Clinical Diagnosis

The following clinical features, similar to those for mucolipidosis III alpha/beta, contribute to early diagnosis of mucolipidosis III gamma (ML III gamma) but are not by themselves diagnostic [Raas-Rothschild et al 2004, Cathey et al 2009]:

• Family history of ML III gamma

• Growth rate deceleration

• Joint stiffness of the fingers, shoulders, and hips

• Gradual mild coarsening of facial features

• Genu valgum

• No organomegaly

In early childhood skeletal radiographs reveal mild to moderate dysostosis multiplex:

• Pelvis and hips. Hypoplastic iliac bones with flared iliac wings and shallow acetabula and moderate-to-severe dysplasia of the proximal femoral epiphyses giving rise to coxa valgaare the most striking radiologic abnormalities in ML III gamma.

• Hands and feet. Diaphyses of metacarpals and phalanges are mildly shortened; carpal bones may be smaller than normal

• Ribs. Widening especially in lateral and frontal (costochondral junction) parts

• Spine. Mild generalized platyspondyly; anterior inferior hook in lower thoracic and/or higher lumbar vertebrae

In late childhood or adolescence the changes observed on skeletal radiographs worsen with the development of generalized osteopenia.

Testing

Activity of lysosomal hydrolases. In ML III gamma the activity of nearly all lysosomal hydrolases is up to tenfold higher in serum and other body fluids than in normal controls because mannose-6-phosphate (M6P), which is essential to proper targeting of lysosomal acid hydrolases to lysosomes, cannot be added adequately to the hydrolases (see Molecular Genetic Pathogenesis).

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)Lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits confirmation of the diagnosis as well. (2) ML III gamma 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 III gamma. (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 ML III alpha/beta) and GNPTG (causing ML III gamma) confirms the diagnosis of ML III alpha/beta and ML III gamma. Note: Such testing is available in only a few research laboratories.

Molecular Genetic Testing

Gene. GNPTG is the only gene in which mutation is known to cause ML III gamma.

Clinical testing

• Sequence analysis. Bidirectional sequencing of the entire GNPTG coding region and flanking intronic regions detects two disease-causing mutations in more than 95% of individuals with ML III gamma. Types of pathologic variants include missense, splice-site, and nonsense mutations as well as small insertions and deletions that result in a frameshift.

• Deletion/duplication analysis. The frequency of deletions that would not be detected by sequence analysis is unknown; although a few have been reported [Persichetti et al 2009].

• Uniparental disomy (UPD) analysis is offered as a clinical test. Although a theoretical possibility, UPD of chromosome 16 has not been reported as causative of mucolipidosis III.

Research testing

• Linkage analysis may be available on a research basis and may be informative for large families with multiple affected individuals or for families with consanguinity.

Table 1. Summary of Molecular Genetic Testing Used in Mucolipidosis III Gamma

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
GNPTG	Sequence analysis	Sequence variants 2	>95%	Clinical
	Deletion / duplication analysis 3	Exonic, intronic, or whole-gene deletions	Unknown
	Uniparental disomy (UPD) analysis 4	UPD of chromosome 16	Unknown; no such reported cases to date

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array genomic hybridization (GH) (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

4. UPD of chromosome 16 has not been reported as causative of mucolipidosis III. See for a list of laboratories performing UPD.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Carrier status for each parent should be confirmed:

• If the proband appears to be homozygous for a mutation by sequence analysis. Confirming the carrier status of the parents helps determine if the proband either (a) is a compound heterozygote for the identified disease-causing mutation and a deletion or (b) has uniparental disomy (which is theoretically possible but has not been reported to date).

• On rare occasion to identify affected parents who were previously undiagnosed compound heterozygotes or homozygotes [Raas-Rothschild, personal communication].

Testing Strategy

To establish the diagnosis in a proband requires the combination of clinical evaluation and laboratory testing. The following order of evaluation is recommended:

• Family history of other affected members and the presence of consanguinity

• Identification of the characteristic clinical and radiographic findings

• Assay of several acid hydrolases in serum (not leukocytes), such as:

  • 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)

  • Arylsulfatase A (EC 3.1.6.1)

• If the clinical findings cannot distinguish between ML III alpha beta and ML III gamma, EITHER:

  • Sequence analysis of:

    • GNPTG if the phenotype is mild

    • GNPTAB if the phenotype is moderate or severe;
      
      OR

  • If the family is large enough and/or if the parents are consanguineous, linkage analysis at 16p13.3 and 12q23.3 to decide whether GNPTG or GNPTAB should be sequenced.

• Sequence analysis of the coding regions and flanking intronic segments of GNPTG and/or sequence analysis of the GNPTG cDNA if cells are available (lymphoblasts or fibroblasts)

• Consideration of deletion/duplication analysis if one parent is not a carrier of one of the mutations identified in the child and paternity is confirmed

• Consideration of UPD analysis. UPD of chromosome 16 has never been reported as a cause of ML III gamma. Such testing may be appropriate in rare cases (e.g., when clinical suspicion is high, only one parent is a carrier, and paternity is confirmed).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) If the affected child cannot be tested, sequence analysis of the GNPTG gene in both carrier parents can be performed to identify the two disease-causing alleles. (2) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: Prenatal diagnosis can be accomplished with assay of lysosomal enzyme activity in cultured chorionic villous cells or cultured amniocytes in pregnancies at increased risk when the disease-causing mutations in the family are not known.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

ML III gamma is the only phenotype known to be associated with mutations in GNPTG.

Natural History

Mucolipidosis III 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 cardiac involvement, results in severe functional impairment and significant morbidity. A few affected individuals may display mild cognitive impairment [Leroy 2007]; the majority do not [Raas-Rothschild, personal communication].

Comprehensive clinical data on ML III alpha/beta have been recently published [Cathey et al 2009]; however, only limited data are available on the natural history of ML III gamma. Therefore, this review discusses the natural history of ML III in general (MLIII alpha/beta and MLIII gamma) with emphasis on ML III gamma when specifics are known.

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 III gamma is often below the 10^th centile on standard growth curves.

Craniofacial. Dysmorphic facial features are absent or minimal in younger children. Coarsening of facial features is more gradual in ML III gamma than ML III alpha/beta.

Ophthalmologic. The corneae are clear by routine clinical inspection, but opacities that do not cause ophthalmologic impairment may be appreciated by slit-lamp examination in some persons.

Respiratory. Mild hoarseness or metallic voice has been reported.

Persons with ML III gamma are small, 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 may be necessary.

Abnormalities of the spine and ribs may limit lung capacity.

Cardiovascular. Individuals with ML III are at risk for cardiac involvement. Gradual thickening and subsequent insufficiency of the mitral valve and the aortic valve are common from late childhood onward [Steet et al 2005]. Valve replacement may be required; therefore, careful follow-up is needed.

Rapid progression of cardiac disease is rarely observed in ML III.

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. 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 III gamma (and earlier in ML III alpha/beta). Hip involvement progresses over years, finally resulting in destruction of the proximal femoral epiphyses. Limited hip mobility and lower limb pain can be significant.

Dupuytren-type palmar contractures may appear from late childhood onward. Moderate to severe claw-like flexion deformity of the fingers worsens with time.

Carpal tunnel syndrome and tarsal tunnel syndrome have been reported [Umehara et al 1997, Tylki-Szymańska et al 2002, Raas-Rothschild et al 2004, Smuts et al 2009].

Odontoid dysplasia and atlanto-axial dislocation were reported Umehara et al [1997] in one older individual.

Neuromotor development and intellect. Neuromotor development may be delayed mainly in reaching motor milestones. Nevertheless, other aspects of development including language and learning skills fit the expected age. Affected children may require school assistance but mostly because of physical limitations.

Other.The skin may become thickened with time.

Temporo-mandibular joint dislocation has been reported in one person, leading to difficulties in speech and feeding [Zolkipli et al 2005]. Less severe temporo-mandibular involvement accompanied by feeding inconvenience was also diagnosed in two individuals [Spiegel, unpublished data].

Genotype-Phenotype Correlations

To date no correlation between severity of disease and type of mutation has been reported.

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]. Mutations in:

• GNPTAB cause the allelic disorders ML III alpha/beta and ML II

• GNPTG cause ML III gamma [Cathey et al 2008]

The trivial name of this enzyme is UPDGlcNAc 1-P-transferase; thus, the three ML phenotypes can be considered “UPDGlcNAc 1-P-transferase deficiency disorders” [Leroy 2007].

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].

Mucolipidosis (ML). The term mucolipidosis was introduced in 1970 by Spranger & Wiedemann [1970], who provided the first clinical classification of the group of metabolic disorders clinically intermediate between the lipidoses and the mucopolysaccharidoses (storage disorders of glycosaminoglycans).

Prevalence

Estimates of ML III gamma prevalence are not yet known.

Most individuals with ML III gamma known to the authors originated from the Mediterranean region [Raas-Rothschild et al 2004, Encarnação et al 2009, Persichetti et al 2009]. This is in contrast to ML III alpha/beta which is pan ethnic.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ML III gamma, the following evaluations are recommended:

• Basic assessment

  • Growth parameters

  • Pain assessment

  • Orthopedic and functional assessments

  • Psycho-developmental evaluation to follow the individual’s developmental progress and program appropriate management

  • Skeletal survey

• Cardiac

  • Clinical examination

  • EKG

  • Echocardiography

• Ophthalmologic evaluation including slit lamp examination

• Metabolic bone disease assessment including evaluation of bone densitometry by DEXA studies and evaluation of biomarkers reflecting bone metabolism [Robinson et al 2002]

Treatment of Manifestations

Supportive and symptomatic management is indicated. Psychosocial support of patients and families is recommended.

No known measures are effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the patient’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 a frequent complaint. Management of pain in the hips is required. In older adolescents and adults with milder ML III gamma, bilateral hip replacement has been successful.

Casts (especially of the hands) during the night hours are usually well tolerated and seem to improve daily functions.

Carpal tunnel signs and rarely tarsal tunnel symptoms may require surgical tendon release procedures for temporary relief [Smuts et al 2009].

In severe cases, when significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered.

Prevention of Secondary Complications

Anesthesia. As with all storage diseases, anesthesia in ML III gamma 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 III gamma 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 III gamma have short necks and atlanto-axial instability has been reported [Umehara et al 1997].

• Jaw and neck movement can be limited

• Abnormalities of the spine and ribs can limit the individual’s capacity to breathe and fully expand their lungs.

Antibiotic prophylaxis. Persons with valvular involvement should be given antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) to prevent bacterial endocarditis.

Surveillance

Young children with ML III gamma and their families usually benefit from out-patient clinic visits once a year. Orthopedic and ophthalmologic assessment should be done at least once a year. Follow-up visits are recommended more frequently if any deterioration is observed.

During yearly visits, attention should be paid to pain relief, daily functional abilities, and psychological interventions.

Although cardiac manifestations are usually asymptomatic, monitoring for progressive valvular insufficiency should occur.

Surveillance for metabolic bone disease includes DEXA in five-year intervals.

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

The authors’ policy is not to test sibs at risk of being affected with ML III gamma since early diagnosis of affected individuals does not delay or halt disease progression [Author, personal observation].

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

Therapies Under Investigation

Several individuals with ML III alpha/beta have been treated with monthly intra-venous administration of pamidronate, a bisphosphonate. At present information is insufficient about when in the ML III alpha/beta disease course or at what age such treatment should be initiated [Robinson et al 2002; Sillence, personal communication]. In a recent consensus meeting on the use of bisphosphonate therapy in oligosaccharidoses doubts were raised regarding its usefulness in ML III gamma [MPS Society 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Mucolipidosis III gamma is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected and a 75% chance of being unaffected.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with ML III gamma are obligate heterozygotes (carriers) for the disease-causing mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

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 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.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation [Falik-Zaccai et al 2003] or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Newly synthesized lysosomal hydrolases have mannose 6-phosphate (M6P) residues that function as recognition markers for specific receptors required for lysosomal targeting. The M6P marker is generated in the Golgi apparatus by the sequential action of two enzymes.

In the first step N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) transfers GlcNac-1-phosphate to the C6 position mannose residues of acid hydrolases.

In the second step, N-acetylglucosamine-1-phosphodiester α-N-acetylglucosminidase (uncovering enzyme) removes N-acetylglucosamine residues thus exposing the M6P residues in order to correctly bind to their lysosomal membrane receptor.

GlcNAc-phosphotransferase is made up of three different subunits: alpha, beta, and gamma in a hexameric α2β2γ2 subunit complex [Bao et al 1996]. The three subunits are the product of two genes: GNPTAB and GNPTG.

GNPTAB, the gene encoding the alpha and beta subunits, maps to chromosome 12q23 [Tiede et al 2005, Kudo et al 2006]. Mutations in this gene result in mucolipidosis type III alpha/beta [Bargal et al 2006] and ML II.

GNPTG, the gene encoding the gamma subunit of GlcNAc-phospotransferse located on chromosome 16p13.3 was identified in 2000 [Raas-Rothschild et al 2000]. Mutations in this gene result in mucolipidosis type III gamma [Raas-Rothschild et al 2004]. The exact role of the γ subunit in the function of GlcNAc-phosphotransferase is not yet understood. Recent studies have proposed that it is important in the proper maintenance of α and β subunits in the GlcNAc-phosphotransferase complex [Pohl et al 2009].

Normal allelic variants. GNPTG contains 11 exons that span 11.13 kb of genomic DNA. It encodes a 305-amino acid protein. After cleavage of the 24-amino acid signal peptide, the mature protein (γ subunit) forms disulfide-linked homodimers that become glycosylated at Asn88 and Asn115 [Raas-Rothschild et al 2000, Tiede et al 2004].

Pathologic allelic variants. More than 16 disease-causing mutations have been reported (Table 2). They include missense, nonsense, and frameshift mutations as well as small intragenic deletions and insertions. In individuals with ML III gamma, homozygous or compound heterozygous mutations are detected. To date no correlation between severity of the disease and type of mutation has been reported. The list of mutations and their resultant protein changes are described in Table 2.

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions

Normal gene product. The exact role of the γ subunit in function of the GlcNAc-phosphotransferase is not entirely understood. Recent studies have proposed that it is important in the proper maintenance of α and β subunits in the GlcNAc-phosphotransferase complex [Pohl et al 2009].

Abnormal gene product. Unknown

Literature Cited

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21. Tappino B, Chuzhanova NA, Regis S, Dardis A, Corsolini F, Stroppiano M, Tonoli E, Beccari T, Rosano C, Mucha J, Blanco M, Szlago M, Di Rocco M, Cooper DN, Filocamo M. Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types II alpha/beta and III alpha/beta in 46 patients. Hum Mutat. 2009;30:E956–73. [PubMed: 19634183]
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Suggested Reading

1. Kornfeld S. Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest. 1986;77:1–6. [PMC free article: PMC423299] [PubMed: 3003148]

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 Dr. Marsha Zeigler, PhD and her team for what she taught us, and for her help in the diagnosis of patients.

We thank Mrs. Ruth Bargal, MSc for her continuous support and cooperation.

We thank the families for their cooperation.

Revision History

• 29 September 2011 (cd) Revision: sequence analysis, UPD, and prenatal testing available clinically

• 28 January 2010 (me) Review posted live

• 28 August 2009 (arr) Original submission