Multiple sulfatase deficiency: A case series of four children Faruk Incecik1, Mehmet N. Ozbek2, Serdal Gungor3, Stefano Pepe4, Ozlem M. Herguner1, Neslihan Onenli Mungan5, Sabiha Gungor3, Sakir Altunbasak1 Department of Pediatric Neurology, Cukurova University Medical Faculty, Adana, 2Department of Pediatric Endocrinology, Diyarbakir State Children Hospital, Diyarbakir, 3Department of Pediatric Neurology, Inönü University Faculty of Medicine, Malatya, Turkey, 4TIGEM, Telethon Institute of Genetics and Medicine, via P. Castellino, Naples, Italy, 5Department of Pediatric Metabolism and Nutrition, Cukurova University Medical Faculty, Adana, Turkey 1
Abstract Multiple sulfatase deficiency is biochemically characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The gene sulfatase‑modifying factor 1 (SUMF1), recently identified, encodes the enzyme responsible for post‑translational modification of a cysteine residue, which is essential for the activity of sulfatases. We describe clinical findings and mutation analysis of four patients. The patients presented with hypotonia, developmental delay, coarse face, ichthyosis, and hepatosplenomegaly. The diagnosis was made through clinical findings, enzymatic assays, and mutation analysis. We were detected to be homozygous for a novel missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 protein.
Key Words Child, multiple sulfatase deficiency, sulfatase-modifying factor 1 gene For correspondence: Mr. Faruk Incecik, Toros Mah., Barış Manço Bul, 78178 sok., Yeşilpark Evleri, kat: 7, No: 13, Çukurova, Adana.
Introduction Multiple sulfatase deficiency (MSD) is a rare lysosomal storage disorder transmitted as an autosomal recessive trait in which all known sulfatases present with deficient activity and resulting in the accumulation of glycosaminoglycans and sulfated lipids.
disorders: Metachromatic leukodystrophy, Morquio A syndrome, Sanfilippo A syndrome, Sanfilippo D syndrome, Maroteaux Lamy syndrome, which are autosomal recessive conditions, Hunter syndrome, which belongs to the group of X‑linked disorders, as well as X‑linked types of ichthyosis and chondrodysplasia punctata.
The gene responsible for MSD is sulfatase‑modifying factor 1 (SUMF1) and maps on chromosome 3p26. The defect involves a modification process common to seven or more sulfatases: The post‑translational conversion of a cysteine to C‑formylglycine (FGly), which is required for generating catalytically active sulfatases.[2,3]
Patients with MSD carry the phenotypical features of these disorders. Psychomotor retardation, coarse face, hepatosplenomegaly, ichthyosis, and skeletal findings like scoliosis and dysostosis multiplex are the most common findings of the disease. Based on the degree of severity and age of onset, neonatal, moderate, and mild types of MSD have been differentiated.
It presents with combined clinical phenotypes of the different sulfatase deficiencies resulting in features of following
Here, we present clinical findings and the mutation analysis of four Turkish patients with MSD.
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Case Reports The patient 1 was a 1.5‑year‑old girl who was admitted to our hospital for developmental delay and epilepsy. Her parents were not consanguineous. She was hypotonic, mentally retarded and unable to sit and walk. Upper and lower tendon reflexes were absent and Babinski sign was bilaterally negative. She also had coarse face, ichthyosis, hypertrichosis,
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
Incecık, et al.: Multiple sulfatase deficiency
and hepatosplenomegaly [Figure 1]. She had seizures since the age of 1 year which were refractory to antiepileptic drugs and mainly consisted of tonic and complex partial seizures. Magnetic resonance of the brain revealed hyperintense lesions in the periventricular white matter. X‑rays of the elbow and vertebral column were compatible with dysostosis multiplex, and scoliosis. Electroencephalogram demonstrated multifocal epileptiform activity. Electromyography and echocardiogram were normal.
In the four patients, clinical findings suggested MSD and the enzymatic assays of three different sulfatases (Arylsulfatase A, Arylsulfatase B, and Iduronate Sulfatase) revealed very low levels of the enzymes [Table 2]. These were also confirmed by DNA analysis and the four patients were homozygous for a missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 gene.
The patient 2 was an 11‑month‑old boy and his primary problem was developmental delay. The parents were consanguineous. He had coarse face, ichthyosis, hypertrichosis, and hepatosplenomegaly. Upon neurological evaluation, eye contact, reaction to sound stimulus, and head control were absent. He had global hypotonia and was not able to sit. Distal tone of the four extremities was decreased and deep tendon reflexes were absent. He did not have epilepsy. Electromyography and echocardiogram were normal.
MSD is a rare autosomal recessive inborn error of metabolism. Its prevalence is 1 in 1 million births. Worldwide, less than 50 cases have been published so far.
The patient 3 was an 18‑month‑girl who presented to our hospital with complaints of developmental delay and deafness. There was a history of consanguinity in parents. She had coarse face, ichthyosis, and hepatosplenomegaly. There was general axial hypotonia with decreased tone in the four extremities, and deep tendon reflexes were absent. X‑rays of the elbow and vertebral column were compatible with dysostosis multiplex. Her echocardiogram showed secundum atrial septal defect. Magnetic resonance of the brain revealed hyperintense lesions in the periventricular white matter. The patient 4 was the cousin of patient 3. She was a 16‑month‑old girl and the primary problem was developmental delay. The parents were also consanguineous. She also had axial hypotonia, coarse face, ichthyosis, and hepatosplenomegaly. She was not able to sit and reflexes in four extremities were absent Babinski sign was bilaterally negative. She did not have epilepsy. Dysostosis multiplex was seen in X‑rays of the elbow and vertebral column. Her echocardiogram showed secundum atrial septal defect. Magnetic resonance of the brain showed hyperintense lesions in the periventricular white matter similar with patient 3 [Figure 2]. Table 1 shows findings of clinical, MRI and X‑rays of all patients.
Figure 1: An 18‑month‑old girl with a multiple sulfatase deficiency with dysmorphic features
MSD is primarily a defect in the posttranslational modification of sulfatase to its active form. FGly is the key catalytic residue within the active catalytic side of sulfatases, and it is converted from cysteine by the action of formylglycine‑generating enzyme (FGE). This enzyme is defective in MSD. The gene encoding for FGE, known as SUMF1, has been identified and disease‑causing mutations have been described. The clinical picture of MSD combines symptoms of the different sulfatase deficiencies. Patients show neurological deterioration and a neurodegenerative course of disease similar to metachromatic leukodystrophy. In addition, developmental delay, dysmorphism, and organomegaly are present as found in various mucopolysaccharidoses. Skeletal abnormalities remind one of Chondrodysplasia punctata type I and skin changes of X‑linked ichthyosis.[1,4] Patients with MSD may also have mental retardation, coarse face, seizures, leukodystrophy, tetraplegia, visceromegaly, ichthyosis, and dysostosis. Early development may be normal following an often rapid clinical progression, with neurodegeneration leading to early death within a few years of clinical onset. Clinical manifestations are markedly variable in patients with MSD. The neurological progression may be slow and there may be no hepatosplenomegaly that is typical for MSD. Patients may have corneal clouding, macrocephaly, dysostosis multiplex, and mild mental retardation, but
Figure 2: Cerebral magnetic resonance imaging showed hyperintense lesions in the periventricular white matter
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
It is important to consider the possibility of MSD in a child with skin problems and neurological deterioration. Detailed skin and physical examination is mandatory in a neurology clinic in a patient with either metachromatic leukodystrophy or mucopolysaccharide deficiency. Molecular genetic analysis of the SUMF1 gene should be performed to elucidate the disease causing mutation as a prerequisite for precise genetic counseling and prenatal molecular genetic diagnosis.
MRI=Magnetic resonance imaging
Table 2: Enzymatic assays of three different sulfatases measured in patients Patient 1 2 3 4
ARS A (50‑250 nmol/mg/h)
ARS B (10‑50 nmol/mg/h)
IDS (494‑1113 nmol/mg/4 h)
0.93 3.58 5.5 8.4
0.51 0.1 0.2 0.2
15 18.3 12 10.5
ARS A=Arylsulphatase A, ARS B=Arylsulphatase B, IDS=Iduronate sulphatase
there is no ichthyosis as Saudi variant of the disease. Yis et al. reported two Turkish patients with MSD. They had mental retardation, spasticity, coarse face, ichthyosis, and hepatosplenomegaly. They were found homozygous for a novel missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 in their patients. In our patients, we found general hypotonia, mental retardation, coarse face, ichthyosis, and hepatosplenomegaly. But, there was not spasticity in our patients. Also, we found cardiac anomaly in two patients. To our knowledge, cardiac anomaly was not reported previously in the literature. Deafness was seen in two patients. One patient had epilepsy. Dysostosis multiplex was detected in three of our patients. We detected same homozygous for a missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 in our patients. 
The responsible gene for MSD is SUMF1 and it is located on chromosome 3p26. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were described. 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.
7. 8. 9. 10.
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 İnherited Disease. 8th ed.. Vol. III. New York: McGraw‑Hill; 2001. p. 3725‑32. Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann‑Pick C1 disease ‑ Lysosomal storage disorders caused by defects of non‑lysosomal proteins. Biochim Biophys Acta 2009;1793:710‑25. 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. 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 İnherited Disease. 8th ed.. Vol. III. New York: McGraw‑Hill; 2001. p. 4241‑62. Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J. Molecular analysis of SUMF1 mutations: Stability and residual activity of mutant formylglycine‑generating enzyme determine disease severity in multiple sulfatase deficiency. Hum Mutat 2008;29:205. Dierks T, Dickmanns A, Preusser‑Kunze A, Schmidt B, Mariappan M, von Figura K, et al. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine‑generating enzyme. Cell 2005;121:541‑52. Annunziata I, Bouchè V, Lombardi A, Settembre C, Ballabio A. Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. Hum Mutat 2007;28:928. 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. Yiş U, Pepe S, Kurul SH, Ballabio A, Cosma MP, Dirik E. Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation. Brain Dev 2008;30:374‑7. Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade‑Martins R, et al. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat 2004;23:576‑81.
How to cite this article: Incecik F, Ozbek MN, Gungor S, Pepe S, Herguner OM, Mungan NO, et al. Multiple sulfatase deficiency: A case series of four children. Ann Indian Acad Neurol 2013;16:720-2. Received: 26-11-2013, Revised: 29-12-13, Accepted: 31-12-13
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
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