Mucolipidosis Iv

Molecular Genetic Testing

Approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Single-gene testing. Sequence analysis of MCOLN1 is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

In individuals of Ashkenazi Jewish ancestry targeted analysis for the two common pathogenic variants – c.406-2A>G and a 6.4-kb deletion beginning in the 5’UTR and extending into exon 6 – can be performed first, as they account for 95% of pathogenic variants in this population. An estimated 70% of individuals with mucolipidosis IV are of Ashkenazi Jewish heritage [Altarescu et al 2002].

• Approximately 60% of individuals with mucolipidosis IV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice site pathogenic variant.
• An estimated 33% are compound heterozygotes for the two common pathogenic variants [Wang et al 2001, Goldin et al 2004a].
• Only one individual homozygous for the 6.4-kb deletion has been identified [Bargal et al 2000, Bassi et al 2000, Sun et al 2000].

Note: The common 6.4-kb deletion cannot be detected by routine sequencing. Other methods such as gene-targeted deletion/duplication analysis or a genotyping assay specifically designed to detect this deletion (e.g., breakpoint PCR or allele-specific primer extension) must be employed.

A multigene panel that includes MCOLN1 and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel 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. (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.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of mucolipidosis IV.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Biopsy

In the past, identification of abnormal lamellar membrane structures and amorphous cytoplasmic inclusions in diverse cell types on skin biopsy was used to confirm the diagnosis of mucolipidosis IV [Bargal et al 2002]. Subsequently, demonstration of typical vacuolation by PAS staining of conjunctival cells obtained with a swab was used for diagnosis [Smith et al 2002].

Typical Mucolipidosis IV

The most common presentation is severe psychomotor delay by the end of the first year of life in a child who is subsequently noted to have visual impairment caused by a combination of corneal clouding and retinal degeneration.

Neurologic findings. Psychomotor development is usually limited to few or no words and poor hand use [Altarescu et al 2002]; some may develop the ability to sit independently or crawl. Most individuals do not achieve independent walking [Altarescu et al 2002]; a few have learned to walk with the aid of a walker [Altarescu et al 2002].

Receptive language is better than expressive language; some individuals have used up to 50 signs to communicate.

Neurologic examination typically reveals severe dysarthria or anarthria, slow chewing, slow eating and swallowing, and spastic diplegia or quadriplegia [Altarescu et al 2002]. Individuals may be hypotonic, but tendon reflexes are usually hyperactive.

Neurologic deficits generally remain static during the first three decades of life [Altarescu et al 2002]; however, some individuals have neurologic deterioration best observed by serial brain magnetic resonance imaging volumetry and diffusion weighted imaging [Schiffmann et al 2014].

Brain MRI typically shows hypoplasia of the corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities in the white matter on T₁-weighted images, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum is observed in older individuals [Frei et al 1998].

Epileptiform discharges on EEG are common but are infrequently associated with clinical seizures [Siegel et al 1998].

Eye findings. Individuals with typical mucolipidosis IV have superficial corneal clouding that is bilateral, symmetric, and most visible in the central cornea [Smith et al 2002]. The corneal opacification is limited to the epithelium without stromal involvement or edema [Authors, personal observation], early reports of stromal abnormalities notwithstanding. On occasion, corneal clouding is the feature that prompts medical evaluation.

Painful episodes consistent with corneal erosions are common, but appear to decrease in frequency and severity with age.

Vision may be close to normal at a young age. Over the first decade of life, progressive retinal degeneration with varying degrees of vascular attenuation, retinal pigment epithelial changes, and optic nerve pallor result in further decrease in vision [Siegel et al 1998, Altarescu et al 2002, Pradhan et al 2002, Smith et al 2002]. Bilateral bull's eye maculopathy was observed in one individual [Smith et al 2002]. Visual acuity is difficult to test in most individuals with mucolipidosis IV, but is decreased in almost all persons older than age five years. Virtually all individuals with mucolipidosis IV develop severe visual impairment by their early teens as a result of the retinal degeneration.

In rare instances, mucolipidosis IV may consist of isolated retinal dystrophy [Goldin et al 2008].

Other ocular findings are strabismus (>50% of individuals), nystagmus, ptosis, and cataract [Bach 2001, Smith et al 2002]. The pupillary response to light is usually sluggish without evidence of relative afferent pupillary defect [Smith et al 2002].

Renal findings. Progressive renal failure which has been recognized in recent years is now considered a feature of the classic form of mucolipidosis IV. It manifests itself in the third decade of life [Author, unpublished data]. Because of chronic muscle atrophy in mucolipidosis IV, blood cystatin c level is the most sensitive way to diagnose renal insufficiency.

Other. Iron deficiency occurs in about 50% of affected individuals, and iron deficiency anemia, which is usually well tolerated, occurs in about 10% of affected individuals [Altarescu et al 2002].

The achlorhydria is asymptomatic.

The face is not typically coarse but has typical features [Goldin et al 2004b].

Affected individuals do not have hepatosplenomegaly or specific skeletal abnormalities.

Atypical and Mild Mucolipidosis IV

Individuals with atypical mucolipidosis IV are less severely affected than individuals with typical mucolipidosis IV or have one organ system disproportionately affected [Altarescu et al 2002].

Some individuals attain the ability to walk independently or have isolated dystrophic retinopathy without neurologic dysfunction [Goldin et al 2008]. They develop slowly progressive ataxia, have mild eye abnormalities, and are usually of non-Ashkenazi Jewish descent [Altarescu et al 2002].

Some present with a congenital myopathy with significant generalized hypotonia and elevated serum muscle creatine kinase (CK) concentration.

Some present with static (non-progressive) motor and cognitive delay and minimal ocular abnormalities.

• One female who presented with progressive visual impairment with corneal clouding with the appearance of cornea verticillata, retinopathy, normal psychomotor development, and behavioral abnormalities developed unstable gait in her twenties [Altarescu et al 2002].
• Two other individuals with no neurologic deficit were diagnosed based on ocular findings [Dobrovolny et al 2007, Goldin et al 2008]. These individuals had all the other typical features of mucolipidosis IV including achlorhydria and autofluorescent inclusions in cultured skin fibroblasts [Dobrovolny et al 2007, Goldin et al 2008].