Cross-sectional Observations on the Natural History of Mucolipidosis Type IV

Abstract

Background and ObjectivesMucolipidosis type IV (MLIV) is an ultra-rare lysosomal disorder initially described as a static neurodevelopmental condition. However, patient caregivers frequently report progressive muscular hypertonicity and functional decline. We evaluated a cohort of patients with MLIV to determine whether neurologic disability correlates with age.MethodsWe performed a cross-sectional, observational study of 26 patients with MLIV in the United States and Israel ranging in age from 2 to 40 years. Medical history was obtained from caregivers, and patients underwent a full neurologic examination. The Brief Assessment of Motor Function (BAMF), Gross Motor Function Classification System, and modified Ashworth scales were applied. Caregivers identified developmental skills on the Oregon Project for Visually Impaired and Blind Children checklist that their child had lost the ability to perform.ResultsThree patients were clinically classified as mildly affected and the remaining 23 patients as typical, severely affected cases. Timing of first symptom onset ranged from 1.5 months to 8 years of age (median 7.25 months). Across typical patients, modified Ashworth scores demonstrated a positive age dependence illustrating worsening spasticity across the lifespan. Signs of extrapyramidal motor dysfunction were also qualitatively observed. In parallel, gross and fine motor function assessed with the BAMF and Gross Motor Function Classification System scales declined across age. All typical patients had restricted tongue mobility and lacked rotary jaw movement when chewing, but BAMF scores for deglutition declined only in the oldest patients. In contrast, scores for articulation were low in all patients and did not correlate with age. Finally, loss of developmental skills frequently occurred in early adolescence.DiscussionThis cross-sectional natural history study of MLIV demonstrates worse motor function in older patients. These data support a neurodegenerative component of MLIV that manifests as developmental regression in the second decade of life. Whether the emergence of functional decline results from the cumulative, nonlinear interactions of steadily progressive neurodegenerative processes or reflects an inflection from impaired CNS development to degeneration is uncertain. However, understanding the relationship between CNS pathology and clinical course of disease will be imperative to guiding future interventional trials and optimizing patient care.

Plasma Proteomic Signature of Mucolipidosis Type IV

“…Typically, patients exhibit delayed developmental milestones within the first year of life and then plateau in psychomotor function, consistent with that of an 18 to 20-month-old healthy child (1). As they progress through life, MLIV patients experience increased muscular hypertonicity, and deteriorating motor function (2,3). Patients additionally develop a continuous decline in vision due to retinal degeneration and corneal clouding, ultimately leading to blindness (1,3).…”

“…In MLIV patients, we simultaneously assessed motor function via the Brief Assessment of Motor Function scales (BAMF) and muscle tone via the modified Ashworth scale as previously described (2). Thus, we next asked if motor function or muscle tone is associated with specific blood protein signatures in MLIV patients.…”

“…Moreover, brain imaging of MLIV patients demonstrates a shortage of subcortical white matter, hypoplasia and dysgenesis in the corpus callosum, and variable white matter lesions (5).. Over time, patients experience a decrease in subcortical white matter and cerebellar volumes, while cortical gray matter volumes remain relatively intact (9). A few MLIV patients exhibit milder neurological impairment, which is associated with residual TRPML1 function demonstrated by certain allelic variants (2,10).…”

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice

“…Although MLIV was originally described as a static neurodevelopmental disorder, progressive neurological deterioration has recently been documented during the second decade of life. 6 In congruence with the clinical course, brain imaging has demonstrated stable white matter abnormalities (corpus callosum hypoplasia and dysgenesis, and white matter lesions) with the emergence of subcortical volume loss and cerebellar atrophy in older patients. 7 , 8 Visual impairment is also a prominent feature of MLIV, with progressive retinal dystrophy and optic nerve atrophy leading to blindness by the second decade of life, 8 , 9 , 10 , 11 further impeding function and negatively impacting quality of life.…”

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

“…Early onset of axial hypotonia and signs of pyramidal and extrapyramidal motor dysfunction prevent independent ambulation in the majority of MLIV patients and severely limit fine motor function. Though MLIV was originally described as a static neurodevelopmental disorder, progressive neurological deterioration has recently been documented during the second decade of life (6). In congruence with the clinical course, brain imaging has demonstrated stable white mater abnormalities (corpus callosum hypoplasia and dysgenesis, and white mater lesions) with the emergence of subcortical volume loss and cerebellar atrophy in older patients (7, 8).…”