Mucolipidosis Iii Gamma
Summary
Clinical characteristics.
Mucolipidosis III gamma (ML IIIγ) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood; the progressive course results in severe functional impairment and significant morbidity from chronic pain. Cardiorespiratory complications (restrictive lung disease from thoracic involvement, and thickening and insufficiency of the mitral and aortic valves) are rarely clinically significant. A few (probably <10%) affected individuals display mild cognitive impairment.
Diagnosis/testing.
The diagnosis of ML IIIγ is established in a proband with suggestive clinical and radiographic findings and biallelic pathogenic variants in GNPTG identified on molecular genetic testing.
Management.
Treatment of manifestations: No measures are known to be effective in treating the progressive limitation of motion in large and small joints. Low-impact physical therapy is usually well tolerated. In older adolescents and adults joint replacement has been successful in relieving hip pain and knee pain. Carpal tunnel signs, and rarely tarsal tunnel symptoms, may require surgical tendon release procedures for temporary relief. Later in the disease course when bone pain of variable intensity may become frequent, management focuses on pain relief. Bisphosphonate treatment in patients with significant skeletal disease and markedly decreased bone mineral densitometry can be considered. When significant cardiac valvular dysfunction disrupts ventricular function, valve replacement needs to be considered. Addressing the social and emotional needs of patients and their families is recommended.
Surveillance: Yearly outpatient clinic visits (unless more frequent pain, cardiac, and/or respiratory monitoring is warranted) to assess pain level, musculoskeletal needs, gross motor and fine motor function, vision, cardiac and respiratory function, development, educational needs, psychological issues, and utilization of community resources. Frequency of DEXA scans depends on age and results of prior studies.
Agents/circumstances to avoid: Vigorous stretching exercises because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons.
Genetic counseling.
ML IIIγ is inherited in an autosomal recessive manner. If both parents are known to be carriers of one GNPTG pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GNPTG pathogenic variants in an affected family member are known, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria for mucolipidosis III gamma have not been established.
Suggestive Findings
Mucolipidosis III gamma (ML IIIγ) should be suspected in individuals with the following clinical and radiographic findings [Raas-Rothschild et al 2004, Tüysüz et al 2018, Nampoothiri et al 2019].
Clinical findings
- Growth rate deceleration
- Joint stiffness of the fingers, shoulders, and hips
- Gradual mild coarsening of facial features
- Genu valgum
- Spinal deformities including scoliosis and hyperlordosis
- No organomegaly
Radiographic findings. In early childhood, skeletal radiographs reveal mild-to-moderate dysostosis multiplex:
- Pelvis and hips. Hypoplastic iliac bones with flared iliac wings and shallow and irregular acetabula and moderate-to-severe dysplasia of the proximal femoral epiphyses – giving rise to coxa valga – are the most striking radiologic abnormalities.
- Hands and feet. Diaphyses of metacarpals and phalanges are mildly shortened with "bullet-shaped" distal end of phalanges; carpal bones may be smaller than normal and with osteoporotic changes.
- Ribs. Widening especially in the lateral and frontal costochondral junctions
- Spine. Generalized platyspondyly; irregularity of the anterior upper and lower vertebral endplates; wedge-shaped and small ovoid vertebral bodies
In late childhood or adolescence, the changes on skeletal radiographs worsen with the development of generalized osteopenia.
Establishing the Diagnosis
The diagnosis of ML IIIγ is established in a proband with suggestive clinical and radiographic findings and biallelic pathogenic variants in GNPTG identified on molecular genetic testing (see Table 1).
Molecular Genetic Testing
Approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing (Option 1) requires that the clinician determine which gene(s) are likely involved, whereas genomic testing (Option 2) does not.
Option 1. A mucolipidosis or lysosomal storage disorders multigene panel that includes GNPTG and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2. Comprehensive genomic testing. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Mucolipidosis III Gamma
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method 3 |
|---|---|---|
| GNPTG | Sequence analysis 4 | ~99%% 5 |
| Gene-targeted deletion/duplication analysis 6 | None detected |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Data from Nampoothiri et al [2019], Velho et al [2019]
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Two intronic deletions reported are of a size detectable by sequencing but could be missed due to their location [Persichetti et al 2009].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Supportive Biochemical Findings
Activity of lysosomal hydrolases. In ML IIIγ the activity of nearly all lysosomal hydrolases is up to tenfold higher in serum dried blood and other body fluids (e.g., media from cultured fibroblasts or amniocytes) than in normal controls because mannose-6-phosphate, which is essential to proper targeting of lysosomal acid hydrolases to lysosomes, cannot be added adequately to the hydrolases and they are overexcreted into the extracellular space.
The following lysosomal hydrolases are of most interest as their increased activity in serum and other body fluids is relevant in the differential diagnosis of ML III and lysosomal storage disorders:
- β-D-hexosaminidase (EC 3.2.1.52)
- β-D-glucuronidase (EC 3.2.1.31)
- β-D-galactosidase (EC 3.2.1.23)
- α-D-mannosidase (EC 3.2.1.24)
Note: (1) The intracellular lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits support of the diagnosis as well. (2) ML IIIγ cannot be diagnosed by assay of acid hydrolases in leukocytes. (In ML II, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes.) (3) Biochemical testing (measurement of lysosomal hydrolase activity) does not distinguish ML III alpha/beta from ML IIIγ. (4) Biochemical testing cannot be used to identify heterozygotes.
UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase enzyme (also known as GlcNAc-phosphotransferase) (EC 2.7.8.17). Demonstration of deficiency of the enzyme GlcNAc-phosphotransferase, encoded by GNPTAB (causing GNPTAB-related disorders) and GNPTG (causing ML IIIγ), confirms the diagnosis of a GNPTAB-related disorder and ML IIIγ.
Clinical Characteristics
Clinical Description
Mucolipidosis III gamma (ML IIIγ) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood and the progressive course, including mild cardiac involvement, results in severe functional impairment and significant morbidity. A few (probably <10%) affected individuals may display mild cognitive impairment [Nampoothiri et al 2019], but the majority do not.
The initial manifestation in most affected individuals is joint stiffness in fingers as early as age 18 months [Tüysüz et al 2018].
Growth. Weight and length at birth are within normal limits. Gradual slowing of growth rate begins in early childhood.
Worsening hip and knee contractures add to the poor growth rate. While frank dwarfism does not occur, the height of individuals with ML IIIγ is often below the tenth centile on standard growth curves.
Craniofacial. Dysmorphic facial features are absent or minimal in younger children. Although most individuals with ML IIIγ develop coarsening of the facial features, it often occurs in the first two decades of life, which is more gradual than in ML IIIα/β.
Ophthalmologic. While the corneae are clear by routine clinical inspection, opacities that do not cause ophthalmologic impairment may be appreciated by slit lamp examination in some individuals [Tüysüz et al 2018].
Respiratory. Individuals with ML IIIγ generally do not have pulmonary impairment; however, mild-to-moderate restrictive lung disease may be present in adults due to abnormalities of the spine and ribs that reduce lung capacity [Oussoren et al 2018].
Cardiovascular. Individuals with ML IIIγ are at risk for cardiac involvement. Although gradual thickening and subsequent mitral valve prolapse and insufficiency of the mitral and aortic valves are common from late childhood onward, cardiac function is normal in most affected adults [Oussoren et al 2018, Tüysüz et al 2018].
Gastrointestinal. Hepatomegaly and splenomegaly are absent.
Skeletal / soft connective tissue. Stiffness of finger joints, a cardinal feature, is usually the initial manifestation of the disorder. Moderate-to-severe claw-like flexion deformity of the fingers worsens with time. Limited range of motion of the shoulders is common early in the disease course. Genu valgum deformity occurs in all affected individuals early in the disease.
Hip involvement usually develops during the end of adolescence in ML IIIγ (earlier in ML IIIα/β). Hip involvement progresses over years, finally resulting in destruction of the proximal femoral epiphyses. Limited hip mobility and lower-limb pain can be significant and may result in waddling gait with age.
Carpal tunnel syndrome develops in most affected individuals and may be clinically significant in the second and third decade [Raas-Rothschild et al 2004, Tüysüz et al 2018, Nampoothiri et al 2019].
Spinal deformities develop over time and include scoliosis and hyperlordosis. In one individual atlantoaxial instability required corrective surgery; however, this complication is very uncommon in ML IIIγ [Tüysüz et al 2018, Nampoothiri et al 2019].
Short neck reported in several individuals had no clinical significance [Tüysüz et al 2018].
Chronic pain syndrome significantly impairs the quality of life. It is common and mainly involves the hips, knees, and entire legs and sometimes the hands. Chronic pain syndrome is attributed to skeletal and connective tissue disease. In some affected individuals spinal cord compression due to spinal stenosis (decreased diameter of the spinal canal) and vertebral osteoarthritic changes may also contribute to the chronic pain syndrome.
Osteopenia, confirmed by reduced bone mineral densitometry measured by dual x-ray absorptiometry (DEXA), is common.
Neuromotor development and intellect. While motor milestones may be delayed, other aspects of development including language and learning skills are as expected for age. Affected children may require school assistance mostly because of physical limitations. While cognitive function is within the normal range in most affected individuals, a few individuals (probably <10%) have cognitive deficiency. It is still to be determined if this manifestation is related to ML IIIγ given the consanguinity in many reported cases and the possibility of additional genetic causes.
Other. The skin may become mildly thickened with time. Recently, scleroderma-like changes were reported in individuals with Moroccan ancestry [Zrhidri et al 2017].
Genotype-Phenotype Correlations
To date no correlation between severity of disease and type of GNPTG pathogenic variant has been reported; however, predicted loss-of-function variants, such as the recurrent variants c.285dupC, c.445delG, and c.499dupC, are associated with a severe phenotype [Tüysüz et al 2018]. See Table 5 for more details.
Nomenclature
UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine 1-phosphotransferasedeficiency disorders. This enzyme is the product of two genes: GNPTAB, encoding the alpha and beta subunits, and GNPTG, encoding the gamma subunit [Bao et al 1996]. Pathogenic variants in:
- GNPTAB cause GNPTAB-related disorders, which include the severe phenotype of ML II and the attenuated form of ML IIIα/β;
- GNPTG cause ML IIIγ [Cathey et al 2008].
The trivial name of this enzyme is UDPGlcNAc 1-P-transferase; thus, the three ML phenotypes can be considered "UDPGlcNAc 1-P-transferase deficiency disorders" [Leroy 2007].
ML IIIγ was previously referred to as variant pseudo-Hurler polydystrophy* or mucolipidosis IIIC [Cathey et al 2008].
*"Pseudo-Hurler polydystrophy" was the term used from 1966 by Maroteaux and Lamy when they first delineated ML III. They used this term because of the resemblance of ML III to Hurler disease, or mucopolysaccharidosis I (MPS I) [Kornfeld & Sly 2001].
Prevalence
The worldwide estimated incidence of ML II, ML IIIα/β, and ML IIIγ varies between 2.5 and 10 cases per 1,000,000 live births [Velho et al 2019]. The exact prevalence of ML IIIγ is unknown; it is considered an ultra-rare disease.
Most individuals with ML IIIγ known to the authors originated from the Mediterranean region [Raas-Rothschild et al 2004, Persichetti et al 2009, Tüysüz et al 2018]. However, more recent reports include individuals with ML IIIγ from other geographic regions including China, India, South America (Brazil), North America, and North Africa [Persichetti et al 2009, Gao et al 2011, Nampoothiri et al 2019, Velho et al 2019], suggesting that the disorder is pan ethnic.
Differential Diagnosis
Mucolipidosis II (ML II), ML IIIα/β, and ML IIIγ are all UDPGlcNAc 1-P-transferase deficiency disorders (see Nomenclature). Whereas the clinical phenotypes of ML IIIα/β and ML IIIγ can be difficult to distinguish, the severe phenotype of ML II is easily differentiated. In general, the ML IIIγ phenotype is less severe than ML IIIα/β.
See Table 2 for inherited disorders to consider in the differential diagnosis of ML IIIγ.
Table 2.
Genes to Consider in the Differential Diagnosis of Mucolipidosis III Gamma (ML IIIγ)
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/ML IIIγ | Distinguishing from ML IIIγ | |||
| GNPTAB | ML IIIα/β (see GNPTAB-Related Disorders) 1 | AR | Clinical features of ML IIIγ are similar to but milder than those of ML IIIα/β. | No specific ethnic predilection has been reported in ML III α/β. 2 |
| CCN6 (WISP3) | Progressive pseudorheumatoid dysplasia | AR |
|
|
| COL2A1 | Osteoarthritis w/mild chondrodysplasia (see Type II Collagen Disorders Overview) | AD |
|
|
| CTSA | Juvenile galactosialidosis (OMIM 256540) | AR |
|
|
| GLB1 | MPS IV B 3 (see GLB1-Related Disorders) | AR |
|
|
| GUSB | MPS VII B 4 (OMIM 253220) | AR |
|
|
| IDS | Slowly progressive MPS II 5 | XL |
|
|
| IDUA | Slowly progressive MPS I 6 | AR |
|
|
| MAN2B1 | Alpha-mannosidosis | AR |
|
|
| SLC17A5 | Free sialic acid storage disorders | AR |
|
|
| SUMF1 | Multiple sulfatase deficiency | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
- 1.
Also referred to as pseudo-Hurler polydystrophy
- 2.
Most individuals with ML IIIγ known to the authors originated from the Mediterranean region [Raas-Rothschild et al 2004, Encarnação et al 2009, Persichetti et al 2009].
- 3.
Also referred to as Morquio syndrome type B
- 4.
Also referred to as Sly disease type B
- 5.
Also referred to as Hunter syndrome
- 6.
Also referred to as Hurler-Scheie syndrome or Scheie syndrome
Other disorders to consider
- Rheumatologic disorders are often suspected in individuals with ML IIIγ because of slowly decreasing range of motion in large and small joints and increasing pain in the hips [Brik et al 1993].
- Rheumatoid arthritis (OMIM 180300) presents with clinical and laboratory signs of inflammation. The activities of the several lysosomal enzymes in serum are normal. Dysostosis multiplex is absent. Family history is not compatible with autosomal recessive inheritance.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mucolipidosis III gamma (ML IIIγ), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Mucolipidosis IIIγ
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Height, weight, head circumference | To assess growth rate |
| Skeletal | Pain assessment | To assess pain scores & involvement |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / PT / OT evaluation | Incl assessment of:
|
| Complete skeletal survey | To better assess skeletal involvement | |
| Metabolic bone disease | DEXA study; biomarkers reflecting bone metabolism | Perform baseline DEXA scan:
|
| Development | Developmental assessment |
|
| Cardiac | Clinical examination, ECG, echocardiogram | To assess for mitral & aortic valve involvement usually beginning in late childhood |
| Ophthalmologic | Visual acuity, slit lamp examination | For evidence of corneal opacities |
| Respiratory | Pulmonary consultation | Lung function studies to evaluate for restrictive lung disease from spine & rib abnormalities |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | Incl genetic counseling |
| Family support/resources | Assess:
|
OT = occupational therapy; PT = physical therapy
Treatment of Manifestations
Supportive and symptomatic management is indicated.
Musculoskeletal
No measures are known to be effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the affected individual's needs. Short sessions of aqua therapy that are "low impact" in regard to joint and tendon strain are usually well tolerated.
Later in the disease course, bone pain of variable intensity may become frequent. Management of pain in the hips is required. In older adolescents and adults, bilateral hip replacement has been successful. In patients with progressive knee involvement, knee replacement has been successful.
Casts (especially of the hands) during the night hours are usually well tolerated and appear to improve daily functions.
Carpal tunnel signs, and rarely tarsal tunnel symptoms, may require surgical tendon release procedures for temporary relief [Oussoren et al 2018, Tüysüz et al 2018].
In cases with severe spinal deformities with or without spinal cord compression, spinal surgical procedures should be considered.
Routine pain assessment and consultation with a pain specialist should be performed as required.
Of note, in patients with significant skeletal disease and considerable decrease in bone mineral densitometry (Z score<-2.5), bisphosphonates (oral or intravenous) should be highly considered [Tüysüz et al 2018; Tüysüz, personal communication].
Cardiac
When significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered. However, such complications are rare in ML IIIγ.
Antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) is appropriate to prevent bacterial endocarditis.
Psychosocial support of patients and families is recommended.
Anesthesia
As with all storage diseases, anesthesia for individuals with ML IIIγ must be well planned. Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care physicians.
The anesthetic team should be aware of the following issues:
- Persons with ML IIIγ are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary.
- Fiberoptic intubation must be available.
- Persons with ML IIIγ have short necks, and atlanto-axial instability has been reported [Tüysüz et al 2018].
- Jaw and neck movement can be limited.
- Abnormalities of the spine and ribs can limit the individual's capacity to breathe and fully expand the lungs.
Surveillance
Table 4.
Recommended Surveillance for Individuals with Mucolipidosis IIIγ