American Journal of Medical Genetics 133A:85–89 (2005) Clinical Report An Adult Sanfilippo Type A Patient With Homozygous Mutation R206P in the Sulfamidase Gene Orazio Gabrielli, 1 * Giovanni V. Coppa, 1 Stefano Bruni, 1 Guglielmo R.D. Villani, 2 Gianfranco Pontarelli, 2 and Paola Di Natale 2 1 Institute of Maternal-Infantile Sciences, Polytechnic University of Marche, Ancona, Italy 2 Department of Biochemistry and Medical Biotechnologies, Medical School University Federico II, Naples, Italy The Sanfilippo type A syndrome, one of the most frequent forms of mucopolysaccharidosis III, is characterized by severe mental retardation, progressive neurological degeneration, and mild somatic changes. It is due to a deficiency of heparan-N-sulfatase (sulfamidase) activity and consequent excretion of heparan sulfate in the urine. The disease is transmitted through an autosomal recessive mechanism, and more than 60 gene mutations have been identified. Up to now, only 10 cases of attenuated form of Sanfilippo type A syndrome have been described, and the specific mutation has been identified only in two of them. We report here on a female patient, 20 years old, with Sanfilippo type A syndrome presenting with a mild clinical phenotype characterized essen- tially by a moderate nonevolving mental retarda- tion. The genetic analysis demonstrated that the patient is homozygous for mutation R206P; pre- sence of polymorphism R456H was also found. This study places R206P as a mild mutation un- derlying Sanfilippo type A disease. ß 2005 Wiley-Liss, Inc. KEY WORDS: Sanfilippo type A syndrome; muco- polysaccharidosis III A; heparan- N-sulfatase (sulfamidase) INTRODUCTION The Sanfilippo syndrome or mucopolysaccharidosis III is characterized by severe central nervous system degeneration resulting in progressive mental retardation and relatively mild somatic features. Clinical symptoms include: hyperactivity, aggressive behaviour, delayed development, coarse hair, hirsutism, sleep disorders, hepatosplenomegaly, and dysostosis multiplex. It is one of the most frequent forms of mucopoly- saccharidosis. The onset of clinical features occurs between 2 and 6 years of age with a progressive worsening and death generally during the second or third decade of life [Neufeld and Muenzer, 2001]. There are four types of Sanfilippo syndrome (A, B, C, and D) due to a deficiency of different lysosomal enzymes, involved in the degradation of heparan sulfate. All these four types are transmitted through an autosomal re- cessive mechanism. Sanfilippo type A results from a deficiency of the lysosomal enzyme heparan N-sulfatase, sulfamidase (EC 3.10.1.1). The gene of sulfamidase is located on chromosome 17q25.3 [Scott et al., 1995], and more than 60 mutations of this gene have been identified so far [Scott et al., 1995; Blanch et al., 1997; Bunge et al., 1997; Weber et al., 1997, 1998; Di Natale et al., 1998; Montfort et al., 1998; Yogalingam and Hopwood, 2001]. Expression studies have been used to demonstrate the pathogenicity of mutant alleles [Perkins et al., 1999; Esposito et al., 2000]. Some authors consider the Sanfilippo type A the most serious of the four Sanfilippo forms, with the earliest onset, fast evolution of symptoms, and the most premature death [Van De Kamp et al., 1981], while others have not observed any significant differences among the various forms [Cleary and Wraith, 1993]. However, among the hundreds of patients affected by mucopolysaccharidosis III, only few cases of adults have been reported with clinical signs of Sanfilippo type A syndrome moderately involved from the neurological and physical point of view: three brothers reported by Wisniewski et al. [1985], two sibs described by Lindor et al. [1994], two more by Date et al. [1998], and another one recently reported by Miyazaki et al. [2002]. Di Natale et al. [2003] described two second cousins, one affected by the classical severe form of the disease and the other affected by a mild form of the illness; in the same year, Van Hove et al. [2003] reported an additional adult patient whose main clinical feature was the presence of severe cardiomyopathy in the absence of any neurological involvement. In patients with the above mentioned atypical forms, the analysis of sulfamidase gene was only performed in three cases [Miyazaki et al., 2002; Di Natale et al., 2003; Van Hove et al., 2003]. We report here on the case of an adult patient with an attenuated form of Sanfilippo type A syndrome in which the DNA analysis showed the R206P mutation in homozygous state and the common R456H polymorphism. CLINICAL REPORT The patient (Fig. 1) was seen for the first time at the age of 6 years and 3 months in order to ascertain the cause of her short stature and mild mental retardation. Neuropsychological—Developmental History The clinical history referred a normal psychomotor develop- ment in the first period of life (head control at 3 months, sitting position at 6 months); later on, a mild delay in attaining autonomous gait (around the age of 18 months) and in speech (first words at the age of 2 years) was observed. In the following years, her parents remarked essentially a poor stature and weight growth and a moderate mental retardation, mostly owing to speech delay. Grant sponsor: Polytechnic University of Marche; Grant sponsor: Italian Society for Mucopolysaccharidoses and Related Diseases. *Correspondence to: Orazio Gabrielli, M.D., Institute of Maternal-Infantile Sciences, Polytechnic University of Marche, Via F. Corridoni, 11, 60123 Ancona, Italy. E-mail: o.gabrielli@mercurio.it Received 7 June 2004; Accepted 14 November 2004 DOI 10.1002/ajmg.a.30552 ß 2005 Wiley-Liss, Inc.