This large Brazilian family with 17 individuals displays a very attenuated form of MPS II, with normal cognitive development and preserved quality of life. The diagnosis of this condition in otherwise asymptomatic people was only possible because of the proband´s acute decompensated heart failure. This disease has been traditionally classified into attenuated and severe subtypes, although variations of severity between these two extremes have been observed.
Cardiovascular involvement was the most common serious complication of the disease in this family, although the proband was the only person to present major cardiovascular symptoms. The fast progression of his heart failure at the young age of 23 years was conspicuous. The failure of the clinical management plus the severity of heart involvement determined his need for a heart transplantation, which was performed for the first time in the context of MPS II. Unfortunately, the surgical approach failed in its objective, as the patient died of primary graft failure at the second day of postoperative.
A remarkable variability of heart involvement was observed among affected individuals. The proband’s 28-year-old brother had only mild aortic regurgitation, while his 19-year-old cousin had a normal echocardiogram. Interestingly, despite the fact that other family members had severe valvar lesion in echocardiography studies, they had no complaints or significative symptoms of heart failure. In the literature, symptomatic individuals constitute more than 80% of all MPS II patients, whereas valvar disease may be found in up to 60%¹⁰. Considering the importance of cardiovascular involvement in MPS II, physicians must always be aware of periodically monitoring heart complications during the follow-up of these patients through comprehensive clinical examination and routine echocardiography, always keeping in mind that some degree of the disease is usually expected, even in healthy patients.
Among surgical interventions, resection of adenoid and/or tonsil tissues was by far the most common procedure; since airway obstruction is progressive and frequent in MPS II¹¹, surgical correction of hypertrophy of the adenoid and tonsil tissue was necessary in nine patients. Likewise, hernias (either umbilical or inguinal) are very common in this disease, demanding surgical intervention in ten individuals.
Articular restriction was noteworthy as well, affecting the shoulders in most individuals; in the mild form of MPS II, joint contractures usually involve the upper more prominently than the lower extremities.
As expected for MPS II patients, none of the individuals had corneal opacities. However, retinopathies were reported: two patients (P10 and P12) presented retinitis pigmentosa and were submitted to peripheral iridotomy due to the primary angle closure (PAC), while other one (P13) showed optic nerve swelling, which responded well to clinical treatment. Besides that, hypermetropia was present in six patients, with retinal detachment secondary to trauma occurring in one of them (P8).
Although life expectancy is close to normal in less severely affected individuals and such individuals may reproduce, as previously reported¹²'¹³'¹⁴, authors believe that sensorineural hearing impairment is progressive and relates to cochlear fragility due to cell cilia dysfunction15,16,17 ; those findings emphasize the importance of referring these patients for an audiological evaluation, as well as monitoring from an auditory perspective.
As a matter of fact, the two affected seniors we identified died of natural causes at advanced ages (both older than 70 years old). The presentation of MPS II in these two individuals must have been mild enough to allow them to procreate and have long normal lives.
According to most sources, it seems to be no clear genotype-phenotype correlation in MPS II. From over 650 variants in IDS reported, nearly half are missense mutations⁴, like the one reported here. However, it is important to point out that the severe forms of the disease are usually associated with mutations that result in complete absence of the enzyme activity, such as nonsense and splicing variants, as well as large CNVs or complex rearrangements.
To this date, the specific mutation of this family (p.A77D) remains unreported by other studies or laboratories, according to databases such as the LOVD (Leiden Open Variant Database). In addition, the analysis from over a dozen silico prediction platforms (including REVEL and MutationTaster) indicate that this variant has, indeed, a disease-causing effect.
Regarding treatment, for many decades following Hunter’s initial description of MPS II (back in 1917), there was no effective therapy for the disease, and management was restricted to a palliative approach. Hematopoietic stem-cell transplantation, which has been a major advance in the treatment of other forms of MPS in the last decades, seems to be quite ineffective for MPS II patients. Various forms of gene therapy (from viral vectors to substrate reduction therapies), although promising, remain distant for the clinical scenario for MPS II⁴ so far.
Fortunately, in the last fourteen years, the advent of enzyme replacement therapy (ERT) has changed the clinical approach of MPS II, adding the possibility of improving the degradation and excretion of GAGs. Given it postpones the systemic development and natural history of the disease, ERT has become the standard of care for MPS II and reinforced the importance of early diagnosis. However, many doubts about its application continue unsolved.
Considering urinary levels of GAGs do not seem to have a clear direct correlation with the clinical severity of disease and ERT for MPS II (or other types of mucopolysaccharidosis) frequently do not normalize GAG levels¹8, therapeutical response tends to be quite difficult to measure through laboratorial parameters. Additionally, long-term benefits are somewhat limited when applied to patients with the severe phenotype, since it’s more and more evident that plasma infusions won’t penetrate the blood-brain barrier (BBB) and thus are unable to prevent the advance of the disease in central nervous system (CNS)¹9’20. At last, the age at which ERT should be initiated and whether asymptomatic individuals presenting the mild form of MPS II must be treated remains uncertain⁴’¹9’21.
On regards towards our family, following diagnosis 10 patients started ERT (Fig. 2/ Table 1): 6 of them were given Idursulfase (Elaprase®) and the other 4, Idursulfase Beta (Hunterase®). In accordance with most of the reviews⁴, none of the men under ERT presented any relevant adverse effect to neither of the two enzymes, to this date (after more than a decade of treatment). Even though the echocardiographic and ophthalmologic findings seem to be more severe in the second group, it is important to point out that the patients in the first group were not only considerably younger, but also received medication for far more time (total time of treatment of 11 against 4 years, respectively). In fact, these older patients opted to initiate ERT majorly due to worsening nocturne vision; at the time, due to bureaucratic reasons, Idursulfase Beta (Hunterase®) was in a disposal and easier to access than Idursulfase (Elaprase®).
In this scenario, we detected some minor alterations (mild mitral insufficiency) in the early stages of ERT (at age of 4) of our pair of identical twins in the first group; however, after their last appointment (at age of 11), only one of the twins (P3) persisted with the valvopathy, while the other (P2) revealed a rather normal echocardiogram. Despite this peculiarity, both of them (who are now 12 years old) always had an unremarkable clinical evaluation. Considering the natural progression of disease, we believe that these contradictory findings of P2 were secondary to multiple echocardiograms performed by different cardiologists.
Other than that, we could not find other significant differences between the two sets of patients; indeed, as most data suggests22, 23, 24 both drugs appear overall equally efficient and well tolerated. Comparatively, progress of the disease was rather uneventful in the four patients without ERT (Fig. 3/ Table 2), regardless of their advanced age (all over 40 years). Despite the variable phenotype (mainly heart dysfunctions and carpal tunnel syndrome), all 14 remaining living patients are still clinically healthy and have an independent style of life.