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Progressive brain atrophy in a girl with Hurler disease. a–d Axial T2-weighted MR images (TR/TE 3,787/99 ms) at age 7 months through the lateral ventricles (a) and basal ganglia (b) and at age 2 years (TR/TE 5,301/124 ms) through the lateral ventricles (c) and basal ganglia (d). There is progressive enlargement of the lateral and third ventricles and progressive widening of the sulci secondary to brain volume loss. TE echo time, TR repetition time
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The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have au...
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... Spine involvement includes abnormalities affecting the intervertebral discs, vertebrae, odontoid process, and dura, causing spinal deformity and cord compression [11]. Central nervous system involvement can include white matter injury, enlargement of perivascular spaces, hydrocephalus, brain atrophy, characteristic enlargement of the subarachnoid spaces, and compressive myelopathy, among other manifestations [12]. Neurodevelopment can become impaired in the first year of life, with progressive decline after the second year [13]. ...
Mucopolysaccharidoses are rare lysosomal storage disorders in which glycosaminoglycans accumulate in tissues, causing multiorgan dysfunction. Mucopolysaccharidosis type I is an autosomal recessive disease caused by a deficiency of the enzyme alpha-L-iduronidase, resulting in the accumulation of dermatan and heparan sulfate. Early diagnosis is crucial for early treatment and improved outcomes.
We report the case of a female child with classic clinical features who was diagnosed early which allowed hematopoietic stem cell transplantation and slowed disease progression. She presented at birth with linea alba and umbilical and inguinal hernias. Since the first months of life, she had recurrent respiratory infections. At nine months, a motor delay was noticed, and at 20 months, craniosynostosis was corrected with surgery. Coarse facial features, thoracolumbar kyphosis, and hepatomegaly prompted a urinary glycosaminoglycan study at 22 months, which showed elevated levels. Alfa-L-iduronidase activity in dried blood spot testing was low, compatible with mucopolysaccharidosis type I. Molecular testing of gene IDUA, performed for genetic counseling, revealed the pathogenic variants c.1205G>A (p.Trp402Ter) and c.1598C>G (p.Pro533Arg) in compound heterozygosity. At 26 months, her development quotient was average for her age. She started enzyme replacement therapy at 29 months and underwent hematopoietic stem cell transplantation at 33 months, which softened the coarse features, reduced respiratory infections, and improved hepatomegaly. However, at age five, her development quotient was 76 (mean = 100, standard deviation = 15). This intellectual impairment might have been prevented with an earlier diagnosis and treatment.
... This deficit leads to chondroitin sulfate buildup in numerous tissues, causing cell and tissue damage that ultimately progresses to organ failure [3]. The classical clinical features of Maroteaux-Lamy syndrome include a significant impairment of the osteoarticular system, with dysostosis multiplex, short stature, and motor dysfunction [4]. Depending on the symptoms, treatment options include enzyme replacement therapy (ERT) or bone marrow transplant, and symptomatic management of the various clinical features [5]. ...
MUCOPOLYSACCHARIDOSIS TYPE VI, ALSO KNOWN AS MAROTEAUX-LAMY SYNDROME IS A RARE GENETIC DISORDER THAT IMPAIRS THE BODY'S ABILITY TO BREAK DOWN GLYCOSAMINOGLYCANS, LEADS TO VARIOUS SYMPTOMS SUCH AS SKELETAL ABNORMALITIES, JOINT STIFFNESS, VISION AND HEARING PROBLEMS, AND HEART AND LUNG COMPLICATIONS. WE REPORT A CASE OF A 15-YEAR-OLD FEMALE PATIENT WITH MAROTEAUX-LAMY SYNDROME, PRESENTING WITH DECREASED HEIGHT, SQUINTING, AND DIFFICULTY WALKING. IMAGING STUDIES REVEALED SEVERAL SKELETAL ABNORMALITIES, AND THE PATIENT'S ACTUAL BONE AGE CORRESPONDED TO THAT OF A THREE-YEAR-OLD FEMALE. ENZYME REPLACEMENT THERAPY AND PHYSIOTHERAPY LED TO CONSIDERABLE IMPROVEMENT IN MOBILITY, DISEASE PROGRESSION, AND BONE GROWTH. THIS CASE REPORT EMPHASIZES THE IMPORTANCE OF EARLY DIAGNOSIS AND TREATMENT IN MANAGING MAROTEAUX-LAMY SYNDROME
... The undegraded GAGs also cause morphological changes, with for example significant decreases in the volume of the thalamus and pallidum (striatum), but no significant shrinkage of the hippocampal formation 4 . Although morphological and behavioral deficits are well characterized in MPS I [5][6][7] , the underlying alterations in functional neural connectivity are unknown in humans and animal models used to develop therapeutic approaches. Evaluation of the efficacy of prospective treatments in animals are often superficial due to testing that involves physical activities such as negotiating mazes and spatial memory. ...
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.
... We additionally found common white matter changes. Again, the direct effect of white matter lesions on neurocognitive function remains unclear [33]. The literature contains case descriptions of MLII patients whose hydrocephalus was relieved by the insertion of a ventriculoperitoneal shunt [32,34]. ...
Mucolipidosis type II (MLII), an ultra-rare lysosomal storage disorder, manifests as a fatal multi-systemic disease. Mental inhibition and progressive neurodegeneration are commonly reported disease manifestations. Nevertheless, longitudinal data on neurocognitive testing and neuroimaging lack in current literature. This study aimed to provide details on central nervous system manifestations in MLII. All MLII patients with at least one standardized developmental assessment performed between 2005 and 2022 were included by retrospective chart review. A multiple mixed linear regression model was applied. Eleven patients with a median age of 34.0 months (range 1.6–159.6) underwent 32 neurocognitive and 28 adaptive behaviour assessments as well as 14 brain magnetic resonance imagings. The scales used were mainly BSID-III (42%) and VABS-II (47%). Neurocognitive testing (per patient: mean 2.9, standard deviation (SD) 2.0) performed over 0–52.1 months (median 12.1) revealed profound impairment with a mean developmental quotient of 36.7% (SD 20.4) at last assessment. The patients showed sustained development; on average, they gained 0.28 age-equivalent score points per month (confidence interval 0.17–0.38). Apart from common (63%) cervical spinal stenosis, neuroimaging revealed unspecific, non-progressive abnormalities (i.e., mild brain atrophy, white matter lesions). In summary, MLII is associated with profound developmental impairment, but not with neurodegeneration and neurocognitive decline.
... Imaging plays a crucial role in the early suspicion and monitoring of disease progression, especially craniocervical junction stenosis, spinal cord compression and hydrocephalus. An early recognition allows prompt intervention, preventing permanent damage [32]. ...
... Imaging difficulties lie in unspecific signs, existing in multiple other degenerative neurological diseases, both progressing and stable. Recently published papers confirm our hypothesis, emphasising the significance of neuroradiological findings and their importance during therapy selection [23,32]. ...
... According to the literature, the PVS enlargement that is located within the CC seems to be the most distinctive for patients with MPS [40]. Some authors reported an unusual location of prominent PVS: peripherally at the cortical junction, naming it a "pearl-of strings pattern" [32]. In contrast to most authors, prominent PVS were found among three of our patients, with only one having the typical localisation. ...
Mucopolysaccharidosis 1 (MPS 1) is a group of rare lysosomal genetic disorders resulting from the accumulation of undegraded glycosaminoglycans (GAGs) leading to multiorgan damage. Neurological symptoms vary from mild to severe. Neuroimaging—mainly magnetic resonance (MRI)—plays a crucial role in disease diagnosis and monitoring. Early diagnosis is of the utmost importance due to the necessity of an early therapy implementation. New imaging tools like MR spectroscopy (MRS), semiquantitative MRI analysis and applying scoring systems help substantially in MPS 1 surveillance. The presented analysis of neuroimaging manifestations is based on 5 children with MPS 1 and a literature review. The vigilance of the radiologist based on knowledge of neuroradiological patterns is highlighted.
... MPS VI, also referred to as Maroteaux-Lamy Syndrome (OMIM 253200), is a lysosomal storage disease with progressive multisystem involvement caused by deficiency of ARSB, leading to the accumulation of dermatan sulfate (4,5). ARSB is a homodimer that belongs to the sulfatase family and is required for the proper degradation of dermatan sulfate (DS) and chondroitin-4-sulfate (C4S) (4,6). The incidence of MPS VI is approximately one in 238 000-300 000 births, depending on the population and geographical region (6,7). ...
... ARSB is a homodimer that belongs to the sulfatase family and is required for the proper degradation of dermatan sulfate (DS) and chondroitin-4-sulfate (C4S) (4,6). The incidence of MPS VI is approximately one in 238 000-300 000 births, depending on the population and geographical region (6,7). Enzyme replacement therapy, which is well tolerated by most patients, is considered beneficial if initiated at an early age (8,9). ...
... Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive metabolic condition in which the lyso-Age (years) 6 The continuous variables were presented as mean±SD and minimum and maximum and categorical variables were presented as frequency (%). The variables were presented as mean±SD and minimum and maximum. ...
... Although clinical symptoms differ by MPS subgroup, coarse aspects, organomegaly, skeletal and joint anomalies, visual and hearing difficulties, and cardiorespiratory issues are all frequent in the said group of population (19). A significant dysfunction of the osteoarticular systems, with dysostosis multiplex, low height, and motor deficits, are the characteristic clinical symptoms (6). Furthermore, ophthalmic anomalies (beyond corneal clouding) and ENT (ear, nose, and throat) symptoms, as well as oro-dental anomalies, were reported often (7). ...
Mucopolysaccharidoses type VI is a rare disorder and establishing the diagnosis requires assays that are unavailable in a routine care setting. There is an increased risk of considerable diagnostic delay and missing patients due to incorrect diagnosis. The present study was conducted to determine the socio-demographic characteristics, clinical manifestations, and anthropometric parameters of patients with MPS type VI. Patients' enzyme levels and genetic profiles were also examined. The present study included a total of 16 patients who had been diagnosed as MPS type VI and were referred to Hivi Pediatric Hospital in Duhok, Kurdistan Region, Iraq, till the time period of March 2022. Diagnoses were made in all the patients by analyzing the enzyme level. Moreover, a genetic study was performed to confirm the diagnosis. From each of the patients, a blood sample was taken to determine the hematological parameters. Among the study participants, 9 were males and 7 were females. The mean age of the patients was 6.81±4.99 years and the age at diagnosis was 21.13±15.19 months. All of them presented with a course facial features, 75% had short stature, 87.5% had corneal clouding, 12.5% had glaucoma, 68.75% had poor vision, 18.75% of them had optic nerve disease, 56.25% had otitis media, 56.25% had poor hearing, 68.75% had a history of recurrent sinusitis, 50% had an enlarged tongue, and 75% had abnormal teeth. Approximately 56.25% of the patients presented with sleep apnea, 37.5% had obstructive and restrictive airway disease, none of the patients had cardiac arrhythmia, 37.5% had cardiomyopathy, 31.25% had abdominal hepatosplenomegaly, 81.25% had skeletal abnormalities, all of the patients had normal intelligence, 9 (56.25%) had a past medical history of other systemic illness and 7 (43.75%) had a past history of surgery. Out of the total number of patients, 13 patients had c.962T>C (p.(Leu321Pro)) mutation, one patient had c.585T>A (p.(ASP195Glu)) mutation, one patient had c.[585T>A];[753C>G] (Asp195 Glu];[Tyr251 Ter]), and one patient had c.{288C>A];[962T>C] (p.[Ser96Arg];[Leu321Pro]) mutations. Due to the rarity in prevalence, early detection of the said disorder is critical; early treatment may result in improved outcomes, which may have potential significance for newborn screening.
... Individuals with MPS often display macrocephaly that is at least in part related to ventriculomegaly and prominent subarachnoid spaces. Other neuroradiological features include focal periventricular white matter signal abnormalities, J-shaped sella and craniocervical junction stenosis, and vertebral anomalies (Figure 4) (76). The measurement of total GAGs excretion in urine is widely used as a biomarker for MPS (77). ...
Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations (SD) above the mean for a given age and sex. Taking into account that about 2–3% of the healthy population has an OFC between 2 and 3 SD, macrocephaly is considered as “clinically relevant” when OFC is above 3 SD. This implies the urgent need for a diagnostic workflow to use in the clinical setting to dissect the several causes of increased OFC, from the benign form of familial macrocephaly and the Benign enlargement of subarachnoid spaces (BESS) to many pathological conditions, including genetic disorders. Moreover, macrocephaly should be differentiated by megalencephaly (MEG), which refers exclusively to brain overgrowth, exceeding twice the SD (3SD—“clinically relevant” megalencephaly). While macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, megalencephaly is most likely due to a genetic cause. Apart from the head size evaluation, a detailed family and personal history, neuroimaging, and a careful clinical evaluation are crucial to reach the correct diagnosis. In this review, we seek to underline the clinical aspects of macrocephaly and megalencephaly, emphasizing the main differential diagnosis with a major focus on common genetic disorders. We thus provide a clinico-radiological algorithm to guide pediatricians in the assessment of children with macrocephaly.
... The classical clinical features of Maroteaux-Lamy syndrome are represented by an important impairment of the osteoarticular system, with dysostosis multiplex, short stature and motor dysfunction [34], among others ( Figure 3a). In addition, ocular (above all corneal clouding) and ENT (ear, nose, throat) manifestations were registered quite commonly [1], as well as orodental anomalies [35,36]. ...
... Finally, other signs, such as organomegaly and cardio-respiratory insufficiencies, typical of MPSs in general, are also present in MPS VI [1]. Figure 3b summarizes the clinical manifestations mainly reported in the patients. In relation to nervous system involvement, some brain structural abnormalities, including white matter lesions, perivascular spaces, communicating hydrocephalus and ventricular enlargement, have been described, together with spinal cord compression, myelopathy and carpal tunnel syndrome [34,37]. ...
Mucopolysaccharidosis type VI, or Maroteaux–Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10–15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.
... Neuroimaging findings MPS I, II, III and VII all involve WMLs and spinal canal stenosis; Types I-III also involve enlarged perivascular spaces, hydrocephalus, and cerebral atrophy [41][42][43]. Cerebellar abnormalities have been identified in MPS I and II, with MPS II patients also exhibiting cerebral infarctions [44,45]. In a study of 69 MPS II patients, 100% were found to have ventriculomegaly suggestive of hydrocephalus, 50% of which were graded as severe [46]. ...
Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood–brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs.
