Misko Albert L, Wood Levi B, DeBono Madeline, Oberman Rebecca, Raas-Rothschild Annick, Grishchuk Yulia, Eichler Florian
Department of Neurology and Center for Genomic Medicine (A.L.M., M.D., R.O., Y.G., F.E.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; George W. Woodruff School of Mechanical Engineering (L.B.W.), Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA; The Institute for Rare Diseases (A.R.-R.), The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel; Sackler Faculty of Medicine (A.R.-R.), Tel Aviv University, Tel Aviv, Israel.
Neurol Genet. 2022 Mar 10;8(2):e662. doi: 10.1212/NXG.0000000000000662. eCollection 2022 Apr.
Mucolipidosis 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.
We 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.
Three 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.
This 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.
IV型粘脂贮积症（MLIV）是一种极为罕见的溶酶体疾病，最初被描述为一种静止性神经发育疾病。然而，患者护理人员经常报告患者出现进行性肌肉张力亢进和功能衰退。我们评估了一组MLIV患者，以确定神经功能障碍是否与年龄相关。
我们对美国和以色列的26例年龄在2至40岁之间的MLIV患者进行了一项横断面观察性研究。从护理人员处获取病史，患者接受全面的神经学检查。应用运动功能简要评估（BAMF）、粗大运动功能分类系统和改良Ashworth量表。护理人员根据俄勒冈视障和盲童项目清单确定其孩子已丧失执行能力的发育技能。
3例患者临床分类为轻度受累，其余23例患者为典型的重度受累病例。首发症状出现时间为1.5个月至8岁（中位年龄7.25个月）。在典型患者中，改良Ashworth评分显示出年龄依赖性，表明在整个生命周期中痉挛逐渐加重。还定性观察到锥体外系运动功能障碍的体征。同时，用BAMF和粗大运动功能分类系统量表评估的粗大和精细运动功能随年龄下降。所有典型患者咀嚼时舌活动受限，缺乏下颌旋转运动，但吞咽的BAMF评分仅在年龄最大的患者中下降。相比之下，所有患者的发音评分都很低，且与年龄无关。最后，发育技能丧失经常发生在青春期早期。
这项MLIV的横断面自然史研究表明，老年患者的运动功能更差。这些数据支持了MLIV的神经退行性成分，其表现为生命第二个十年的发育倒退。功能衰退的出现是由于稳定进展的神经退行性过程的累积、非线性相互作用，还是反映了从中枢神经系统发育受损到退化的转变，尚不确定。然而，了解中枢神经系统病理学与疾病临床病程之间的关系对于指导未来的干预试验和优化患者护理至关重要。
