A total of 142 disease-causing mutations (Human Gene Mutation Database, 2019/4) have been described to date, most of them (77%) are missense mutations. The variant c.734G > A, p.R245H is the most common pathologic mutation within the SGSH-gene in northern Europe. It leads to a nearly complete loss of sulfamidase activity. In a homozygous state, it is associated with rapid and severe disease progression. The c.892T > C, p.S298P mutation shows a milder course of the disease. Compound heterozygous patients with both variants, as in our patient, have been reported with a mild and attenuated course .
A large Dutch study on 111 patients with MPS IIIa reported allelic frequencies of p.R245H and p.S298P of 44.9% and 18.6% respectively. Twenty-three patients (23%) had the combination of both mutations . Within the highly heterogeneous phenotype of MPS IIIa the rate of disease progression is related to variations in residual enzyme activity and allelic heterogeneity and shows strong genotype-phenotype correlations. Some mutations or combination of mutations are associated with a severe phenotype (p.R245H, p.Q380R, p.566W), whereas other variants (p.S298P, p.G122R, p.R206P, p.I322S, p.E369K) are associated with an intermediate or mild, attenuated course of the disease [4,5,6,7,8]. Patients, who are compound heterozygous for p.S298P in combination with one of the severe mutations (e.g. p.R245H), also showed a milder phenotype . The milder course within these patients may be due to a residual sulfamidase activity of up to 3 to 11% of normal controls [9, 10].
The so far described clinical phenotype of patients with the same compound heterozygous mutations of p.R245H and p.S298P is similar to the clinical course of our patient. In this patient group, the median age at loss of speech was 15y and the median age at loss of independent walking was 25y. The reported median age of death was 33.5 to 38y [4, 5]. Diagnosis of patients with a slowly progressive course of the disease was on average 5y later than in patients with rapid progression [6, 11].
Radiologic features in mucopolysaccharidosis comprise focal or diffuse, characteristically periventricular or bilateral T2-hyperintensity, enlarged periventricular spaces, involvement of the corpus callosum and brain atrophy. Hydrocephalus is more frequent in other types of mucopolysaccharidosis. In our patient, the most obvious abnormalities were a significant loss in volume and enlarged periventricular spaces, whereas increased T2-signalintensity was limited to a narrow band of the periventricular white matter. The severity of mental retardation has been shown to be associated with the severity of neuroimaging anomalies [2, 12].
The history of complications during delivery and in early neonatal life may have contributed to the delayed recognition of MPS IIIa in our patient. Developmental delay was initially seen as a consequence of perinatal asphyxia. Early, non-specific symptoms as behavioural abnormalities, hyperactivity and sleep disturbances may mislead to diagnoses of attention deficit / hyperactivity disorder and / or autism spectrum disorders . Somatic features are usually mild and non-specific and therefore not indicative in the diagnostic process. Patients with MPS IIIa are often diagnosed by paediatricians specialized in the broad field of metabolic disorders. Patients with a slowly progressing phenotype may have less contact with specialized paediatricians and consult doctors later in adolescence or early adulthood when neurodevelopmental regression is becoming obvious. Diagnostic delay may thus be due to a limited awareness of metabolic disorder spectrum in adult patients.
MPS III is a diagnostic challenge, particularly in the early stages and in patients with an attenuated course of the disease, due to a variable course, nonspecific early neuropsychiatric symptoms and the lack of obvious somatic features. The possibility of a metabolic disorder should be kept in mind in young children with developmental and / or speech delay in combination with behavioural abnormalities and / or sleeping difficulties and in adults, especially when pre-existing health conditions may obscure the clinical picture.