Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease

Martins, Carla; Medeiros, Paula Frassinetti Vasconcelos de; Leistner‐Segal, Sandra; Dridi, Larbi; Elçioğlu, Nursel; Wood, Jenny; Behnam, Mahdiyeh; Noyan, Bilge; Lacerda, Lúcia; Geraghty, Michael T.; Labuda, Damian; Giugliani, Roberto; Pshezhetsky, Alexey V.

doi:10.1002/humu.23752

Cited by 20 publications

(38 citation statements)

References 45 publications

(97 reference statements)

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“…However, the progression of the disease, even within the same genetic subtype, is highly variable. The first clinical manifestations in MPS III patients can appear as early as during the first year of life [31,32], but more commonly between the ages of 2 to 6 years [11,16,18,33]. It is thought that the disease progresses in three phases [15].…”

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

“…Somatic disease is relatively mild in Sanfilippo patients and consists typically of frequent ear-nose-throat infections, episodic diarrhea, hepatomegaly and/or splenomegaly, skeletal abnormalities, hirsutism, and coarse facies [11,[15][16][17][18][31][32][33][35][36][37][38][39][40]. At an early age, MPS III patients are typically taller with an increased head circumference compared to healthy children, but their growth slows around 5 years of age and by their late teens they are generally shorter than average [41].…”

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

“…The main burden of the disease is the cognitive decline and associated behavioral problems. Indeed, the majority of patients first present with developmental (particularly speech) delay [11,[15][16][17][18][31][32][33][35][36][37][38][39][40]. In a study of 105 MPS IIIA, B, and C patients, the authors found that only 60 children acquired early language skills and that this acquisition was often later than 3 years of age [17].…”

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

“…Importantly, all subtypes generally included two groups of patients: Those with earlier onset of clinical presentation and higher rate of neurodegeneration and cognitive decline (so called rapid progressing or RP) and those with later onset and slower progress (slow progressing or SP). During the period of rapid decline, the patients start showing behavioral alterations that are difficult to manage, such as uncontrollable hyperactivity, aggression, anxiety, crying spells and sleep disorders, with problems falling asleep and frequent waking [11,[15][16][17][18][31][32][33]35,36,39,40,[47][48][49]. They may also develop autistic behavior as the disease progresses [17,39,50,51], and children with MPS IIIA and MPS IIIB show reduced fear [32], correlating with changes in amygdala volume [52].…”

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

“…The enzyme deficiencies underlying all four subtypes of the disease, MPS III A, B, C and D, were subsequently identified: MPS IIIA was found to be caused by defects in N-sulfoglucosamine sulfohydrolase (SGSH) (EC 3.10.1.1) [5], MPS IIIB, by defects in N-acetyl-α-D-glucosaminidase (NAGLU) (EC 3.2.1.50) [6], MPS IIIC, by defects in acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT) (EC 2.3.1.78) [7], MPS IIID, by defects in N-acetylglucosamine-6-sulfate sulfatase (GNS) (EC 3.1.6.14) [8]. For each disorder, the causative gene has been identified and dozens of pathogenic variants have been described [9][10][11][12][13]. All four subtypes of the disease are rare, but the MPS IIIA and MPS IIIB subtypes, having an incidence of 0.29-1.89 and 0.42-0.72 per 100,000 births, are more common as compared with MPS IIIC and MPS IIID, that have an incidence of 0.07-0.21 and 0.1 per 100,000 births, respectively (reviewed in [14]).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

Section: Neurobehavioral Abnormalities and Cognitive Decline As The Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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Clinical, biochemical, and molecular characterization of mucopolysaccharidosis type III in 34 Egyptian patients

Al-Menabawy

Ramadan

Kamel

et al. 2023

American J of Med Genetics Pt A

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Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.

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A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis

Schiff

Varela

Robson

et al. 2020

American J of Med Genetics Pt C

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Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide Nacetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset lysosomal storage disorder, and adult-onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to-date of HGSNATassociated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late-onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543-2A>C; c.1708delA], three of which were considered to be retina-disease-specific alleles. The most prevalent retina-disease-specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of transacting genetic or environmental modifying factors.

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Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease

Cited by 20 publications

References 45 publications

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Clinical, biochemical, and molecular characterization of mucopolysaccharidosis type III in 34 Egyptian patients

A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis

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