A 15-year-old girl diagnosed with multiple sulfatase deficiency (MSD) was referred to Mayo Clinic for severe headaches, worsening musculoskeletal pain, and management of congenital heart disease.
Her complex clinical history is remarkable for short stature, progressive scoliosis, multiple contractures, coarse facial features, hearing and vision loss, bilateral corneal opacities, absent puberty, abnormal echocardiogram, and hepatosplenomegaly. She has normal intelligence without progressive loss of cognitive function and does not have ichthyosis.
Her diagnosis of MSD, established before age 1, was based on low enzymatic activities of arylsulfatases A and B.
Due to suspicion of misdiagnosis, a series of biochemical tests were performed. Analysis of glycosaminoglycans (GAGs) in urine showed increased excretion of dermatan sulfate; heparan sulfate and keratan sulfate were normal. Urine sulfatide excretion was within the normal range, and the enzymatic activities of several sulfatases were either low or normal (Table 1).
The correct answer is ...
The clinical and biochemical profiles are suggestive of MPS VI.
MPS VI (Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB, the gene that encodes for arylsulfatase B.
The clinical features of MPS VI include short stature, dysostosis multiplex, contractures, corneal clouding, hepatosplenomegaly, cardiorespiratory insufficiencies, and hearing loss. Notably, cognitive and behavioral abnormalities are rare.
The enzyme defect in MPS VI leads to elevated urinary excretions of dermatan sulfate and chondroitin-4-sulfate with normal levels of both heparan sulfate and keratan sulfate. Since the enzyme is not directly involved in sphingolipid metabolism, sulfatide excretion is expected to be normal.1
Incorrect — The clinical and biochemical profiles are indicative of MSD.
MSD is a rare autosomal recessive disorder caused by pathogenic variants in SUMF1, resulting in reduced or absent formylglycine-generating enzyme (FGE) activity. FGE catalyzes a post-translational modification necessary to activate all cellular sulfatases — the generation of formylglycine, a unique amino acid residue found only in the catalytic domains of sulfatases.
Most sulfatases are lysosomal enzymes involved in GAG and sulfated sphingolipid (sulfatide) catabolism. Genetic defects in the lysosomal sulfatases are associated with distinct subtypes of lysosomal storage disorders, in particular, mucopolysaccharidosis (MPS) types II, III, IV, and VI, and metachromatic leukodystrophy (MLD).
FGE deficiency leads to diminished activities of all or multiple sulfatases and consequently to a progressive multisystem disorder with combined clinical features of single sulfatase deficiencies.
Individuals with MSD invariably have neurological complications, the majority presenting with developmental regression and hypotonia. Epilepsy, sensorineural hearing loss, and spasticity are also frequently observed. Brain MRI findings, including leukodystrophy and cerebral atrophy, can be similar to those observed in MLD and may lead to a misdiagnosis.
Common non-neurological signs overlap with those frequently observed in several MPS subtypes, e.g., growth restriction, dysostosis multiplex, hepatosplenomegaly, coarse facies, and corneal clouding. In contrast, most individuals with MSD present with ichthyosis, which is not commonly observed in MPS.
Biochemical investigations are expected to reveal decreased activities of multiple sulfatases, elevated urinary excretion of all GAGs, and increased excretion of sulfatides.2,3
Incorrect — The biochemical results are inconclusive; they could point to either metachromatic leukodystrophy (MLD) or MSD.
MLD results from a low or absent activity of arylsulfatase A, an enzyme involved in lysosomal sulfatide catabolism, caused by either deficiency of the enzyme itself or its activation protein, sphingolipid activator protein B (sapB). Clinically, MLD is characterized by progressive motor and cognitive impairment due to damage to myelin sheaths in the central and peripheral nervous systems.
Besides low arylsulfatase A activity, the biochemical hallmark of MLD is the accumulation of sulfatides in tissues, particularly in myelin sheaths, and their elevated excretion in urine.4
Of interest, a disease-causing sapB deficiency does not result in low enzyme activity in vitro but can be detected by elevated sulfatide excretion. Conversely, relatively common polymorphisms in ARSA cause decreased arylsulfatase A activity in vitro but no detectable clinical symptoms — a phenomenon referred to as pseudodeficiency.
Incorrect — The biochemical results are suggestive of MPS IVA.
MPS IVA (Morquio A syndrome) results from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, an enzyme necessary for keratan sulfate and chondroitin 6-sulfate catabolism.
The syndrome is characterized by severe skeletal dysplasia, e.g., short stature with short trunk and neck, kyphoscoliosis, platyspondyly, and odontoid hypoplasia. Hearing loss, corneal clouding, hypermobile joints, as well as cardiac and respiratory complications are common. Most individuals with MPS IVA have normal intelligence.
Biochemically, MPS IVA is distinguished by elevated keratan sulfate and chondroitin 6-sulfate in blood and urine.5
The case presented here was diagnosed with MSD at an early age based on low activities of arylsulfatases A and B. Her clinical symptoms at an older age were atypical for the syndrome, particularly the normal intelligence and absence of cognitive regression and ichthyosis. This incongruity between the clinical picture and diagnosis prompted further biochemical and genetic (see below) testing.
The biochemical results were unambiguous — sulfatide excretion was normal, only the excretion of dermatan sulfate was elevated, and of all sulfatases tested, only the activity of arylsulfatase B was consistently low.
Molecular testing was performed using a NGS lysosomal storage disease panel (74 genes) and no pathogenic variants or VUSs were detected in SUMF1. However, a homozygous variant was detected in ARSB, not previously reported but predicted to be pathogenic.
Interestingly, a polymorphism in ARSA was detected involving the same amino acid change as a known pseudodeficiency allele, which might explain the reduced activity measured in arylsulfatase A.
This case illustrates that extensive biochemical testing is often necessary to establish a correct diagnosis in the complex landscape of biochemical genetic diseases confounded by frequent pseudo deficiencies, VUSs, and variable clinical expressions.
Freyr Johannsson, Ph.D.
Fellow, Clinical Biochemical Genetics
Silvia Tortorelli, M.D., Ph.D.
Consultant, Biochemical Genetics
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
Linda Hasadsri, M.D., Ph.D.
Consultant, Laboratory Genetics & Genomics
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science