Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

Abstract

Background: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce.

Methods: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor.

Results: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia.

Conclusions: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.

Keywords: Bone marrow cell transplantation; Cognitive function; Hematopoietic stem cell transplantation; I-cell disease; Life quality; Lysosomal storage disorder; Mucolipidosis type II; Treatment.

Graphical abstract

Fig. 1

Targeting of lysosomal enzymes in health and disease (a) GlcNAc-1-phosphotransferase is involved in tagging mannose 6-phosphate (M6P) residues (yellow circles) on lysosomal enzymes (blue circles) for their targeting to lysosomes by M6P-receptors. In MLII, missorting of multiple lysosomal enzymes lacking M6P-residues due to reduced GlcNAc-1-phosphotransferase activity results in accumulation of macromolecules in lysosomes. (b) Hematopoietic donor cells produce functional M6P-containing lysosomal enzymes (green circles), which are taken up by MLII cells and transported to the lysosomes for degradation of macromolecules. Of note, hypersecretion of M6P-lacking lysosomal enzymes is not prevented despite metabolic cross-correction.

Fig. 2

Biochemical and clinical outcome. (a) Timeline of the patient history. (b) Levels of urinary glycosaminoglycans/creatinine (GAGs/crea) and deoxypyridinoline/creatinine (Dpd/crea) ratios before (blue dots) and after HSCT (green dots). (c) Progression of facial disease stigmata. (d) Plain pelvic radiography. (left) Radiograph at birth with bowing of the long bones, metaphyseal widening, periosteal cloaking and rickets-like changes of the bones. (right) Radiograph at 2.8 years of age with short acetabular coverage, constriction of the supra-acetabular parts of the os ilium, flared iliac wings, widening of the epiphysis of the proximal femora and mild femoral bowing.

Fig. 3

MRI of the brain at 1.5 years (a,d), 3.8 years (b,f) and 5.3 years of age (c,e,g). Sagittal T1 images. (a,b,c) show a progressive enlargement of the sella and approximation of the clivus and the pons with increasing flexure of the lower brainstem. The cerebellar tonsils are deep, but do not protrude into the foramen magnum. The subarachnoidal space around the optic nerve is progressively enlarged (Arrows in d,e,f,g) without papilledema or signs of increased intracranial pressure. Myelination shows no alteration in T1 (f,g) or T2 weighted images (data not shown).