Mucopolysaccharidosis type I S (MPS IS) or Scheie syndrome (OMIM #607016) is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-L-iduronidase (EC 3.2.1.76), leading to storage of dermatan sulfate and heparan sulfate. MPS IS is caused by mutations in the IDUA gene, located on chromosome 4p16.3. In MPS IS patients, treatment with recombinant human alpha-L-iduronidase (laronidase) - the deficient enzyme - reduces lysosomal storage in the liver and improves some clinical manifestations whilst stabilizing others. Although the incidence of tuberculosis (TB) in Latvia is decreasing (23 cases per 100,000 in 2020), Latvia remains in the top six EU and European Economic Area countries with the highest TB case notifications and there is a high burden of multi-drug resistant (MDR) TB. BCG vaccination in Latvia is offered to all newborns between the 2nd and 5th day after birth; booster vaccinations are not given at an older age. Routine screening for TB is not performed; however, patients (including children) are tested if they show signs/symptoms or have been in contact with a TB patient. To date, there are no published reports of TB treatment in MPS IS patients receiving enzyme replacement therapy (ERT) and as such it is not known whether both conditions can be treated simultaneously. Here, we report the case of a 14-year-old male with MPS IS receiving ERT who was diagnosed with a latent TB infection (positive IGRA test) after contact with an MDR TB patient.
The patient was born at 40 weeks' gestation to non-consanguineous parents and received his BCG vaccination post birth. Early psychomotor development was normal. During preschool years, he suffered from frequent upper respiratory tract infections, sinusitis, otitis media and bronchial asthma. At the age of 5 years, the patient developed knee pain and joint stiffness. At the age of seven years, he was diagnosed with polyarthritis and chronic uveitis and was initially treated for juvenile idiopathic arthritis. However, when an elevated level of mucopolysaccharide in his urine was detected, further diagnostic enzyme analysis revealed pathologically low alpha-L-iduronidase activity and two heterozygous disease-causing mutations in the IDUA gene were identified - the first one in exon 2 (c.208C>T p.Q70*) and the second one in intron 12 (c.1727+4C>T). A diagnosis of MPS type I was made, and he was put under the supervision of a multidisciplinary team. Consequently, ERT was started with intravenous laronidase 100 U/kg once a week. In response, the patient's joint mobility improved, and no joint pain was reported. However, he continued to endure mild bilateral carpal tunnel syndrome, extension contractures of the distal phalanges, restricted mobility of the wrists and rigid equinus deformity of both feet. The lattermost was corrected by reconstructive surgeries and bilateral Achilles tendon extension. The patient developed mild mitral regurgitation, but this did not require any treatment. His lung function (FVC, FEV1) also improved and fewer respiratory infections were noted. The patient wears spectacles. His most recent ophthalmologic evaluation in 2022 revealed disseminated point-like dystrophic changes in the cornea (corneal dystrophy) and hypermetropic astigmatism with amblyopia ex anopsia. He has never displayed a neurological or intellectual deficit and attends a mainstream school.
In 2017, at the age of 10 years, the patient was in contact with a family member with MDR TB resistant to the first line of anti-tuberculosis drugs. He was subsequently tested for TB infection (Mantoux tuberculin skin test) and a skin induration of 14 mm was observed, but IGRA test was negative. A lung CT scan was conducted, and no pathologic changes were detected. A diagnosis of latent tuberculosis infection was made, but during this period, prophylaxis with second line anti-tuberculosis drugs was not recommended by the WHO, so the prophylaxis was not prescribed. No other family members were infected.
In 2021, at the age of 14 years, the patient was in contact with a close neighbor with MDR TB (resistant to isoniazid, rifampicin and pyrazinamide; preserved sensitivity to moxifloxacin). All family members were tested again, and the patient showed a positive IGRA test. Lung and intrathoracic lymph node CT scans were conducted, and no TB process was detected. A diagnosis of latent TB infection was made and prophylactic treatment was started with peroral moxifloxacin 400 mg once a day for 6 months. Due to the high burden of MDR TB in Latvia and to ensure patient compliance, monitoring of TB drug treatment via Skype (DOT or directly observed therapy) is used with patients who cannot attend a medical institution each day to receive the prescribed medication. DOT was used in this case.
The patient reported nausea and dizziness shortly after administration of moxifloxacin and vomiting once a week, which continued throughout the duration of the treatment. During the treatment, no abnormal liver function tests were observed, the corrected QT interval on ECG was normal, and the patient continued to receive ERT once a week. No complications were reported and no active TB disease has been detected to date.