Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement

Abstract

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.

Keywords: Care; Consensus; Leukodystrophy; Mucopolysaccharidoses; Multiple sulfatase deficiency; Outcomes; Prevention; Therapy.

Figure 1:. Timeline of two individuals affected by MSD demonstrating clinical variability.

Individual 1 shows a later onset and slower acquisition of symptoms, while Individual 2 presented earlier, with faster progression and multisystemic complications. (A) On physical examination of Individual 1, mildly dysmorphic features including midface hypoplasia, full cheeks, periorbital fullness, hypertelorism, and short, thick fingers were noted. Pertinent findings on neurologic exam included babbling, difficulties with motor planning, and tremulousness. (B) Individual 2 was noted to have coarse facial features, hypertelorism, choanal stenosis, global hypotonia, hirsutism, persistent inspiratory stridor, and ichthyosis. His psychomotor development slowly progressed over the following months with the highest achievement of babbling at the age of 16 months and partially rolling to one side at 22 months of age. He did not attain speech, sitting, or crawling. By 3.5 years of age, he developed severe spasticity and epilepsy with generalized tonic clonic seizures. Ultimately, he lost the ability to react to tactile or auditory stimuli and purposefully move.

Figure 2:. Comparative brain imaging findings of individuals with MSD, MLD, and MPS.

A-C represents the radiographic spectrum findings from children with MSD. This 2 year old individual with MSD (not presented in text) demonstrates periventricular and frontal white matter involvement (A) similar to the findings in individuals with MLD (D) (16). The solid arrows indicate corpus callosum involvement. Individual 1 (B) demonstrates periventricular white matter involvement with preservation of the U-fibers. Enlarged ventricles are indicated by dotted arrows. Individual 2 (C) imaging reveals diffuse hypomyelination and severe hydrocephalus. E and F demonstrate the typical imaging findings found in individuals with MPS disorders with diffuse hypomyelination, atrophy, and hydrocephalus. All images shown are T2 weighted MR images.