Phenotypic expansion of ARSK ‐related mucopolysaccharidosis

Mucopolysaccharidosis (MPS) are monogenic, multisystem disorders resulting from enzymatic defects in the degradation of glycosaminoglycans (GAGs). Although each of the 11 MPS subtypes is linked to a specific enzyme deficiency, phenotypic overlap is considerable. Recently, a 12th disorder, MPS type X, due to biallelic variants in the arylsulfatase K gene (ARSK) was reported (Verheyen et al., 2021). We describe herein two additional affected sibs and expand the phenotype. The younger individual (Individual 1) was noted to have a waddling gate as a toddler. At presentation at age 7 years, he complained of stiffness and pain in his legs, and was diagnosed with Legg-Calvé-Perthes disease (LCPD). He experienced increasing pain in his hips, thighs, knees, legs, hands, and back. Radiographic changes in his hips were visible by age 7 years. Additional diagnostic suggestions at that time were multiple epiphyseal dysplasia or Meyers dysplasia. Assessment by a multispecialist skeletal dysplasia clinic at age 8 years 5 months concluded that he might have a MPS given his increasing symptoms as well as his similarly affected sibling. Radiological changes were not present in the hand of Individual 1 at age 2 years, but at age 8 years 5 months several carpal bones were either not ossified or small for his age. Lack of ossification of some carpal bones and osteonecrosis of the femoral heads were suggestive of a mild MPS (Figure 1). The 2 years older sibling (Individual 2) complained of pain in her knees, thighs and hips from age 9 years. By age 10 years, she had developed pain in her legs, ankles, and back. Initial imaging showed slight anterior wedging of her vertebrae and lack of ossification of carpal bones, in keeping with a tentative diagnosis of MPS. Both individuals used paracetamol for pain. On repeated analyzes, urinary GAG quantitation by dimethyl methylene blue (DMB) test was slightly increased in both children. Thin layer chromatography showed a normal glycosaminoglycan profile. Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose-6-sulfatase and beta-galactosidase. Whole exome sequencing for the sibs and their parents was initially performed assuming that the father was affected due to longstanding complaints of stiffness in his joints. When no molecular cause was detected, the variant data were re-interpreted with both parents considered unaffected. Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK, NM_198150.3:c.1251C > G p.(Tyr417*). The variant is located in the penultimate exon and is predicted to target ARSK-mRNA to nonsense-mediated decay. Urinary GAG excretion in both sibs assessed by HPLC-MS/MS (liquid chromatography–tandem mass spectrometry) analysis detected a threefold increase of dermatan sulfate (DS) while heparan sulfate (HS) was slightly above the upper reference range in Individual 2. The increased DS level is similar to that described in two of four individuals in the original report of MPS type X (Verheyen et al. 2021). Clinical findings in the two children we describe and in the original report are summarized in Table 1. In contrast to the two individuals described by Verheyen et al. for whom data are available, the sibs we report were normocephalic at birth, and did not have recurrent ear infections or sleep apnea as young children. Furthermore, at age 9 years 5 months and at 11 years, respectively, they did not have coarse facial features or short stature, and were not disproportionate. The individuals we report are younger than those reported previously (ages 14–18), which might explain the absence of short stature, a disproportionally short trunk, and coarse facies. Both children have slightly hypomineralized enamel on their permanent teeth. The older sibling had several teeth extracted due to enamel defects and has hypoplasia of a permanent incisor (an enamel pit). Defective enamel might be a feature of MPS type X, analogous to what is seen in MPS type IV (Barker & Welbury, 2000; Ribeiro et al., 2015). Both children had hypermobile interphalangeal finger joints, which is also a feature of MPS type IV (Raff & Byers, 1996). Both individuals have vertical striae in the metaphyses similar to those described by Verheyen et al., but noted at an earlier age (Figure 1). Osteochondral lesions were present in the dorsal aspect of the patellae in Individual 1 and in some metacarpal heads. Similar lesions were seen in the metatarsals of Individual 2 (not shown), this may be a distinguishing feature of MPS type X. In conclusion, the two individuals described herein illustrate that short stature, a short trunk and coarse facies are not necessarily present in young children with MPS type X. A waddling gait and joint pain, accompanied by skeletal radiological changes resembling mild MPS warrants examination for ARSK-related MPS. Normal urinary GAG quantitation does not rule out the diagnosis (Verheyen et al., 2021). As in the four previously published individuals, MPS was suspected, though one of the children we report was originally thought to have LCPD. Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes (Mendelsohn et al., 2013). The diagnosis of MPS type X allows for tailored cardiac, ophthalmologic and audiological surveillance, and can inform genetic counseling. Conception and design: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Data collection: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Data analysis and interpretation: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Drafting the article: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Critical revision of the article: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Final approval: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. The authors are grateful to the family for their generous contribution to this work. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.