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 individuals 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 affected individuals 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 DXA 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.

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 (or likely pathogenic) variants in GNPTG identified on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic GNPTG variants of uncertain significance (or of one known GNPTG pathogenic variant and one GNPTG variant of uncertain significance) does not establish or rule out the diagnosis.

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-energy x-ray absorptiometry (DXA), 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.

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.

Treatment of Manifestations

Supportive and symptomatic management is indicated.

Surveillance

Agents/Circumstances to Avoid

Vigorous stretching exercises are not recommended because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Mucolipidosis III gamma (ML IIIγ) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are typically heterozygotes (i.e., carriers of one GNPTG pathogenic variant).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GNPTG pathogenic variant and to allow for reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
  In one family, only the father of the proband was heterozygous for a GNPTG pathogenic variant (a GNPTG pathogenic variant was not detected in maternal DNA) and the proband was presumed to have ML IIIγ as the result of one inherited and one de novo GNPTG pathogenic variant [Ludwig et al 2017].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be a carrier 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with ML IIIγ are obligate heterozygotes (carriers) for a pathogenic variant in GNPTG.

Other family members. If both parents are a carrier of one GNPTG pathogenic variant, sibs of the proband's parents are at a 50% risk of being carriers of a GNPTG pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the GNPTG pathogenic variants in the family.

Note: Biochemical testing cannot be used to identify heterozygotes.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GNPTG pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

N-acetylglucosamine-1-phosphotransferase is a hexameric enzyme complex composed of two alpha, two beta, and two gamma subunits. The membrane-bound alpha and beta subunits are synthesized as a common alpha/beta precursor encoded by GNPTAB, whereas the soluble gamma subunit is encoded by GNPTG.

In the Golgi apparatus the gamma subunit directly binds to the alpha subunit and enhances N-acetylglucosamine-1-phosphotransferase activity for mannose-6-phosphate (M6P) modification of specific lysosomal enzymes. Once modified with M6P, the lysosomal hydrolases can attach to the M6P receptor and be targeted to the mature lysosome.

Mechanism of disease causation. ML IIIy occurs by a loss-of-function mechanism. Most disease-associated variants are predicted to be loss-of-function variants. The majority of reported missense variants are located in the M6P receptor homology (MRH) domain. It is speculated that these variants impair MRH domain function, which plays a major role in binding phosphorylated and non-phosphorylated high-mannose-type N-glycans.

Acknowledgments

We thank the "Vaincre les Maladies Lysosomales" association for their continuous support and for the research grants for our research projects on ML III gamma and ML II.

We thank the families for their cooperation.

Revision History

• 21 November 2019 (bp) Comprehensive update posted live
• 5 July 2012 (me) Comprehensive update posted live
• 28 January 2010 (me) Review posted live
• 28 August 2009 (arr) Original submission

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