-Vega MR, Medina C, Valdes-Flores M, Rizzo WB, et al. Unusual clinical presentation in two cases of multiple sulfatase deficiency. Pediatr Dermatol 2001;18:388–92.
377
[9] al Aqeel A, Ozand PT, Brismar J, Gascon GG, Brismar G, Nester M, et al. Saudi variant of multiple sulfatase deficiency. J Child Neurol 1992;7:S12–21. [10] Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, et al. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Cell 2003;113:435–44. [11] Schirmer A, Kolter R. Computational analysis of bacterial sulfatases and their modifying enzymes. Chem Biol 1998;5:R181–6.