Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands

Abstract

Background: Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose 6-phosphate recognition marker is not synthesised on to lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase.

Objectives: Clinical, biochemical and molecular findings in 61 probands (63 patients) are presented to provide a broad perspective of these mucolipidoses.

Methods: GNPTAB was sequenced in all probands and/or parents. The activity of several lysosomal enzymes was measured in plasma, and GlcNAc-1-phosphotransferase was assayed in leucocytes. Thirty-six patients were studied in detail, allowing extensive clinical data to be abstracted.

Results: ML II correlates with near-total absence of phosphotransferase activity resulting from homozygosity or compound heterozygosity for frameshift or nonsense mutations. Craniofacial and orthopaedic manifestations are evident at birth, skeletal findings become more obvious within the first year, and growth is severely impaired. Speech, ambulation and cognitive function are impaired. ML III retains a low level of phosphotransferase activity because of at least one missense or splice site mutation. The phenotype is milder, with minimal delays in milestones, the appearance of facial coarsening by early school age, and slowing of growth after the age of 4 years.

Conclusions: Fifty-one pathogenic changes in GNPTAB are presented, including 42 novel mutations. Ample clinical information improves criteria for delineation of ML II and ML III. Phenotype-genotype correlations suggested in more general terms in earlier reports on smaller groups of patients are specified and extended.

Figures

Figure 1

Manifestations in ML II. a–c, same patient at 5 10/12 years; d and e, same patient at ages 3 months and 20 months; f and g, same patient at 1 and 2 years; h and i, different patients at 3 years; j and k, same patient at 13 months and 3 years. Coarsening of facial features is apparent from infancy and evolves in the first years of life. The common features include flat facies with depressed nasal bridge, prominent mouth, and gingival hypertrophy. The shallow orbits, thick skin and full cheeks contribute to the appearance of deep infraorbital creases and prominent cutaneous veins and capillaries on the face. Metopic prominence that gives the impression of craniosynostosis is depicted in b, h and i. Short, broad “claw” hands and contractures of knees and ankles are seen in c.

Figure 2

Manifestations in ML III. a–d, same female patient at 17 years; e–h, same male patient at 9 years. Coarsening of facial features is mild and gradual in ML III and more apparent in profile, with full cheeks, low nasal bridge and prominent mouth. Stiffness in all large and small joints is slowly progressive but disabling hip pain is the major contributor to morbidity. Contractures of the hips and knees cause the squatting appearance of the standing posture. Limited range of motion in the shoulders may be the presenting symptom. Hand configuration is near normal although contractures are evident.

Figure 3

Photographs and radiographs of hands of ML II and ML III. a–c, different ML II patients at 3 years, 15 months, and 4 10/12 years; d and e, same ML III patient at 29 years. The metacarpals and phalanges appear short and broad by 15 months (b). Irregular constriction causes proximal and distal pointing and the pinched appearance of the metacarpals (c). The hand contractures are clinically evident at a later age and remain milder than in ML II. The tubular bones of the hands (e) maintain near normal length and width.