Mucolipidosis IV

An autosomal recessive lysosomal disorder caused by loss of function of the cation channel mucolipin-1 (TRPML1), encoded by MCOLN1, with severe psychomotor delay, corneal clouding, progressive retinal dystrophy, achlorhydria with hypergastrinaemia and kidney disease in adulthood; it includes Lisch epithelial corneal dystrophy, an autosomal dominant allelic disorder

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1 Definition and scope

Mucolipidosis IV (ML IV) is an autosomal recessive lysosomal disorder caused by biallelic loss-of-function variants in MCOLN1, the gene encoding mucolipin-1, also called transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1) [2, 4]. Unlike most lysosomal storage disorders, the lysosomal hydrolases have normal activity, and the heterogeneous storage of lipids and water-soluble substances results from a defect in membrane trafficking in the late stages of endocytosis and in cation release from lysosomes [1, 16]. The typical clinical picture, present in about 95% of patients, combines severe psychomotor delay evident in the first year of life, epithelial corneal clouding, progressive retinal dystrophy leading to severe visual impairment in early adolescence, and constitutive achlorhydria with hypergastrinaemia; about 5% of patients have atypical forms, with milder psychomotor involvement or involvement limited to one organ, but with retinal degeneration and achlorhydria [4]. For decades the disease was described as a mainly static encephalopathy; the natural history studies of 2014 and 2022 documented a neurodegenerative component that manifests as functional regression in the second decade, and the most recent series have added chronic kidney disease in adults to the phenotype [9, 11, 17].

The scope covers both entities associated with the MCOLN1 gene. ML IV, with autosomal recessive inheritance, is the main entity. Lisch epithelial corneal dystrophy (LECD), with autosomal dominant inheritance and very reduced penetrance, was attributed in 2024 to heterozygous loss-of-function variants in the same gene and is treated as an allelic disorder [3, 7]. Mucolipidoses II and III (genes GNPTAB and GNPTG), sialidosis (formerly mucolipidosis I), the skeletal lysosomal disorders and the free sialic acid storage disorders appear here only in the differential diagnosis.

1.2 Original description and historical overview

In 1974, Berman and colleagues described an Ashkenazi Jewish infant with congenital corneal clouding and systemic storage bodies, with normal lysosomal hydrolases; the disease was classified as a new variant of mucolipidosis because electron microscopy showed lysosomal storage of lipids together with water-soluble granular material [1, 18]. In 1975, Merin and colleagues used the term “mucolipidosis IV” for four unrelated Ashkenazi children whose families came from southern Poland: corneal clouding was present from birth or from the first months, psychomotor delay became evident at the end of the first year, and there was no skeletal dysplasia, facial dysmorphism or hepatosplenomegaly; the conjunctival biopsy showed cytoplasmic vacuoles bounded by a single membrane, with fibrillogranular material and membranous lamellae, and concentric bodies similar to those of Tay-Sachs disease [1]. Goutières and colleagues described five non-Jewish patients in 1979, and Crandall and colleagues, in 1982, documented the absence of urinary excretion of oligosaccharides and mucopolysaccharides, with increased phospholipids in the liver, fibroblasts and urine [1].

The series of Amir, Zlotogora and Bach (1987), with 20 patients aged 2 to 17 years, established the first systematic description of the clinical spectrum: the initial manifestations appeared in the first year, the maximum level of motor and language development lay between 12 and 15 months, and the course was protracted, with some patients improving slightly and others showing little or no deterioration [19]. In the 1990s and 2000s, the natural history programme of the National Institutes of Health (NIH) in the United States characterised constitutive achlorhydria (Schiffmann and colleagues, 1998), the typical brain magnetic resonance imaging (MRI) changes (Frei and colleagues, 1998), the ophthalmological phenotype and non-invasive diagnosis by conjunctival cytology (Smith and colleagues, 2002), and the neurogenetics in a cohort of 28 patients (Altarescu and colleagues, 2002) [20–23]. The conclusion of Altarescu and colleagues that ML IV is both a developmental and a degenerative disease was reinforced by the serial brain volumetry of Schiffmann and colleagues (2014) and by the cross-sectional study of Misko and colleagues (2022) [9, 17, 23].

Before the gene was identified, several authors attributed the disease to a partial deficiency of ganglioside sialidase; Caimi and colleagues even proposed the name “sialolipidosis” to distinguish it from classical sialidosis, a hypothesis that was not confirmed [1].

1.3 Molecular milestones

In 1999, Slaugenhaupt and colleagues mapped the locus to 19p13.3-p13.2 by linkage studies in 13 families (maximum lod score of 5.51) and demonstrated two founder chromosomes in the Ashkenazi population, a major haplotype in 75% and a minor one in 21% of 52 chromosomes [1]. In the same year, Goldin and colleagues showed by complementation studies in cells from more than 20 patients, including non-Jewish patients, that all had variants in the same gene [1]. In 2000, three groups identified the gene independently: Bargal and colleagues, by positional cloning, found the two Ashkenazi founder variants in 21 patients; Bassi and colleagues named the gene “ML4” and the protein “mucolipidin”, homologous to polycystin-2 and to the transient receptor potential (TRP) channels; Sun and colleagues proposed the name “mucolipin” and described a TRP cation channel with six transmembrane domains [16, 24, 25]. In 2004, Goldin and colleagues described the first case of a hereditary genetic disease caused by the insertion of a fragment of mitochondrial DNA (93 base pairs of the MT-ND5 gene) into a nuclear gene, precisely MCOLN1 [8]. In 2024, Patterson and colleagues attributed Lisch epithelial corneal dystrophy to MCOLN1 haploinsufficiency, establishing the second phenotype associated with the gene [7].

1.4 Nomenclature and classification

The term “mucolipidosis” was coined for disorders in which electron microscopy revealed simultaneous storage of lipids and water-soluble substances, and it covers four inborn errors with no common mechanism [4, 26]. Mucolipidosis I corresponds to sialidosis, due to alpha-neuraminidase deficiency (NEU1); mucolipidoses II and III result from deficiency of N-acetylglucosamine-1-phosphotransferase (GNPTAB, GNPTG), which prevents formation of the mannose-6-phosphate marker; ML IV results from the loss of a cation channel of the lysosomal membrane [4, 26]. In the classification of Inborn Metabolic Diseases (Saudubray, 7th edition), ML IV is described with the oligosaccharidoses and the mucolipidoses by historical convention; Orphanet classifies it as a lysosomal storage disease, and the International Classification of Diseases (ICD) places it under code E75.1 (ICD-10) and 5C56.0Y (ICD-11), in both cases as an inclusion term of a broader category [2, 26]. There is no formal classification of the typical and atypical forms: GeneReviews distinguishes the typical or severe form (about 95%) from the atypical or mild form (about 5%), and Misko and colleagues classified as mild those patients who had ever achieved independent walking [4, 9].

Table 1. The mucolipidosis class and the disorders associated with MCOLN1

Sources: [1, 3, 4, 7, 26]. AD, autosomal dominant; AR, autosomal recessive.

2. Molecular Genetics and Pathophysiology

2.1 The MCOLN1 gene and mucolipin-1

The MCOLN1 gene lies at 19p13.2, has 14 exons spread over about 14 kb and encodes a protein of 580 amino acids, of about 65 kDa [8, 18]. The MANE Select reference transcript is NM_020533.3, which encodes NP_065394.1; the genomic reference sequence is NG_015806.1 [4, 6]. Mucolipin-1 has six transmembrane domains, with the amino- and carboxy-terminal ends in the cytoplasm; the TRP channel domain spans amino acids 331 to 521, and the pore, formed by the loop between the fifth and sixth transmembrane segments, amino acids 496 to 521 [8]. Between the first and second segments there is a loop with two proline-containing sequences and four cysteines, where a serine lipase domain is located; the protein also has a nuclear localisation signal; a carboxy-terminal di-leucine motif directs the protein to late endosomes and lysosomes, and serine 557, the main phosphorylation site, is located in the pore [4, 8, 18]. Expression is ubiquitous and highest in the brain, kidney, spleen, liver and heart [18]. The TRPML family also includes TRPML2 and TRPML3, encoded by MCOLN2 and MCOLN3, with no associated human disease in the sources consulted [18].

2.2 Function of the TRPML1 channel and cellular mechanism

TRPML1 is a non-selective cation channel of the late endosomal and lysosomal membranes, permeable to Ca2+, Fe2+, Zn2+, Na+ and K+ [5, 27]. Calcium release from the lysosomal lumen controls the fusion of lysosomes with other organelles, membrane trafficking, lysosomal exocytosis, autophagy and phagosome–lysosome fusion, and takes part in a feedback loop with the mTORC1 complex and the transcription factor TFEB: phosphorylation of mucolipin-1 by mTORC1 reduces channel activity and, consequently, TFEB activation [5, 18]. Absence of the channel does not prevent the degradation of substrates that reach the lysosome; what changes is their routing. Bargal and Bach showed in 1997 that phosphatidylcholine, other phospholipids, sphingolipids, acid mucopolysaccharides and gangliosides are transported to the lysosomes at an increased rate instead of being recycled to the plasma membrane, and Chen and colleagues (1998) observed that a fluorescent lactosylceramide analogue accumulates faster in the lysosomes of patients' fibroblasts and leaves them more slowly [1]. Fibroblasts have increased basal autophagy, with autophagosomes that contain aggregates of ubiquitinated proteins and fuse late with lysosomes, and they accumulate fragmented mitochondria [1, 18]. Lack of the channel also alters lysosomal handling of iron and zinc, with zinc accumulation in lysosomes and in brain tissue [18]. The cellular result is heterogeneous storage, visible on electron microscopy as single-membrane vacuoles with fibrillogranular material and concentric lamellae, present in practically all cell types, and which makes fibroblasts autofluorescent [1, 5, 18]. The disease mechanism in ML IV is loss of function [4].

2.3 Tissue mechanisms

Central nervous system. Mucolipin-1 deficiency affects the development of the white matter and corpus callosum and the maintenance of retinal and optic nerve cells [4]. In the fetus, MRI at 32 and 35 weeks showed progressive curvilinear hypointensities in the deep frontal white matter and a thin corpus callosum, and neuropathology revealed hypercellular white matter with reactive astrocytes and microglia, mineralised deposits and microglial aggregates with intracellular iron, demonstrating that white matter involvement begins before birth [28]. MR spectroscopy and serial volumetry indicate diffuse neuronal dysfunction in the early stages, with a reduced N-acetylaspartate/creatine ratio, without cortical volume loss, followed by volume loss of the subcortical white matter and cerebellum as the disease advances [9, 17]. Patients' plasma has increased pro-inflammatory cytokines, with the interferon axis (interferon gamma, interferon alpha-2 and interferon gamma-induced protein 10 kDa, IP-10) correlating with motor dysfunction, and a proteomic signature with reduced neuronal and synaptic proteins and increased muscle proteins [29, 30]. Iron deposition in the basal ganglia, similar to that of neurodegeneration with brain iron accumulation, has been associated with the extrapyramidal signs [9].

Stomach. Parietal cells are present in normal numbers but contain large lysosomal inclusions and secrete almost no hydrochloric acid, although they maintain intrinsic factor secretion; both subunits of H+/K+-ATPase are present and are partly located in the apical membrane [1, 20]. The defect prevents trafficking of the proton pump to the apical membrane, the achlorhydria is constitutive and gastrin rises secondarily; prolonged hypergastrinaemia causes enterochromaffin-like (ECL) cell hyperplasia, and chronic atrophic gastritis worsens with age [1, 4, 18]. Malabsorption of dietary iron explains the iron deficiency [4].

Kidney. In the Mcoln1−/− mouse, loss of the channel impairs autophagy and the endolysosomal compartment of proximal and distal tubular cells, accumulates megalin in the subapical region of proximal tubular cells and blocks receptor-mediated endocytosis of albumin, transferrin and other low-molecular-weight proteins, with tubular proteinuria, enzymuria, early nuclear factor kappa B (NF-κB)-dependent inflammation and fibrosis; the glomerulus shows no significant changes, and the pattern has been described as a partial Fanconi syndrome, restricted to proteins [11].

Muscle. Persistent elevation of creatine kinase (CK) and muscle biopsy with lysosomal storage myopathy suggest a role for mucolipin-1 in muscle homeostasis, possibly through sarcolemmal repair dependent on lysosomal exocytosis [31].

2.4 Inheritance, penetrance and expressivity

ML IV has autosomal recessive inheritance; heterozygotes do not develop the systemic disease [4]. In Lisch corneal dystrophy, the same class of variants acts in the heterozygous state, with autosomal dominant inheritance and very low penetrance, which amounts to two inheritance patterns in the same gene, each with its own phenotype [3, 7]. The expressivity of ML IV varies between families and, to a lesser extent, within the same family, which should be taken into account in counselling [18].

2.5 Variant spectrum

By 2020, 35 pathogenic or likely pathogenic variants had been described; the spectrum includes splicing, nonsense, frameshift, in-frame deletion and missense variants, a large deletion removing the promoter and the first exons, and an insertion of mitochondrial DNA [8, 18]. In the cohort of Misko and colleagues, 16 distinct variants included 3 splicing, 2 nonsense, 2 frameshift with a stop codon, 1 frameshift, 1 insertion, 1 deletion and 6 single-nucleotide substitutions [9]. Variant nomenclature has changed several times: early studies numbered the complementary DNA from the start of the transcript rather than from the initiation codon, and the major variant was thus designated IVS3-2A>G, c.486-2A>G or c.416-2A>G before settling on c.406-2A>G [8, 32]. The variants in the following table were normalised in VariantValidator on transcript NM_020533.3 and checked against ClinVar [6, 33].

Table 2. Clinically relevant MCOLN1 variants (NM_020533.3; GRCh38)

Sources: [4, 6, 8, 18, 32–39]. Genomic coordinates were obtained from VariantValidator; rows without a coordinate were not submitted to this tool and keep the designation of the sources.

The 6.4 kb deletion was described by Bargal and colleagues as a 6450 bp deletion from 928 bp upstream of exon 1 to nucleotide 31 of exon 7, and by Bassi and colleagues as a 6432 bp deletion extending to exon 6; GeneReviews gives its extent as from the 5' untranslated region to exon 6 and warns that the published breakpoints vary slightly [4, 8]. As the deletion extends beyond the start of the transcript, the designation c.-1015_789del is rejected under the nomenclature rules of the Human Genome Variation Society (HGVS), and the correct form is the genomic one [6]. Variant c.1406A>G appears in GeneReviews with two protein descriptions, p.Asn469Ser in the table and p.Phe454_Asn569del in the text: the first is the predicted translation of the substitution, the second the effect of the aberrant splicing described by Altarescu and colleagues [4, 6]. The dual notation c.1221_1223delCTT and c.1222_1224delTTC corresponds to the same three-nucleotide deletion, whose form normalised by the 3'-most position rule is c.1222_1224del [6].

2.6 Founder variants and origin

In the Ashkenazi Jewish population, two variants account for about 95% of pathogenic alleles: c.406-2A>G, with 72% to 78% of alleles depending on the series, and the 6.4 kb deletion, with 18% to 23% [4, 10, 24, 32]. Haplotypes of more than 70 Ashkenazi chromosomes with ML IV showed two founders in 95% of families, a major one in 72% and a minor one in 23%, the remaining 5% being distinct haplotypes, each found in a single patient [24]. Raas-Rothschild and colleagues interviewed 17 Israeli families and found that, although they had emigrated from various European countries, all had roots, three to four generations earlier, in northern Poland or neighbouring Lithuania; the under-representation of ultra-Orthodox families among the 70 to 80 known Ashkenazi families led the authors to place the origin of the variant in the 18th or 19th century, after the great demographic expansion of this population [1]. About 60% of Ashkenazi patients in the United States are homozygous for c.406-2A>G and about 33% are compound heterozygous for the two variants; only one homozygote for the deletion has been described [4]. Outside this population, c.406-2A>G accounts for only 6% to 10% of alleles [4, 18]. In two apparently unrelated Omani families, variant c.237+5G>A was not found in a sample of the general population, which did not allow a founder effect to be demonstrated [38].

2.7 Genotype–phenotype correlations

Ashkenazi patients, who carry the founder variants that abolish the protein, generally have the severe form, and homozygotes and compound heterozygotes for the two variants have similar severity [4, 8]. The location of missense or in-frame variants in the protein relates to severity: variants in the loop between the first and second transmembrane segments (one in the lipase domain and another that removes one of the four cysteines) have been associated with independent ataxic walking and feeding autonomy, although c.694A>C p.(Thr232Pro), in the same region, causes the severe form because the protein does not leave the endoplasmic reticulum; c.1084G>T p.(Asp362Tyr), in the third segment, has been associated with slower retinal progression and a milder neurological phenotype in several patients from the south-eastern United States, even though the protein has no channel activity in vitro; c.1222_1224del p.(Phe408del), in the fourth segment, causes the mildest known phenotype; and most variants between the fifth and sixth segments, in the pore region, are associated with the severe form [4, 34]. Isolated ocular forms have been associated with variants that preserve some expression, such as c.1704A>T, which allows about 40% of normal transcript, and c.1615del [4, 8]. In a functional study of 10 patient mutants, nine lost calcium and zinc permeability after agonist stimulation; p.(Phe408del) retained partial permeability and was the only one with constitutive calcium flux, and the non-functional mutants that reach the lysosome were associated with more severe phenotypes than those retained in the endoplasmic reticulum, which led the authors to propose a dominant-negative or toxic effect in the lysosome [27]. Jezela-Stanek and colleagues concluded that there is no robust genotype–phenotype correlation and drew attention to intrafamilial heterogeneity [18].

2.8 Allelic disorder: Lisch epithelial corneal dystrophy

LECD is characterised by grey, feathery or whorled corneal bands of variable width, consisting of clear, densely clustered intraepithelial microcysts, which are best identified by indirect illumination and reduce vision only when they involve the pupillary axis; progression is slow [3]. The original German family, described by Lisch and colleagues in 1992, included 5 members and 3 isolated cases aged 23 to 71 years, with unilateral or bilateral opacities and diffuse vacuolation of the epithelial cell cytoplasm; epithelial debridement was followed by recurrence within months [3]. A linkage to Xp22.3, published in 2000, was not confirmed [3]. Patterson and colleagues (2024) studied 27 patients from 17 families and found nine rare heterozygous MCOLN1 variants in 23 patients from 13 families; seven were truncating and one missense variant showed loss of function, so the mechanism is haploinsufficiency [7]. Four of the nine variants cause ML IV in the homozygous or compound heterozygous state, including c.406-2A>G and c.514C>T p.(Arg172Ter); in the original German family the variant was c.576C>A p.(Cys192Ter) [7, 8]. Diagnosis was made between the second and ninth decades, about three quarters of patients had bilateral involvement and visual acuity was preserved in most [3]. A 64-year-old carrier from the original family had no signs of the disease, and the six carrier parents of three patients with ML IV did not have LECD; based on gnomAD, the penetrance of loss-of-function variants was estimated at 0.2% [3, 7]. The proposed hypothesis is a second somatic event on the other allele in limbal stem cells, which would create areas of epithelium with an ML IV phenotype, explaining the unilateral and sporadic cases [3].

2.9 Heterozygotes and candidate associations

In 2026, Ying and colleagues described two heterozygous MCOLN1 variants with loss of function in vitro in two Chinese patients with synucleinopathy, p.E376K in a patient with multiple system atrophy and p.L315del in a patient with early-onset Parkinson disease; the authors present MCOLN1 as a candidate gene to be studied in larger cohorts, and the report does not establish a risk for carriers [40].

2.10 Animal models

The Mcoln1−/− mouse reproduces the human disease: dense inclusions in all brain cells, especially neurons, raised plasma gastrin, vacuolation of parietal cells, retinal degeneration and a gait deficit that progresses to complete hindlimb paralysis and death at around 8 months [8]. In Drosophila, loss of the homologue causes an autophagy defect, oxidative stress and reduced clearance of apoptotic cells, corrected by expression of the normal gene in neurons, glia or haematopoietic cells; in the nematode Caenorhabditis elegans, loss of the homologue cup-5 increases uptake of fluid-phase markers and accumulates vacuoles [8]. The mouse is the model used in preclinical studies of gene therapy, bone marrow transplantation and pharmacological activation of lysosomal channels [26, 41–43].

3. Clinical Spectrum and Manifestations by System

3.1 Data sources

Knowledge of the natural history of ML IV rests on a small number of cohorts, almost all North American and Israeli, and on case reports from other populations. No study describes patients treated with a disease-modifying therapy, so all data correspond to natural history under supportive care.

Table 3. Main cohorts and clinical series

Sources: [9, 11, 17, 19–23, 44].

3.2 Typical form

3.2.1 Onset and presentation

Pregnancy and the neonatal period are usually uneventful, and birth weight and length are normal [4, 9, 18]. In the cohort of Misko and colleagues, the first symptom appeared between 1.5 months and 8 years (median 7.25 months): inability to roll at 6 months or to sit without support at 9 months in 21 of the 26 patients, strabismus in 6, hypotonia in 5, visual impairment in 4, inability to crawl in 3, weak grasp in 1 and inability to stand in 1; the interval between the first symptom and diagnosis was 21 ± 20 months (2.5 months to 7 years) [9]. Because hypotonia with developmental delay is non-specific, many patients receive a provisional diagnosis of cerebral palsy; corneal clouding detected on slit-lamp examination is the most specific finding and is often what leads to genetic testing [4, 23].

3.2.2 Motor function and tone

Axial hypotonia and motor delay are the first neurological signs [4]. Most patients are able to sit without support and to move by crawling or bottom-shuffling; some walk with a walker, and only a minority achieve independent walking [4, 26]. Fine motor function is very limited: in the cohort of Misko and colleagues, no typical patient had a superior pincer grasp, 14 (61%) used an inferior pincer grasp, 1 (4%) a tripod grasp and 8 (35%) did not pick up objects with their fingers; most bring food to their mouth with their hands and some use adapted cutlery [4, 9]. Pyramidal and extrapyramidal signs appear early, and in the first decade there is a mixture of spasticity (velocity-dependent resistance) and cogwheel rigidity or paratonia, with dystonic postures of the limbs and symmetrical hypertonia in all four limbs; weakness on voluntary activation is of the upper motor neurone type, with relative preservation of muscle and the neuromuscular junction [4, 9].

Spasticity increases with age in all joints studied: Spearman correlation coefficients between age and the modified Ashworth scale were 0.880 at the elbows (95% confidence interval, 95% CI, 0.728 to 0.949), 0.771 at the wrists (0.518 to 0.900), 0.828 at the knees (0.631 to 0.924) and 0.664 at the ankles (0.348 to 0.845) [9]. Brief Assessment of Motor Function (BAMF) gross motor scores correlated negatively with age (r = −0.658; 95% CI −0.841 to −0.337), with a slope of −0.102 points per year (95% CI −0.155 to −0.050), and the Gross Motor Function Classification System (GMFCS) level increased with age (r = 0.691; slope of 0.041 per year); fine motor function also decreased with age (r = −0.644) [9]. On examination, tendon reflexes are symmetrical and brisk and most have a bilateral Babinski sign [18]. In adults with forms that allow walking, progressive weakness of predominantly muscular type has been described [18].

3.2.3 Language, cognition and behaviour

Development reaches a plateau equivalent to 12 to 15 months in the older series and to 18 to 21 months of a healthy child in the description of Misko and colleagues [9, 19, 24]. Receptive language is better than expressive language; there is dysarthria or anarthria, and some patients use up to 50 gestures to communicate [4]. Social development is uniformly preserved, with strong social engagement, an amiable disposition and enjoyment of music [4]. In adults in a British series, recurrent depression and, in one woman, anorexia have been described [18].

3.2.4 Oromotor function, swallowing and feeding

All typical patients in the cohort of Misko and colleagues had limited lateral tongue mobility, absence of rotary jaw movements during chewing and poor control of secretions; speech articulation was severely impaired at all ages, whereas swallowing was severely affected only in the two oldest patients, who were dependent on gastric tube feeding and were the only ones with aspiration [9]. Few patients aspirate in the first decade, and swallowing studies are generally normal at that stage; later, aspiration may require gastrostomy or tracheostomy [4]. In a series by Chitayat and colleagues, coughing during and after meals was reported in 86% of patients and all had sialorrhoea [18]. Feeding difficulties contribute to growth restriction [18].

3.2.5 Epilepsy and electroencephalogram

Epileptiform discharges on the electroencephalogram (EEG) are frequent, described in 60% of patients in one series, but are rarely accompanied by clinical seizures; the most frequently reported epileptic phenomena are 3 Hz spike-and-wave complexes and absence seizures [4, 18]. Patients who reach stage 2 sleep have non-synchronous spindles and vertex waves, attributed to deficient myelination of the corpus callosum and thalamocortical projections [18]. In a recent report, generalised seizures began at 6 months [36].

3.2.6 Neuroimaging

In 15 consecutive patients, 14 with the typical picture had hypoplasia of the corpus callosum with an absent rostrum and a dysplastic or absent splenium, T1 white matter signal changes and increased ferritin deposition in the thalamus and basal ganglia; there was cerebellar and cerebral atrophy in the older patients, and the only patient with the mild variant had a normal corpus callosum [21]. Cerebellar atrophy is not present at birth, appears at around 4 years and becomes evident in the second or third decade [18]. Annual quantitative MRI in 5 patients, for up to 3 years, showed clinical stability, a trend towards increased grey matter and ventricular volumes and decreased white matter and cerebellar volumes, with increased mean diffusivity and decreased fractional anisotropy in all regions; anisotropy in the corticospinal tract correlated with the Vineland scale motor score (coefficient 0.39) [17]. The initial pattern, with scarce subcortical white matter, a hypoplastic corpus callosum, iron in the basal ganglia and a preserved cortex, is that of a hypomyelinating leukodystrophy with brain iron accumulation [9]. Autopsy showed neuronal loss and astrocytosis in the thalamus, hippocampus (CA3), substantia nigra, basis pontis, inferior olive, anterior horn of the spinal cord and Purkinje cell layer [18].

3.2.7 Eye

Corneal clouding is bilateral, symmetrical, most visible centrally and limited to the epithelium, without stromal involvement or oedema, despite older descriptions of stromal changes [4]. It results from the accumulation of phospholipids, mucopolysaccharides and gangliosides in epithelial cells; the endothelium, Bowman's membrane and Descemet's membrane are spared [18]. In the series of Amir and colleagues, the clouding was congenital in 11 of the 20 patients, and it generally becomes apparent between infancy and 5 years; one 5-year-old patient had no clouding but had severe myopia and retinal degeneration [1, 18]. Anterior segment optical coherence tomography (OCT) shows a hyperreflective, thickened epithelium and has been proposed as a non-invasive screening examination [18, 36, 45]. Painful episodes compatible with corneal erosions are frequent in children and decrease with age [4].

Vision may be almost normal in the first years. In the first decade, a progressive retinal degeneration sets in, with vascular attenuation, changes of the pigment epithelium and optic nerve pallor; visual acuity is difficult to measure but is reduced in almost all patients over 5 years, and practically all have severe visual impairment by early adolescence [4, 22]. In a prospective study of 22 patients, all had some degree of epithelial haze, optic disc pallor, vascular attenuation and pigment epithelium changes, more severe in older patients [22]. In a review of 93 patients, the frequencies were: corneal clouding 90.3%, strabismus 58.1%, optic disc pallor 52.2%, retinal dystrophy or pigmentary changes 50.5% and retinal vascular attenuation 38.9%, with nystagmus, photophobia, eye pain, lacrimation, ptosis and cataract less frequent [44]. In the series of Smith and colleagues, strabismus was the first sign in 63% of children (before 3 months in 5, between 3 and 6 months in 8, and between 7 and 12 months in 4); abnormal eye movements were present in 23% [18]. The pupillary light response is sluggish, without a relative afferent pupillary defect, and a bilateral bull's eye maculopathy has been described [4]. The electroretinogram (ERG) may be normal at an early stage; in two patients, rod and cone responses were mildly subnormal at 12 months and became electronegative to the bright scotopic flash at 6.6 years, with greater loss of the b-wave than of the a-wave, which places the primary dysfunction at or beyond the photoreceptor terminals [18, 36, 46]. In the experience of Misko and colleagues, most patients are legally blind in the second decade, coinciding with functional regression [9].

3.2.8 Digestive system, iron and blood

Achlorhydria is present in all patients, and plasma gastrin is raised in practically all: mean 1507 pg/mL, range 400 to 4100 pg/mL, against a normal value of 0 to 200 pg/mL [4, 23]. In the series of Schiffmann and colleagues, 14 of the 15 patients had markedly raised gastrin and none had vitamin B12 deficiency; gastroscopy showed macroscopically normal mucosa at 4 and 7 years and atrophy at 22 years [20]. Chronic atrophic gastritis and ECL cell hyperplasia are present even in the youngest patient studied and worsen with age [1, 18]. Constipation and bile reflux, non-acid because of the achlorhydria, are the digestive complaints that prompt gastroenterology follow-up [4]. In the series of Amir and colleagues, frequent diarrhoea was reported in 38% and constipation in 5% [18]. Iron deficiency affects about half of patients (46% in the series of Altarescu and colleagues) and iron deficiency anaemia, generally well tolerated, about 10%, according to GeneReviews; in the same series, 12 of the 28 patients had iron deficiency or anaemia [4, 18, 23]. In the adults of Pakistani origin, persistent iron deficiency anaemia and constipation were constant complications, and a 20-year-old woman had abnormal liver function tests (alanine aminotransferase 123 U/L, alkaline phosphatase 1078 U/L) with a normal liver ultrasound and a gallbladder polyp [18]. In a 10-year-old boy from Bahrain, intermittent transfusions were required [47].

3.2.9 Kidney

Progressive renal failure has come to be regarded as part of the typical phenotype and manifests in the second or third decade [4]. In the retrospective MGH study, with records of 28 patients, 6 adults had laboratory evidence of renal dysfunction (all over 25 years of age at the time of data collection) and a seventh had recorded kidney disease without laboratory data; no minor had signs of renal dysfunction [11]. Most adults had a diagnosis of acute kidney injury or stage 3 chronic kidney disease (CKD) [11]. In the 6 patients with plasma chemistry (17 to 38 years; mean 28), the estimated glomerular filtration rate (eGFR) ranged from 45 to 48.7 mL/min/1.73 m², cystatin C from 1.38 to 1.51 mg/dL (mean 1.41) and creatinine from 0.2 to 2.02 mg/dL; in the 4 patients with urinalysis (27.6 to 36.9 years), all had proteinuria (from 100 mg/dL to 3+), 75% haematuria and 75% leucocyturia [11]. Because muscle atrophy lowers baseline creatinine, cystatin C is the most sensitive marker of renal dysfunction in ML IV [4].

3.2.10 Growth, face and puberty

Growth slows with age: in one series, 10 of 16 patients had height below the 3rd centile and 8 of 16 weight below the 3rd centile; in another, all patients between 20 months and 32 years had growth delay despite adequate intake [4, 18]. The face is not coarse but has “hypotonic” features, with a tented upper lip, anteverted nares and an open mouth; an automated facial phenotyping analysis (DeepGestalt) of 50 images from 10 patients distinguished them from controls with an area under the curve of 0.822 and from 100 other syndromes with 0.885 [4, 18]. Puffy eyelids, a long face that narrows with age and, rarely, congenital anomalies or dysmorphic features have been described [1, 18]. There is no hepatosplenomegaly or specific skeletal dysplasia [4]. One patient entered puberty at 20 years and developed coarse facies at 30 [1]; two adult sisters had premature ovarian insufficiency [18].

3.2.11 Muscle

Raised CK has been described in several presentations. A 7-year-old boy followed in London had persistently raised CK (780 to 15,000 IU/L) and the biopsy showed a lysosomal storage myopathy with mild regenerative changes; he had homozygous nonsense variants [31]. Two adult siblings in the British series had CK of 1400 and 3100 U/L, and a 10-year-old boy from Bahrain had persistent hyperCKaemia [18, 47]. Muscle biopsy has no value in confirming ML IV and is useful only in the differential diagnosis [18].

3.2.12 Hearing and other manifestations

Sensorineural hearing loss was found in the three adult siblings of the British series, and another study reports hearing impairment in about 10% of patients [18]. One of the siblings had osteofibrous dysplasia and adamantinoma of the leg, and another gynaecomastia; these isolated findings are not established as part of the phenotype [18].

3.3 Course: developmental component and degenerative component

The older series described a protracted, stable course in the first two to three decades, similar to that of cerebral palsy, and estimated that only about 15% of patients had psychomotor deterioration; in the cohort of Altarescu and colleagues, motor function worsened in 3 of the 28 patients, and repeated neurological examination was stable in 70% of children [1, 18, 23, 26]. The more recent data show a different course. In the cohort of Misko and colleagues, loss of gross and fine motor, cognitive, social, self-care and compensatory skills began in the early second decade, and loss of language occurred at all ages [9]. The authors propose three phases: slow gains in the first years, with signs of central nervous system dysfunction (abnormal tone and visual impairment); a plateau in which hypertonia worsens and motor function gradually declines; and, in early adolescence, functional regression resulting from the sum of hypertonia, motor decline and visual loss [9]. The 2021 GeneReviews adopts this interpretation and describes progressive spastic tetraparesis and loss of skills from the second decade in most patients [4]. The divergence between the 15% of the older series and the majority in recent studies reflects the length of follow-up, the age of the patients assessed and the use of quantitative scales; the scales themselves (BAMF, GMFCS) have a floor effect and little sensitivity for tracking progression [9].

3.4 Atypical forms

About 5% of patients have milder psychomotor involvement or a disproportionately affected system, and these patients are more often of non-Ashkenazi origin [4]. The presentations described include: independent walking with slowly progressive ataxia and mild ocular changes; isolated retinal dystrophy without neurological dysfunction, with achlorhydria and autofluorescent inclusions in fibroblasts; visual loss with cornea verticillata-like clouding, normal psychomotor development, behavioural changes and unsteady gait in the third decade; congenital myopathy with generalised hypotonia and raised CK; and static motor and cognitive delay with minimal ocular changes [4]. In the Indian series of Bindu and colleagues, four patients aged 14 to 18 years had no corneal changes and presented with slowly progressive spastic paraparesis from the second decade or from childhood, with a thin corpus callosum; one had been diagnosed with non-compressive myelopathy [18]. A non-Ashkenazi girl developed corneal clouding at 2 years and retinal dystrophy at 12, with compensatory hypergastrinaemia and normal psychomotor development [1]. In four Iranian siblings with variant c.362C>T p.(Thr121Met), the picture included cognitive decline, progressive visual and pyramidal changes, severe oromandibular dystonia and parkinsonism, possibly with later onset [39]. A Japanese patient followed for 14 years, homozygous for p.(Phe313del), had progressive psychomotor delay, atrophy of the corpus callosum and cerebellum, stable corneal clouding and progressive optic pallor and retinal degeneration, with a non-recordable photopic ERG [48].

3.5 Prenatal manifestations

In a fetus with ML IV, the sibling of an affected child, fetal MRI at 32 and 35 weeks showed progressive curvilinear T2 hypointensities in the deep frontal white matter and a thin corpus callosum; autopsy, after termination of pregnancy, revealed hypercellular white matter with reactive astrocytes and microglia, mineralised deposits and microglial aggregates with iron [28]. This is the first description of the disease in the fetal period, and it indicates that white matter changes begin before birth [28].

3.6 Survival

Patients generally survive into adulthood, but life expectancy is reduced by the complications of severe neurological disability and by renal failure [4]. The cohort of Misko and colleagues included patients up to 40 years of age, and the MGH cohort up to 43 [9, 11]. One patient died of aspiration at 17 years and another was alive at 32 [1]. The sources consulted do not provide survival curves or the median age at death.

4. Clinical Recognition and Warning Signs

4.1 When to suspect

First year of life. The combination of axial hypotonia and motor delay with bilateral corneal clouding or early strabismus should prompt consideration of ML IV; strabismus is the first sign in about two thirds of children, and corneal clouding may be present from birth [4, 18]. A child with congenital bilateral corneal clouding and developmental delay should be investigated for metabolic and genetic disorders even in the absence of coarse dysmorphism, visceromegaly or skeletal changes and regardless of ethnic origin or consanguinity [36]. Inborn Metabolic Diseases includes ML IV among the disorders in which corneal clouding is a presenting sign and reports significant visual impairment by the end of the first year, sometimes with dystonia [49].

Child diagnosed with cerebral palsy. A child diagnosed with cerebral palsy without a perinatal cause should be assessed for ML IV, particularly if there is strabismus, visual impairment, a thin corpus callosum or iron deficiency anaemia [4, 38]. Jezela-Stanek and colleagues propose gastrin measurement as a low-cost test in any child with unexplained global delay, especially if hypotonic, non-ambulant and non-verbal [18].

Neuroimaging. Hypoplasia of the corpus callosum with an absent rostrum and dysplastic splenium, white matter changes and signal suggestive of iron in the basal ganglia and thalamus, in a child with psychomotor delay, should prompt gastrin measurement and MCOLN1 testing [18, 21].

Older child, adolescent or adult. The atypical forms may present as isolated retinal dystrophy, cornea verticillata-like clouding, slowly progressive spastic paraparesis, ataxia, myopathy with raised CK, dystonia with parkinsonism or refractory iron deficiency anaemia [4, 18, 31, 39]. A raised CK does not exclude ML IV [47].

Population context. Ashkenazi Jewish ancestry increases the pre-test probability and justifies targeted genotyping of the two founder variants; the disease has been described in many other populations, including patients of Arab Druze, Bahraini, Iranian, Omani, Indian, Pakistani, Moroccan, Japanese, Italian, Turkish and Canadian origin [4, 8, 18, 36, 38, 39, 47, 48].

4.2 Warning signs and emergency situations

ML IV has no acute metabolic decompensations. The situations that require prompt action are aspiration (coughing with meals, recurrent respiratory infections, food refusal), which may appear in the second decade and lead to gastrostomy or tracheostomy; seizures; acute eye pain from corneal erosion; symptomatic iron deficiency anaemia; and deterioration of renal function in adults, which creatinine underestimates [4, 9].

4.3 Newborn screening

ML IV is not part of newborn screening panels in the sources consulted; presymptomatic detection depends on carrier screening and diagnosis in siblings of patients [50, 51].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no formal clinical criteria published by a scientific society. According to GeneReviews, ML IV should be suspected in the presence of early developmental delay, static or with loss of skills, dystrophic retinopathy with or without corneal clouding, raised plasma gastrin and achlorhydria; the diagnosis is established in a proband with these findings and biallelic pathogenic or likely pathogenic variants in MCOLN1 or, if molecular testing is unavailable or uninformative, with raised plasma gastrin [4]. The presence of characteristic inclusions in a skin biopsy or in conjunctival cells may guide the diagnosis [4]. Two variants of uncertain significance, or one pathogenic variant and one of uncertain significance, neither establish nor exclude the diagnosis [4]. The MGH natural history studies used equivalent criteria: two known pathogenic variants, or a compatible clinical picture with raised gastrin or with electron microscopy of cells showing lysosomal accumulation; the protocol of the ongoing study describes raised gastrin, in the context of a neurodevelopmental disorder, as pathognomonic of ML IV [9, 52].

5.2 Algorithm

1. Clinical suspicion: psychomotor delay with hypotonia and corneal clouding, strabismus, retinal dystrophy, a thin corpus callosum or iron deficiency [4, 18].
2. Plasma gastrin: raised in practically all patients; in the series of Schiffmann and colleagues, 14 of the 15 patients had markedly raised values [4, 20].
3. Molecular testing: in individuals of Ashkenazi ancestry, genotyping of the two founder variants (c.406-2A>G and the 6.4 kb deletion), followed by sequencing if only one or none is found; in others, MCOLN1 sequencing followed by deletion/duplication analysis if one or no variant is found; alternatively, a multigene panel, exome or genome when the phenotype is non-specific [4].
4. Complementary confirmation, when molecular testing is inconclusive: electron microscopy of a skin biopsy or conjunctival cytology [4, 22].
5. Assessment after diagnosis (section 5.8) and genetic counselling of the parents, with segregation testing [4].

5.3 Biochemistry

Plasma gastrin is the diagnostic biomarker: mean 1507 pg/mL, range 400 to 4100 pg/mL, against a reference of 0 to 200 pg/mL [4, 23]. In other laboratories and units, the patients described had 710 and 526 pg/mL (reference 0 to 99 pg/mL), 191 pmol/L (reference 11 to 54 pmol/L), 726 ng/L (reference 0 to 90 ng/L) and 157 to 198 pmol/L (reference below 40 pmol/L) [18]. In the mouse, gastrin may rise up to 13 times normal [8]. The elevation is secondary to constitutive achlorhydria [20]. Lysosomal hydrolases are normal, unlike in most lysosomal storage disorders, and in one case studied there was no urinary excretion of oligosaccharides or mucopolysaccharides [1, 18, 36]. Increased urinary phospholipids were described in early cases [1]. The full blood count and iron studies document iron deficiency, and cystatin C assesses renal function [4].

Biomarkers under investigation include MRI diffusion imaging, plasma cytokines of the interferon axis (with IP-10 separating patients from controls) and plasma proteomics, in which the reduction of synaptic proteins such as GABARAP correlated best with severity; none is validated for clinical use [17, 29, 30].

5.4 Electron microscopy and cytology

Before the gene was identified, diagnosis rested on electron microscopy of a skin or conjunctival biopsy, with lamellar membranous structures and amorphous cytoplasmic inclusions in various cell types [4, 19]. Smith and colleagues showed that exfoliative conjunctival cytology, obtained by swab, displays characteristic lysosomal inclusions on light microscopy, with periodic acid–Schiff (PAS) staining, and on electron microscopy, allowing a non-invasive diagnosis [4, 22]. The inclusions are also found in eccrine duct cells, endothelium, keratocytes, goblet cells, skeletal muscle, cerebral white matter and granulocytes [18, 48]. Cultured fibroblasts are autofluorescent [1, 18].

5.5 Molecular testing and its limits

Table 4. Proportion of pathogenic variants detected by method (GeneReviews)

Source: [4]. The values represent the proportion of pathogenic alleles identified by each method, according to Human Gene Mutation Database data, and not the clinical sensitivity of the test.

The 6.4 kb deletion, responsible for about one fifth of Ashkenazi alleles, is not detected by routine sequencing; it requires deletion/duplication analysis (quantitative or long-range polymerase chain reaction, multiplex ligation-dependent probe amplification, MLPA, or a targeted microarray) or a specific assay, such as breakpoint PCR or allele-specific primer extension [4]. Therefore, a panel or exome without copy number variant analysis may leave an Ashkenazi compound heterozygous patient undiagnosed; GeneReviews recommends, if the exome is not diagnostic, considering an exome array for deletions and duplications of one or more exons [4]. There are no data on the detection rate of deletions other than the 6.4 kb deletion [4]. Variants that act through alternative splicing and retain part of the normal transcript, such as c.1704A>T, or the mitochondrial DNA insertion described by Goldin and colleagues, may not be correctly interpreted by the usual tools; in such cases, messenger RNA analysis in fibroblasts or leucocytes helped to clarify the effect [8]. When only one parent is a carrier, a de novo variant in the proband and uniparental isodisomy should be considered [4]. Jezela-Stanek and colleagues report that molecular analysis identifies the cause in 99% of patients [18]; this figure corresponds to the authors' experience and not to a sensitivity study.

The molecular report should state the gene, the versioned transcript (NM_020533.3), the HGVS nomenclature, the zygosity, the phase of the variants when known and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [4, 6]. The large deletion should be described in genomic coordinates (NC_000019.10:g.7521736_7528169del or the laboratory's designation with confirmed breakpoints), since the form c.-1015_789del does not comply with HGVS nomenclature [6, 33]. Parental testing confirms that the variants are in trans [4].

5.6 Ophthalmological examination and electrophysiology

Slit-lamp examination detects the central epithelial haze; anterior segment OCT documents the hyperreflectivity and thickening of the epithelium, with pachymetry of 587 and 604 µm in one reported case [4, 36, 45]. Fundus examination and the ERG assess the retinal dystrophy; a normal ERG on a single examination does not exclude later dysfunction and should be repeated [36, 46]. Visual evoked potentials may show optic neuropathy [36].

5.7 Neuroimaging and other tests

Brain MRI is part of the initial assessment and shows the changes described in 3.2.6; an EEG is performed if seizures are suspected [4]. CK may be raised, and muscle biopsy, when performed, shows a storage myopathy but is not necessary for diagnosis [18, 31].

5.8 Assessment after diagnosis

Table 5. Recommended assessments after diagnosis

Source: [4].

5.9 Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [4]. Historically, prenatal diagnosis was performed by electron microscopy of amniocytes or chorionic villus endothelial cells [1]. Fetal MRI may show white matter changes and a thin corpus callosum in the third trimester, but published experience is limited to one fetus [28].

6. Differential Diagnosis

6.1 Principles

The first signs of ML IV (axial hypotonia, developmental delay and strabismus) are non-specific and often lead to a diagnosis of cerebral palsy; the association of corneal clouding with these neurological signs is relatively specific and should prompt targeted investigation [4]. The differential is organised by the dominant ocular finding (corneal clouding, cornea verticillata or retinal dystrophy), by the presence of diffuse storage on biopsy and by the MRI pattern [4]. Two negative features help to separate ML IV from the other storage disorders with corneal clouding: the absence of coarse facies, hepatosplenomegaly and specific skeletal anomalies, and the normal activity of lysosomal hydrolases; the most useful positive feature is raised plasma gastrin [1, 4].

6.2 Comparative table

Table 6. Differential diagnosis of mucolipidosis IV

Sources: [3, 4, 7, 9, 26, 36, 49]. AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.

6.3 Main differentials

Lysosomal disorders with corneal clouding. GeneReviews includes in the ocular differential MPS I, III, IVA and VI, GM1 gangliosidosis and MPS IVB, and mucolipidoses II and III; Inborn Metabolic Diseases adds cystinosis and tyrosinaemia type II (in which clouding is a presenting sign), steroid sulphatase deficiency, late-onset alpha-mannosidosis, lecithin-cholesterol acyltransferase deficiency, pyroglutamic aciduria, Tangier disease, Fabry disease, juvenile galactosialidosis and Wilson disease [4, 49]. In ML IV, the clouding is epithelial and central, without stromal involvement, as anterior segment OCT documents; there are no coarse facies, visceromegaly or dysostosis, and gastrin is raised [4, 36]. Bousellam and colleagues also include the congenital hereditary corneal dystrophies in the differential of bilateral congenital corneal clouding [36].

Mucolipidoses II and III. Despite the shared name, mucolipidosis II presents with severe skeletal dysplasia, frequent microcephaly, cardiomyopathy, valvular disease and coronary disease, and most children die of respiratory failure in the first decade; mucolipidosis III allows survival into adulthood, with almost universal carpal tunnel syndrome, frequent valvular disease and erosive arthropathy of the ball-and-socket joints [26]. The defect in these disorders is post-translational (phosphotransferase) rather than in a channel [26].

Syndromic retinal dystrophies. Alström syndrome, Bardet-Biedl syndrome and the neuronal ceroid lipofuscinoses share retinal dystrophy with ML IV; Fabry disease shares a verticillate pattern of corneal clouding, present in an atypical form of ML IV, but without retinal dystrophy [4]. The isolated ocular form of ML IV may be confused with a non-syndromic retinal dystrophy; achlorhydria and raised gastrin are also present in these forms [1, 4].

Hypomyelinating leukodystrophies and cerebral palsy. The white matter changes and the thin, dysplastic corpus callosum may suggest hypomyelinating leukodystrophies, such as free sialic acid storage disease (Salla disease) [4]. Neurodegeneration with brain iron accumulation shares iron deposition in the basal ganglia and extrapyramidal signs [9]. The cohort of Altarescu and colleagues showed that presentation as a cerebral palsy-like encephalopathy delays the diagnosis [23].

Disorders with diffuse storage on biopsy. Neurological findings with diffuse storage on biopsy may suggest mucolipidosis I, mucolipidosis II and the MPS [4].

Myopathies. In presentations with raised CK, ML IV may be confused with a congenital myopathy or a muscular dystrophy; the combination with corneal clouding, delay and raised gastrin distinguishes it [4, 31, 47].

7. Treatments and Risk Management Strategies

7.1 General principles and guidelines

There are no published clinical practice guidelines for ML IV; the 2021 GeneReviews states this explicitly, and the recommendations it presents result from author consensus and observational data, without interventional trials [4, 5]. There is no authorised treatment and no disease-modifying therapy: management is supportive and multidisciplinary, directed at each manifestation, and seeks to preserve motor function, communication, residual vision, nutrition and renal function [4, 18]. The drugs used (muscle relaxants, botulinum toxin, antiseizure medications, iron) follow the usual indications and doses in paediatrics and neurology, and none has been studied specifically in ML IV [4]. The recommendations on carrier screening (section 8) come from the American College of Medical Genetics and Genomics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) [50, 51, 53].

7.2 Treatment by manifestation

Table 7. Treatment of manifestations

Source: [4].

7.3 Motor function, tone and rehabilitation

Physiotherapy seeks to maximise mobility and reduce the risk of late orthopaedic complications, such as contractures, scoliosis and hip dislocation; wheelchairs, walkers, bath chairs, orthoses and adapted strollers are part of the usual equipment [4]. For hypertonia and dystonia, GeneReviews recommends involving a physical and rehabilitation medicine physician in the management of baclofen, tizanidine, botulinum toxin (Botox®), antiparkinsonian agents or orthopaedic procedures [4]. Because hypertonia in ML IV combines spasticity and extrapyramidal rigidity, Misko and colleagues suggest that characterising these two components may guide more targeted interventions, and the modified Ashworth scale allows the course of spasticity to be documented [9]. Occupational therapy works on the fine motor skills needed for feeding, hygiene and dressing [4].

7.4 Communication, development and school

Because receptive language is better than expressive language and social engagement is preserved, assessment for augmentative and alternative communication, low-tech (picture exchange) or high-tech (voice output devices), should be carried out by a speech and language therapist; these means do not hinder speech development [4]. GeneReviews describes the United States model: early intervention from 0 to 3 years, developmental preschool from 3 to 5 years, an individualised education plan reviewed annually with vision specialists, curricular adaptations and a transition plan in adolescence; the organisation differs between countries [4]. The dual motor and visual disability requires high-contrast materials and support from vision services [4].

7.5 Feeding, digestive system and iron

Oromotor function should be assessed at each visit; choking, poor weight gain, frequent respiratory infections or food refusal without another explanation justify a clinical feeding assessment or videofluoroscopy [4]. If the child can eat safely by mouth, feeding therapy improves coordination; foods may be thickened or chilled; in severe dysfunction, a nasogastric tube or gastrostomy is used [4]. In the cohort of Misko and colleagues, the two oldest patients were fully dependent on gastric tube feeding [9]. The reflux is biliary and non-acid, and constipation is frequent [4]. Iron supplementation is given orally when there is deficiency; the intravenous route is reserved for symptomatic patients [4]. In a boy from Bahrain, intermittent transfusions were required, in addition to iron and nutritional optimisation [47].

7.6 Eye

Ocular treatment is supportive: preservative-free lubricating eye drops for the intermittent irritation of young children, surgical correction of strabismus and visual rehabilitation with high-contrast materials [4]. Corneal transplantation and epithelial debridement are not recommended, because the donor epithelium is eventually replaced by the patient's abnormal epithelium or the latter regrows; avoiding a transplant without sustained visual benefit is one of the reasons for establishing the diagnosis early [4, 18, 36].

7.7 Kidney

Renal function is monitored by cystatin C, because creatinine, low owing to muscle atrophy, underestimates the dysfunction; established kidney disease is treated by nephrology with supportive measures [4, 11]. The sources consulted do not describe dialysis or kidney transplantation in patients with ML IV.

7.8 Agents to avoid

Chloroquine may be contraindicated: cultured fibroblasts from patients are very sensitive to chloroquine, and other structurally similar antimalarials, such as primaquine and quinacrine, had the same effect, unlike artemisinin [1, 4]. This recommendation rests on in vitro data.

7.9 Haematopoietic cell transplantation

Bone marrow transplantation suppressed the motor deficit in a murine model of ML IV, but there is no published human experience; Inborn Metabolic Diseases classifies the indication as “favourable animal data, no human experience” [26].

7.10 Pregnancy, perioperative care and transition

No patients with ML IV are known to have reproduced, and there is no information on reproductive capacity in the mild forms; two adult sisters in a British series had premature ovarian insufficiency [4, 18]. The sources consulted do not describe specific anaesthetic or perioperative recommendations; the intrathecal gene therapy trial requires patients to meet age-appropriate anaesthesia and sedation criteria and excludes severe contractures and scoliosis with a Cobb angle of 50° or more, which illustrates the practical problems of neuraxial access in this population [12]. Transition to adult care should include renal surveillance, nutrition, aspiration prevention and reassessment of spasticity, because functional regression and kidney disease manifest from the second decade [4, 9, 11].

7.11 Lisch epithelial corneal dystrophy

Most patients with LECD retain normal visual acuity and need no treatment; when the bands involve the visual axis, epithelial debridement has been followed by recurrence of the opacities within months, with the same reduction in acuity [3].

7.12 Regulatory status

Table 8. Regulatory status of therapies directed at ML IV (31 October 2026)

Sources: [5, 12, 13]. AAV9, adeno-associated virus serotype 9; IND, investigational new drug application.

7.13 Registered trials and studies

Table 9. Studies registered on ClinicalTrials.gov (query of 31 October 2026)

Sources: [12, 52, 54].

There are no phase 2 or 3 trials, no trials stopped for safety and no clinical results of any intervention. The Chinese trial has safety as its only primary outcome, with only one patient planned, so it will not produce efficacy estimates; its exclusion criteria (dependence on tube feeding, severe scoliosis, severe contractures, ventilatory support) leave out some of the older patients [12]. The North American and Chinese programmes differ in the route of administration described, intracerebral and intrathecal, respectively [12, 13]. Misko and colleagues stress that existing motor scales have a floor effect in this disease and that specific scales are needed to serve as outcomes in future trials; the ongoing natural history study includes an ML IV-specific scale for this purpose [9, 52].

7.14 Preclinical research

Table 10. Therapeutic strategies under investigation

Animal results do not allow benefit in patients to be predicted: in the AAV.CPP.16 study, the already degenerated retina did not recover thickness, and the 2026 review on miglustat stresses that central nervous system penetration and on-target biochemical action are not equivalent to clinical disease modification [42, 55]. Development of the gene therapy has been funded mainly by the patient organisation: the ML4 Foundation made it a priority in 2017 and supported the preclinical work at MGH, the final studies with the gene therapy centre of the University of Massachusetts from 2023, toxicology and manufacture of the clinical batch [13]. There are declared conflicts of interest in the preclinical studies, including provisional patents and links to gene therapy companies [42].

7.15 Developments in the last 12 months

Between November 2025 and October 2026 the following events were recorded, by level of evidence. Clearance of a clinical trial: the FDA cleared the ML4 Foundation's IND application to proceed for the first North American AAV9-MCOLN1 gene therapy trial, announced in September 2026; this is an authorisation to study in humans, not a marketing authorisation [13]. Trial started: the Chinese phase 1 trial NCT07398872 began on 13 January 2026, with no results [12]. Published case reports: persistent hyperCKaemia in a child from Bahrain (March 2026) [47], a homozygous nonsense variant in a Moroccan child (July 2026) [36] and a novel variant in an Iranian family (December 2025) [37]. Shortly before this period, in 2025, the study of tubular kidney disease and adult CKD [11] and that of plasma proteomics as a source of biomarkers [30] were published. Laboratory studies: the functional characterisation of 10 patient mutants (November 2025) [27] and the proposal of MCOLN1 as a candidate gene in synucleinopathies, based on two patients (August 2026) [40]. Review (September 2026): miglustat still lacks controlled clinical evidence in ML IV [55]. The search found no opinions of the Committee for Medicinal Products for Human Use (CHMP) and no authorisation decisions for ML IV, which does not exclude the existence of orphan designations not searched for.

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

The parents of a child with ML IV are obligate heterozygotes, and molecular testing of both is recommended to confirm carrier status and to calculate the recurrence risk reliably [4]. If the variant is found in only one parent, two explanations should be considered: a de novo variant in the proband or uniparental isodisomy of the chromosome 19 carrying the variant, which makes the proband homozygous [4]. When both parents are heterozygous, each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier; each sibling of the parents has a 50% chance of being a carrier [4]. Patients with ML IV are not known to reproduce [4]. Clinical variability within the same family should be explained in counselling [18].

8.2 Carriers

Heterozygotes do not develop ML IV [4]. MCOLN1 haploinsufficiency may, however, cause Lisch epithelial corneal dystrophy: the penetrance estimated from gnomAD is 0.2%, and the six carrier parents of patients with ML IV examined by Patterson and colleagues had no signs of the disease [3, 7]. LECD has autosomal dominant inheritance, so a patient with LECD transmits the variant to half of their children, and most of those who inherit it will not have opacities [3, 7]. Four of the nine variants associated with LECD cause ML IV in the biallelic state, so the identification of LECD in a person justifies offering carrier testing to the partner before a pregnancy, in line with the general recommendations for testing the partner of a carrier [7, 53]. The association of heterozygous variants with synucleinopathies rests on two patients and on in vitro studies and does not justify, in the sources consulted, neurological surveillance of carriers [40].

8.3 Testing of relatives and carrier screening

Carrier testing in relatives requires prior identification of the familial variants [4]. In 2008, the ACMG recommended offering all individuals of Ashkenazi Jewish ancestry who are pregnant or planning a pregnancy screening for cystic fibrosis, Canavan disease, familial dysautonomia and Tay-Sachs disease, and, in addition, for Fanconi anaemia group C, Niemann-Pick disease type A, Bloom syndrome, ML IV and Gaucher disease; for ML IV, screening for the c.406-2A>G variant and the 6.4 kb deletion detects 95% of carriers, and the carrier frequency is 1 in 127 [50]. The same document recommends that screening should ideally be performed before pregnancy, that one Jewish grandparent is sufficient to offer it, that, in a couple in which only one member is Ashkenazi, that member should be tested first and, if a carrier, then the partner, explaining that the residual risk of a non-Jewish partner with a negative result cannot be calculated accurately, and that counselling should include the possibility of mild phenotypes and the residual risk after a negative result [50]. In 2021, the ACMG adopted an ethnicity-neutral, tiered approach: tier 3 includes conditions with a carrier frequency of 1 in 200 or higher and should be offered to all pregnant individuals and those planning a pregnancy; MCOLN1 is included in tier 3, with a maximum carrier frequency of 0.008531 in a gnomAD population; tier 4 is considered in the presence of consanguinity or family history; and the document advises against offering only tiers 1 and 2, as they are not equitable [51]. The ACMG notes that some tier 3 genes have variants that next-generation sequencing alone does not detect, which applies to the 6.4 kb MCOLN1 deletion [4, 51]. ACOG Committee Opinion No. 691, from 2017 and reaffirmed in 2025, recommends that information on carrier screening be given to all pregnant patients and that, after counselling, the patient may decline some or all of the tests; that screening and counselling should preferably take place before pregnancy, so that the couple can consider all reproductive options, including preimplantation genetic diagnosis and the use of donor gametes; that the partner of a carrier should be tested, concurrently if the time to decide on prenatal diagnosis is short; that, if both are carriers, genetic counselling should be offered and prenatal diagnosis and assisted reproductive techniques discussed; and that the carrier should be encouraged to inform relatives, without the professional disclosing the result without their permission [53]. ACOG considers of Ashkenazi Jewish ancestry those with Jewish relatives originating from Eastern or Central Europe and, in this population, maintains its previous recommendation to offer screening for four diseases: Canavan disease, cystic fibrosis, familial dysautonomia and Tay-Sachs disease [53]. ML IV belongs to a second list, of less frequent autosomal recessive disorders (carrier frequencies between 1 in 15 and 1 in 168), for which screening should be considered in Ashkenazi individuals, alongside Bloom syndrome, familial hyperinsulinism, Fanconi anaemia, Gaucher disease, glycogen storage disease type I, Joubert syndrome, maple syrup urine disease, Niemann-Pick disease and Usher syndrome; inclusion in this list follows the criteria defined in ACOG Committee Opinion No. 690 [53]. When only one member of the couple is Ashkenazi, ACOG recommends testing that member first and, if a carrier, offering testing to the other, informing the couple that, with the exception of Tay-Sachs disease and cystic fibrosis, the carrier frequency and detection rate in non-Jewish individuals are unknown, so the risk of having an affected child is difficult to estimate accurately; in these couples, genetic counselling helps to choose how to estimate the risk [53]. The document adds that screening for each condition is, as a rule, performed once in a lifetime and recorded in the medical record, and that repetition with more recent panels including additional variants should only be decided with a genetics professional; that a test requested by the patient, available and acceptable in another screening strategy, should be offered regardless of ethnicity and family history, after counselling on risks, benefits and limitations; and that prenatal carrier screening and newborn screening do not replace each other [53]. The recommendations diverge on two points. As to the strength of the recommendation in Ashkenazi individuals, the 2008 ACMG document includes ML IV among the disorders for which screening should be offered, whereas the 2017 ACOG document places it among the disorders for which screening should be considered [50, 53]. As to scope, the 2017 ACOG document maintains an ancestry-based strategy for ML IV, whereas the 2021 ACMG document includes MCOLN1 in tier 3, to be offered to all pregnant individuals and those planning a pregnancy, regardless of ethnicity [51, 53]. The documents agree on the preference for screening before pregnancy, on sequential testing starting with the Ashkenazi member of mixed couples and on the impossibility of accurately estimating the risk when the non-Jewish partner has a negative result [50, 53].

8.4 Prenatal and preimplantation diagnosis

Once the familial variants have been identified, molecular prenatal diagnosis and preimplantation genetic testing are possible; the best time to clarify the risk and discuss the options is before pregnancy [4]. In an Israeli case, third-trimester fetal MRI showed white matter changes in an affected fetus, and the parents requested termination of pregnancy under local regulations [28]. Perspectives on the use of prenatal and preimplantation diagnosis differ between professionals and families, and the decision is a personal one [4]. In a Moroccan case, the family had recurrent first-trimester miscarriages in the mother and the maternal grandmother, and the diagnosis made it possible to offer genetic counselling [36]; the relationship between these miscarriages and ML IV has not been established.

8.5 Counselling of young people and adults

Genetic counselling, including discussion of the risks to offspring and of reproductive options, should be offered to young adults who are carriers or at risk of being carriers [4]. The sources consulted do not specifically address carrier testing in minors.

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence and incidence

The worldwide point prevalence of ML IV is classified by Orphanet as unknown [2]. The ML4 Foundation identified about 100 patients worldwide in 2022, and the 26 patients of the cohort of Misko and colleagues represented about 25% of the patients known to the foundation [9]. In September 2026, the same foundation reported fewer than 100 known children [13]. These numbers are counts of identified patients and not prevalence estimates; confusion with cerebral palsy or isolated retinal dystrophy suggests underdiagnosis [4]. Orphanet records a birth prevalence of 0.1 per 100,000 in Sweden, from a study of the two national laboratories for the diagnosis of lysosomal disorders between 1980 and 2009 (433 patients with lysosomal disorders, overall incidence of 1 in 6100 births), and of 2.5 per 100,000 in a specific population, based on the Ashkenazi carrier studies [2, 10, 32, 56, 57]. Hantash and colleagues calculated a predicted incidence of 1 in 42,436 births in the Ashkenazi Jewish population [10].

9.2 Founder populations: Ashkenazi Jews

Depending on the series, between 70% and more than 80% of the patients described are of Ashkenazi Jewish origin, with roots in northern Poland and Lithuania [1, 18, 24, 35]. In the multinational cohort of Misko and colleagues, 15 of the 26 patients (58%) were Ashkenazi, 8 (31%) non-Jewish Caucasian and 3 of Asian, Latin American or mixed African American and Caucasian origin [9].

Table 11. Carrier frequency studies in the Ashkenazi Jewish population

Sources: [4, 10, 32, 34, 35].

The 6.4 kb deletion is much rarer in Israel (1 in 2000) than in the New York metropolitan area (1 in 406), and the splicing variant is at least three times more frequent than the deletion [4]. Raas-Rothschild and colleagues observed that among the 70 to 80 Ashkenazi families with ML IV known worldwide only one or two were ultra-Orthodox, although this community represents at least 10% of the Ashkenazi population [1]. The carrier frequency of 1 in 100 to 1 in 127 is what underpins targeted screening in this population [4, 50].

9.3 Other populations

ML IV has been described outside the Ashkenazi population with distinct variants: a homozygote for p.(Arg322Ter) in a consanguineous Arab Druze family, c.237+5G>A in two Omani families, c.1256G>C p.(Arg419Pro) in three adult siblings of Pakistani origin in the United Kingdom, c.1384G>T p.(Glu462Ter) and c.362C>T p.(Thr121Met) in Iranian families, c.169C>T p.(Arg57Ter) in a Moroccan child, p.(Phe313del) in a Japanese patient, an allele with two changes in cis in an Italian patient, c.1367C>T p.(Ser456Leu) in a Turkish patient, and c.1084G>T p.(Asp362Tyr) in several patients from the south-eastern United States [4, 8, 18, 36–39, 48]. Variant c.1406A>G was found in a Canadian family from Newfoundland [4]. In non-Ashkenazi patients, atypical forms predominate, and diagnostic suspicion tends to arise later because the disease is not expected [4, 36]. The maximum carrier frequency of 0.008531 cited by the ACMG refers to the gnomAD population with the highest frequency and not to a pan-ethnic estimate [51]. The sources consulted do not include data from Portugal or Brazil.

9.4 Special populations

Children with dual motor and visual disability need adapted educational support [4]. Adults accumulate severe spasticity, feeding dependence, blindness and kidney disease, and data on this phase come from small series [9, 11, 18]. Gene therapy trials exclude patients with severe scoliosis, severe contractures, ventilatory support or predominantly tube feeding [12].

9.5 Reference networks and patient organisations

In Europe, the European Reference Network for hereditary metabolic disorders (MetabERN) covers lysosomal disorders, and ERN-EYE covers rare eye diseases [14, 15]. The Mucolipidosis IV Foundation (ML4 Foundation), based in Atlanta, United States, maintains a community of families, funds research, supports the natural history study and is the sponsor of the gene therapy IND application [4, 13, 58]. GeneReviews also lists the MPS Society (United Kingdom), the National MPS Society (United States) and the Norton & Elaine Sarnoff Center for Jewish Genetics [4].

10. Illustrative Clinical Case

10.1 Congenital corneal clouding in a non-Ashkenazi child (Bousellam and colleagues, 2026)

A 9-year-old Moroccan boy, the only child of non-consanguineous parents, was seen for bilateral visual loss and corneal opacities present since birth [36]. Pregnancy and delivery had been uncomplicated; the mother had had four first-trimester miscarriages, and the maternal grandmother three [36]. From 6 months of age he had had generalised seizures, psychomotor delay and axial hypotonia, and on examination he had midface hypoplasia, a flat nasal bridge and relative microcephaly, with no other systemic findings [36].

Corrected visual acuity was limited to light perception in both eyes and intraocular pressure was normal. Biomicroscopy showed a bilateral epithelial-stromal corneal dystrophy, with a clear lens and a deep anterior chamber, and there was photophobia, blepharospasm, alternating esotropia and manifest latent nystagmus; the fundus was not visible (Figure 1) [36]. Anterior segment OCT showed diffuse epithelial-stromal hyperreflectivity, with thickening of the anterior stroma and pachymetry of 587 µm in the right eye and 604 µm in the left (Figure 2); B-mode ultrasound showed a normal posterior segment with an attached retina [36]. The flash ERG was normal, whereas visual evoked potentials showed markedly reduced P100 amplitudes bilaterally, compatible with bilateral optic neuropathy [36].

Exome sequencing identified the nonsense variant NM_020533.3:c.169C>T p.(Arg57Ter) in the homozygous state, which introduces a premature stop codon in exon 2 of the gene's 14 exons (Figure 4, pedigree and molecular result) [36]. The variant is classified in ClinVar as pathogenic or likely pathogenic, by multiple submitters and without conflicts [33]. The patient was referred for multidisciplinary follow-up (neurology, ophthalmology and genetics), with visual rehabilitation, supportive care and genetic counselling; corneal transplantation was not proposed, because of recurrence of the storage material in the graft [36].

The case illustrates three points already supported by the published series: corneal clouding may be the first finding and the one that leads to the diagnosis; the disease occurs outside the Ashkenazi population and without known consanguinity; and a normal ERG on a single examination does not exclude retinal dystrophy, which may set in later [4, 36, 46]. Two aspects depart from the usual picture: the authors describe the dystrophy as epithelial-stromal, whereas GeneReviews considers it limited to the epithelium, and clinical epilepsy from 6 months is less frequent than epileptiform discharges without seizures [4, 36]. The report does not mention gastrin measurement or iron studies, which are part of the recommended assessment [4, 36].

10.2 Three adult siblings with multisystem disease (Jezela-Stanek and colleagues, 2020)

In a British series, three siblings of Pakistani origin, homozygous for c.1256G>C p.(Arg419Pro), in the loop between the fourth and fifth transmembrane segments, were followed in adulthood [18]. A 20-year-old woman had a gastrin of 157 pmol/L (reference below 40), corneal clouding, cataract, optic atrophy and retinal pigmentation, sensorineural hearing loss, severe intellectual disability, microcephaly, premature ovarian insufficiency, abnormal liver function tests and episodes of depression and anorexia [18]. Her 23-year-old sister had a gastrin of 179 pmol/L, iron deficiency anaemia at presentation, legal blindness due to optic atrophy and retinitis pigmentosa, sensorineural hearing loss, loss of speech between 8 and 10 years, CK of 1400 U/L and premature ovarian insufficiency [18]. Their 27-year-old brother had a gastrin of 198 pmol/L, constipation, iron deficiency anaemia, visual deterioration from 5 years with nystagmus, exotropia and subcapsular cataracts, sensorineural hearing loss, CK of 3100 U/L, an atrophic corpus callosum and loss of the ability to communicate at 15 years [18]. All three walked, with progressive myopathy in adulthood; sensorineural hearing loss, present in all three, had not been described as a typical manifestation [18]. The series shows the course in adulthood, with loss of skills in the second decade and accumulation of complications in several organs, in agreement with the natural history described by Misko and colleagues [9, 18].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

In the typical form, development reaches a plateau equivalent to 12 to 21 months, followed by progressive worsening of hypertonia and motor function and by functional regression in early adolescence [9, 19]. Visual impairment is severe in practically all patients by early adolescence, and most are legally blind in the second decade [4, 9]. Swallowing deteriorates late, and older patients may become dependent on gastrostomy; aspiration was the cause of death in a 17-year-old patient [1, 9]. Stage 3 chronic kidney disease is frequent in the adults studied, with an eGFR of 45 to 48.7 mL/min/1.73 m² in the six patients with laboratory data, and no child had renal dysfunction [11]. Survival into adulthood is the rule, with patients described up to 40 and 43 years of age, but life expectancy is reduced; there are no published survival curves [4, 9, 11]. The atypical forms have a better neurological prognosis, with independent walking and, in some patients, normal development, but retain retinal degeneration [1, 4]. In LECD, visual acuity is preserved in most patients [3].

11.2 Surveillance

Table 12. Recommended surveillance in ML IV

GeneReviews does not set the age at which surveillance should start for the annual examinations other than cystatin C; the “Diagnosis” column reflects the recommendation to include them in the initial assessment and to repeat them thereafter [4]. GeneReviews does not recommend gastric endoscopic surveillance, despite the documented atrophic gastritis and ECL cell hyperplasia [1, 4]. The sources consulted do not recommend hearing surveillance; sensorineural hearing loss has been described in a series of adults [18]. Brain MRI with diffusion imaging, quantitative motor scales and plasma biomarkers are, for now, research tools [9, 17, 30].

12. Summary and Final Considerations

Mucolipidosis IV is an autosomal recessive lysosomal disorder caused by loss of the cation channel TRPML1, encoded by MCOLN1, in which the lysosomal hydrolases are normal and the storage results from a disturbance of endolysosomal trafficking and of the release of calcium, iron and zinc from lysosomes. The typical form, present in about 95% of patients, manifests in the first year with hypotonia, motor delay, strabismus and epithelial corneal clouding; development reaches a plateau between 12 and 21 months, retinal dystrophy causes severe visual impairment in adolescence, and constitutive achlorhydria, with markedly raised plasma gastrin, leads to iron deficiency. The most recent natural history studies have shown that the disease is not static: spasticity worsens with age, functional regression begins in the second decade and chronic kidney disease appears in adulthood.

Diagnosis rests on plasma gastrin and molecular testing, which must include testing for the 6.4 kb deletion, not detected by sequencing; in individuals of Ashkenazi ancestry, two founder variants account for about 95% of alleles, and the carrier frequency, of 1 in 100 to 1 in 127, justifies the carrier screening recommended by the ACMG. The same haploinsufficiency that defines carriers may, rarely, cause Lisch epithelial corneal dystrophy, an isolated eye disease with dominant inheritance and very low penetrance.

Treatment remains supportive, centred on motor rehabilitation, communication, protection of the ocular surface, safe feeding, correction of iron deficiency and renal surveillance by cystatin C, avoiding corneal transplantation and chloroquine. Gene therapy with AAV9 vectors corrected the neurological and renal phenotype in the mouse and entered the human trial stage in 2026, in a phase 1 safety trial in China and in a programme cleared to proceed by the FDA in the United States; none of these studies has results yet, and efficacy in patients is unknown.

13. References

1. Online Mendelian Inheritance in Man (OMIM). #252650 Mucolipidosis IV; ML4. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/252650 [accessed 31 October 2026].
2. Orphanet. Mucolipidosis type IV (ORPHA:578). Paris: INSERM; updated 23 June 2026. Available from: https://www.orpha.net/en/disease/detail/578 [accessed 31 October 2026].
3. Online Mendelian Inheritance in Man (OMIM). #620763 Corneal dystrophy, Lisch epithelial; LECD. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/620763 [accessed 31 October 2026].
4. Misko A, Grishchuk Y, Goldin E, Schiffmann R. Mucolipidosis IV. 2005 Jan 28 [updated 2021 Feb 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1214/
5. GeneGuidance. MCOLN1 — mucolipin TRP cation channel 1: identifiers, clinical curation and treatment [database; extracted 26 September 2026].
6. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348
7. Patterson K, Chong JX, Chung DD, Lisch W, Karp CL, Dreisler E, et al. Lisch epithelial corneal dystrophy is caused by heterozygous loss-of-function variants in MCOLN1. Am J Ophthalmol. 2024;258:183-195. doi:10.1016/j.ajo.2023.10.011
8. Online Mendelian Inheritance in Man (OMIM). *605248 Mucolipin TRP cation channel 1; MCOLN1. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/605248 [accessed 31 October 2026].
9. Misko AL, Wood LB, DeBono M, Oberman R, Raas-Rothschild A, Grishchuk Y, et al. Cross-sectional observations on the natural history of mucolipidosis type IV. Neurol Genet. 2022;8(2):e662. doi:10.1212/NXG.0000000000000662
10. Hantash FM, Olson SC, Anderson B, Buller A, Chen R, Crossley B, et al. Rapid one-step carrier detection assay of mucolipidosis IV mutations in the Ashkenazi Jewish population. J Mol Diagn. 2006;8(2):282-287. doi:10.2353/jmoldx.2006.050026
11. Grieco G, Montefusco S, Nusco E, Capuozzo A, Cervellini F, Polishchuk E, et al. TRPML-1 dysfunction and renal tubulopathy in mucolipidosis type IV. J Am Soc Nephrol. 2025;36(4):587-601. doi:10.1681/ASN.0000000567
12. The Children's Hospital of Zhejiang University School of Medicine. Safety and efficacy of AAV9.hMCOLN1co for patients with mucolipidosis type IV. ClinicalTrials.gov identifier NCT07398872. Available from: https://clinicaltrials.gov/study/NCT07398872 [accessed 31 October 2026].
13. Rare Daily Staff. FDA allows first gene therapy clinical trial for ultra-rare pediatric neurodegenerative disease. RARE Daily (Global Genes). 2026 Sep 3. Available from: https://globalgenes.org/raredaily/fda-allows-first-gene-therapy-clinical-trial-for-ultra-rare-pediatric-neurodegenerative-disease/
14. European Reference Network for Hereditary Metabolic Disorders (MetabERN). Available from: https://metab.ern-net.eu/ [accessed 31 October 2026].
15. European Reference Network for Rare Eye Diseases (ERN-EYE). Available from: https://www.ern-eye.eu/ [accessed 31 October 2026].
16. Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G. Cloning of the gene encoding a novel integral membrane protein, mucolipidin—and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet. 2000;67(5):1110-1120. doi:10.1016/S0002-9297(07)62941-3
17. Schiffmann R, Mayfield J, Swift C, Nestrasil I. Quantitative neuroimaging in mucolipidosis type IV. Mol Genet Metab. 2014;111(2):147-151. doi:10.1016/j.ymgme.2013.11.007
18. Jezela-Stanek A, Ciara E, Stepien KM. Neuropathophysiology, genetic profile, and clinical manifestation of mucolipidosis IV—a review and case series. Int J Mol Sci. 2020;21(12):4564. doi:10.3390/ijms21124564
19. Amir N, Zlotogora J, Bach G. Mucolipidosis type IV: clinical spectrum and natural history. Pediatrics. 1987;79(6):953-959.
20. Schiffmann R, Dwyer NK, Lubensky IA, Tsokos M, Sutliff VE, Latimer JS, et al. Constitutive achlorhydria in mucolipidosis type IV. Proc Natl Acad Sci U S A. 1998;95(3):1207-1212. doi:10.1073/pnas.95.3.1207
21. Frei KP, Patronas NJ, Crutchfield KE, Altarescu G, Schiffmann R. Mucolipidosis type IV: characteristic MRI findings. Neurology. 1998;51(2):565-569. doi:10.1212/wnl.51.2.565
22. Smith JA, Chan CC, Goldin E, Schiffmann R. Noninvasive diagnosis and ophthalmic features of mucolipidosis type IV. Ophthalmology. 2002;109(3):588-594. doi:10.1016/s0161-6420(01)00968-x
23. Altarescu G, Sun M, Moore DF, Smith JA, Wiggs EA, Solomon BI, et al. The neurogenetics of mucolipidosis type IV. Neurology. 2002;59(3):306-313. doi:10.1212/wnl.59.3.306
24. Bargal R, Avidan N, Ben-Asher E, Olender Z, Zeigler M, Frumkin A, et al. Identification of the gene causing mucolipidosis type IV. Nat Genet. 2000;26(1):118-123. doi:10.1038/79095
25. Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS Jr, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9(17):2471-2478. doi:10.1093/hmg/9.17.2471
26. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 41, Mucopolysaccharidoses and Oligosaccharidoses (41.2.5 Table 41.3; 41.3.1 Mucolipidosis type IV).
27. Rue BE, Dischler AM, Salvagio LA, Zhu M, Xu G, Flores PC, et al. Differential ion selectivity and disease-associated dysfunction of TRPML channels revealed by patient and engineered mutants. J Biol Chem. 2026;302(1):110953. doi:10.1016/j.jbc.2025.110953
28. Zerem A, Ben-Sira L, Vigdorovich N, Leibovitz Z, Fisher Y, Schiffmann R, et al. White matter abnormalities and iron deposition in prenatal mucolipidosis IV—fetal imaging and pathology. Metab Brain Dis. 2021;36(7):2155-2167. doi:10.1007/s11011-021-00742-3
29. Misko AL, Weinstock LD, Sankar SB, Furness A, Grishchuk Y, Wood LB. Peripheral inflammatory cytokine signature mirrors motor deficits in mucolipidosis IV. Cells. 2022;11(3):546. doi:10.3390/cells11030546
30. Tobin BR, Misko A, Miller-Browne V, Sangster M, Grishchuk Y, Wood LB. Exploring human plasma proteomic variations in mucolipidosis type IV. Mol Ther Methods Clin Dev. 2025;33(2):101479. doi:10.1016/j.omtm.2025.101479
31. Zambon AA, Lemaigre A, Phadke R, Grunewald S, Sewry C, Sarkozy A, et al. Persistently elevated CK and lysosomal storage myopathy associated with mucolipin 1 defects. Neuromuscul Disord. 2021;31(3):212-217. doi:10.1016/j.nmd.2020.12.009
32. Bach G, Webb MB, Bargal R, Zeigler M, Ekstein J. The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations. Hum Mutat. 2005;26(6):591. doi:10.1002/humu.9385
33. National Center for Biotechnology Information. ClinVar: MCOLN1 variants (VCV000005131, VCV000005132, VCV000005135, VCV000208024, VCV001072635, VCV001878328). Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=MCOLN1%5Bgene%5D [accessed 31 October 2026].
34. Bargal R, Avidan N, Olender T, Ben Asher E, Zeigler M, Raas-Rothschild A, et al. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat. 2001;17(5):397-402. doi:10.1002/humu.1115
35. Edelmann L, Dong J, Desnick RJ, Kornreich R. Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population. Am J Hum Genet. 2002;70(4):1023-1027. doi:10.1086/339519
36. Bousellam B, Eddaoui HA, Regragui A, Benchekroun N, Belmekki M. Bilateral corneal dystrophy revealing mucolipidosis type IV: a case report. Cureus. 2026;18(7):e112877. doi:10.7759/cureus.112877
37. Mohsenipour M, Nejati P, Khosravi T, Alimoradi E, Salehi M, Oladnabi M, et al. A novel bi-allelic pathogenic MCOLN1 variant underlying mucolipidosis type IV in an Iranian family: clinical, genetic, and molecular dynamics-based structural analysis. BMC Med Genomics. 2025;18(1):198. doi:10.1186/s12920-025-02271-9
38. Al-Alawi B, Harikrishna B, Al-Thihli K, Al Zuhabi S, Ganesh A, Al Hashami Z, et al. Mucolipidosis type IV in Omani families with a novel MCOLN1 mutation: search for evidence of founder effect. Genes (Basel). 2022;13(2):248. doi:10.3390/genes13020248
39. Ghasemi A, Eslami Ardakani M, Togha M, Yazdi N, Lang AE, Amini E, et al. A novel homozygous variant in the MCOLN1 gene associated with severe oromandibular dystonia and parkinsonism. Can J Neurol Sci. 2025;52(1):110-118. doi:10.1017/cjn.2024.47
40. Ying C, Chen X, Cen Z, Feng X, Jin N, Li J, et al. Rare heterozygous loss-of-function variants in MCOLN1 identified in two sporadic patients with α-synucleinopathies. Mov Disord. 2026. doi:10.1002/mds.70469
41. DeRosa S, Salani M, Smith S, Sangster M, Miller-Browne V, Wassmer S, et al. MCOLN1 gene therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV. Hum Mol Genet. 2021;30(10):908-922. doi:10.1093/hmg/ddab093
42. Sangster ML, Bishop MM, Yao Y, Feitor JF, Shahriar S, Miller ME, et al. A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice. Mol Ther Methods Clin Dev. 2024;32(2):101269. doi:10.1016/j.omtm.2024.101269
43. Scotto Rosato A, Krogsaeter EK, Jaślan D, Abrahamian C, Montefusco S, Soldati C, et al. TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. EMBO Mol Med. 2022;14(9):e15377. doi:10.15252/emmm.202115377
44. Gibson D, Brar V, Li R, Kalra A, Goodwin A, Couser N. The high association of ophthalmic manifestations in individuals with mucolipidosis type IV. J Pediatr Ophthalmol Strabismus. 2022;59(5):332-337. doi:10.3928/01913913-20211206-03
45. Yangzes S, Verma A, Kaur A, Spalkit S, Kakkar N, Gupta A. Multimodal imaging in mucolipidosis type IV: siblings with novel genetic variant. Cornea. 2025;44(1):104-107. doi:10.1097/ICO.0000000000003612
46. Pradhan SM, Atchaneeyasakul LO, Appukuttan B, Mixon RN, McFarland TJ, Billingslea AM, et al. Electronegative electroretinogram in mucolipidosis IV. Arch Ophthalmol. 2002;120(1):45-50. doi:10.1001/archopht.120.1.45
47. Alsahlawi Z, Isa HM, Ghassan L, Taha RA, Elshafey Y, Aboultaif A, et al. Elevated creatine kinase in mucolipidosis type IV: investigating an atypical manifestation and its clinical complications. Cureus. 2026;18(3):e105879. doi:10.7759/cureus.105879
48. Hayashi T, Hosono K, Kubo A, Kurata K, Katagiri S, Mizobuchi K, et al. Long-term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1. Am J Med Genet A. 2020;182(6):1500-1505. doi:10.1002/ajmg.a.61575
49. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical Approach to Inborn Errors of Metabolism in Paediatrics (1.5.2.1; 1.6.11, Table 1.42).
50. Gross SJ, Pletcher BA, Monaghan KG; Professional Practice and Guidelines Committee. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008;10(1):54-56. doi:10.1097/GIM.0b013e31815f247c
51. Gregg AR, Aarabi M, Klugman S, Leach NT, Bashford MT, Goldwaser T, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(10):1793-1806. doi:10.1038/s41436-021-01203-z
52. Massachusetts General Hospital. Mucolipidosis type IV natural history study. ClinicalTrials.gov identifier NCT05782387. Available from: https://clinicaltrials.gov/study/NCT05782387 [accessed 31 October 2026].
53. American College of Obstetricians and Gynecologists' Committee on Genetics. Committee Opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55 (reaffirmed 2025). doi:10.1097/AOG.0000000000001952
54. ClinicalTrials.gov. Registered studies for “mucolipidosis IV”: NCT00015782, NCT01067742, NCT02298673, NCT01793168. Bethesda (MD): National Library of Medicine. Available from: https://clinicaltrials.gov [accessed 31 October 2026].
55. Lipiński P, Węgrzyn G. Miglustat in neuronopathic lysosomal storage disorders: biological rationale, clinical evidence, and limits of repurposing. Int J Mol Sci. 2026;27(18):8336. doi:10.3390/ijms27188336
56. Hult M, Darin N, von Döbeln U, Månsson JE. Epidemiology of lysosomal storage diseases in Sweden. Acta Paediatr. 2014;103(12):1258-1263. doi:10.1111/apa.12807
57. Geer JS, Skinner SA, Goldin E, Holden KR. Mucolipidosis type IV: a subtle pediatric neurodegenerative disorder. Pediatr Neurol. 2010;42(3):223-226. doi:10.1016/j.pediatrneurol.2009.10.002
58. Mucolipidosis IV Foundation (ML4 Foundation). Available from: https://www.ml4.org/ [accessed 31 October 2026].