Mucolipidosis type III, a series of adult patients

The characteristics of the 13 adult patients are outlined in Table 1. Median age at last follow-up was 30 years (range 18–68 years). Most patients were of Caucasian descent, and both genders were equally represented. Patients 9, 11 and 10, 12 are siblings. Out of the 13 patients, one was initially misdiagnosed as MPS II and three as MPS IV. In one of these patients, diagnosed with MPS IV at the age of 30 years, the correct diagnosis was established as late as age 64 years.

Most patients developed clinical symptoms in the first decade of life. The diagnosis of ML was made in ten patients by the establishment of elevated levels of lysosomal enzymes in plasma, confirmed by a concomitant decreased lysosomal enzyme activity in fibroblasts in four patients (in one patient, only enzyme measurements in fibroblasts were performed) and in one patient by a decreased activity of GlcNAc-1-PTase. In seven patients, DNA analysis was performed; three patients had mutations in the GNPTAB gene and four patients in the GNPTG gene. The mutations and clinical features of patient number 2 were published 13 years ago by Raas-Rotschild et al. (2004). The GNPTAB gene c.1178A>G; p.(His393Arg) mutation (patient number 1), the GNPTG gene homozygous variants c.411 + 9_411 + 35del27 (patient number 3) and c.318-1G>C (patient numbers 6 and 7) and the GNPTG gene heterozygous mutation c.122_138del; p.(Pro41fs) with the c.331T>C variant (patient number 5) have not been published before.

Five patients had notably short statures (range 129–158 cm, median 145 cm) (Table 2). In patient number 13, height could not be measured. Six patients needed help with ADL and/or were wheelchair-dependent. All but one patient suffered from carpal tunnel syndrome (CTS) (Supplemental Table 2).

Four patients had mild cognitive impairment (patient numbers 4, 5, 10 and 13), while cognitive function was normal in the other nine patients (Table 2). Ten patients were employed at any time during their adult life. Pregnancies with healthy offspring were reported in two patients (patient numbers 3 and 11).

The most prominent clinical signs were the skeletal abnormalities. All patients had abnormally shaped bones (dysostosis multiplex) and progressive osteoarthritis, characterised by cartilage destruction in joints and areas of radiolucency in bones that may reflect erosive bone lesions (Supplemental Table 1). These abnormalities were found on X-rays of the hand, feet, shoulders, elbows, hips, knees and spine (Freisinger et al. 1992; Hetherington et al. 1999; Haddad et al. 2000; Robinson et al. 2002; David-Vizcarra et al. 2010; Pantoja Zarza and Diez Morrondo 2014; Kadar et al. 2017). In four patients, the carpal and/or tarsal bones were hypoplastic, with secondary osteoarthritic changes observed in the older patients (examples in Fig. 1a and Supplemental Table 1). In 11 patients, the same abnormalities were seen in the humeral/ femoral heads and femoral neck (examples in Fig. 1a, b). In all patients of whom data on hip morphology were available (n = 9), hip dysplasia and altered pelvic shape were present (examples in Fig. 1b). Abnormalities of the spine were present in all patients; the most common findings were atypically shaped vertebrae (hypoplasia), subluxation and scoliosis (examples in Fig. 1a). The majority of patients reported pain of the glenohumeral joints, and/or the hands, feet, hips, knees and the lumbar spine. In six patients, signs of spinal cord or nerve root compression were present (Supplemental Table 1).

Figure 1a shows exemplary radiographs of the skull, spine, shoulder, elbow, knee, hand, ankle and foot of three MLIII patients (patient numbers 4, 5 and 7) at the ages of 18, 28 and 65 years, respectively. The findings in these radiographs are described in the legend of Fig. 1a. Separately, X-rays of the pelvis of four MLIII patients (patient numbers 1, 5, 6 and 7) over time are shown in Fig. 1b. In all patients, there is severe hip dysplasia, with flaring of iliac wings as well as significant ossification disorders of the femoral heads, with arthritic changes of the hips. In the most severely affected patient (patient number 1), there is near total destruction of the femoral heads by the age of 11 years. In contrast, in patient number 5, the femoral heads are hardly affected at the age of 8 years, but by the second decade of life, severe osteoarthritis of both hips had developed.

The oldest patient (patient number 7) was completely wheelchair-dependent from the age of 23 years. In this patient, no surgical hip interventions have been performed, for unknown reasons. The femoral heads were abnormally shaped, with severe secondary osteoarthritis. This is also seen on macroscopic and histopathological examination of the left hip, which was removed after her death at the age of 69 years (Fig. 1b), when she succumbed to metastatic bladder cancer.

For all patients, the type of orthopaedic surgeries and age at which these were performed are depicted in Fig. 2. Details of the specific surgical procedures can be found in Supplemental Table 2. The most frequent intervention was hip surgery, performed in eight patients, with first interventions in the second or third decades of life. In all of these patients, total hip replacement (THR) was eventually required.

Eight patients underwent bilateral CTS release, mostly in the second decade of life. In one patient, this intervention was performed more than once. Less frequently, surgical interventions of the knees, feet and spinal cord were performed. Several patients were treated with repeated corticosteroids injections in the glenohumeral or knee joint to reduce pain. Two patients were treated with bisphosphonates at their last outpatient visit (patient numbers 8 and 10).

Echocardiography was performed in 12 patients (Supplemental Table 3). In patient number 4, there were limited signs of cardiac hypertrophy, with thickening of the posterior left ventricular wall. Systolic ventricular function was normal in all patients. Mild dilated right ventricle with normal systolic function was seen in patient number 10. Five patients (patient numbers 1, 4, 5, 10 and 13) had mild regurgitation of one or more valves (mitral, aortic, pulmonary or tricuspid) and one patient had moderate stenosis and regurgitation of the aortic valve (patient number 5). None of the patients had required valve replacement at the time of their last follow-up.

Pulmonary function tests were performed in six patients (Supplemental Table 3). Two patients had mild to moderate restrictive lung disease (patient numbers 1 and 4).