Mucopolysaccharidosis type IV also known as Morquio syndrome is a rare autosomal recessive lysosomal storage disorder due to deficiency of either N-acetyl-galactosamine-6-sulfatase (type A) or deficiency of beta-galactosidase (type B) which results in damages of bones, cartilages, eye corneas, skin and connective tissue. The objective of this study was to explore the relationship between specific gene mutations (c.860C>T, c.421T>A, c.1196delA) and clinical manifestations in patients with mucopolysaccharidosis type IV (MPS IV. The study was conducted at Heevi Tertiary Hospital in Duhok, Iraqi Kurdistan, till the period of September 2024, it involved 10 patients with confirmed MPS IV. Data on demographics, family history, consanguinity, skeletal, intelligence, and genetic mutations were collected. Results showed that mean age at diagnosis of 7.94 years, with females predominating. Consanguinity and family history were common. Short stature, macrocephaly, fatigue, generalized pain, and various skeletal abnormalities such as dysostosis multiplex and others. Hip dysplasia was present in 50% of patients, while intelligence was normal in most. The most frequent genetic mutation was c.860C>T, followed by c.421T>A and c.1196delA. Biochemical and hematological parameters were within normal ranges, but growth retardation was evident. Geographic clustering of mutations was noted, with c.860C>T prevalent in Zakho and c.1196delA exclusive to Akre. In conclusion, the study highlights the severe phenotypic expression associated with these mutations and underscores the influence of consanguinity and regional genetic predispositions. These findings emphasize the need for targeted genetic counseling and population screening programs in high-risk areas.

Collagen fibrils are the primary supporting scaffolds of vertebrate tissues, but the mechanism of assembly is unclear. Here, using CRISPR-tagging of type I collagen, high-resolution light imaging, and SILAC labelling, we elucidated the cellular mechanism underlying the spatiotemporal assembly of collagen fibrils in cultured fibroblasts. Our findings reveal the multifaceted trafficking of collagen, including constitutive secretion, intracellular pooling, and plasma membrane-directed fibrillogenesis. Notably, we differentiated the processes of collagen secretion and fibril assembly and identified the crucial involvement of endocytosis in the regulation of fibril formation. By employing Col1a1 knockout fibroblasts, we demonstrated the incorporation of exogenous collagen into the nucleation sites at the plasma membrane through these recycling mechanisms. Our study sheds light on a complex and previously unidentified collagen assembly process and its regulation of health and disease. Mass spectrometry data were available via ProteomeXchange with the identifier PXD036794. Fibrous tissue such as tendons, ligaments, skin and even the heart, contain millimetre long fibres that resist pulling forces and help maintain the shape and form of the tissue during everyday activities. The fibres are made of collagen protein molecules – by analogy, the collagen molecules are the building bricks in a wall or the steel rods in reinforced concrete. Studies of collagen fibres provide insights into a wide-spectrum of diseases associated with ageing and tissue degeneration. The fibres were seen using electron microscopes over 80 years ago but how they are formed was unknown, with several theories being proposed. In this study we tagged collagen molecules with probes that can be seen with light microscopes and observed, in real time, cells producing collagen and assembling the molecules into the fibres. We could visualise collagen molecules being synthesised within cells and being trafficked to the outer membrane (the plasma membrane) where the fibrils grew out from the cells and into the extracellular space. Therefore, the fibres grow on the surfaces of cells. We discovered that cells do not produce a continuous stream of collagen fibres but instead produce an intracellular pool of collagen that is ‘emptied’ on a rhythmic basis to make individual fibres. We looked at cells from people with mucopolysaccharidosis (a lysosome storage disorder) and showed that these cells were partially defective in starting new fibrils. This hints to how cells make the fibres, which could help medical scientists produce collagen-trafficking strategies to treat disease.

Lysosomal storage disorders (LSDs) are a group of rare and genetic diseases produced by mutations in genes coding for proteins involved in lysosome functioning. Protein defect leads to the lysosomal accumulation of undegraded macromolecules including glycoproteins, glycosaminoglycans, lipids, and glycogen. Depending on the stored substrate, several pathogenic cascades may be activated leading to multisystemic and progressive disorders affecting the brain, eye, ear, lungs, heart, liver, spleen, kidney, skin, or bone. In addition, for some of these disorders, hematological findings have been also reported. In this paper, we review the major hematological alterations in LSDs based on 56 case reports published between 2010 and 2020. Hematological alterations were reported in sphingolipidosis, mucopolysaccharidoses, mucolipidoses, neuronal ceroid lipofuscinosis, glycogenosis, glycoproteinosis, cystinosis, and cholesteryl ester storage disease. They were reported alterations in red cell linage and leukocytes, such as anemia and morphology changes in eosinophils, neutrophils, monocytes, and lymphocytes. In addition, changes in platelet counts (thrombocytopenia) and leukocyte abnormalities on non-peripheral blood samples were also reported for some LSDs. Although in most of the cases these hematological alterations are not pathognomonic of a specific disease or group of LSDs, since they can be easily identified in general clinical laboratories, their identification may contribute to the diagnosis of these disorders. In this sense, we hope that this review contributes to the awareness of the importance of hematological alterations in the diagnosis of LSDs.

Mucolipidosis type 3 gamma (ML-IIIγ) is an autosomal recessive, rare and slowly progressive lysosomal storage disease. Short stature, restricted joint mobility, thick skin, and flat face with mildly coarse features are major clinical findings. It usually manifests in the third year. With advancing age, claw hand deformities, carpal tunnel syndrome, and scoliosis may develop. Morbidity is determined mainly by skeletal involvement. N-acetyl glucosamine-1 phospotransferase enzyme is composed of 2α, 2β and 2γ subunits. The active enzyme is essential in the transport of hydrolases to the lysosomes, via addition of mannose-6-phosphate in the Golgi apparatus. GNPTG gene encodes the γ2 subunits, and biallelic mutations cause ML-IIIγ. A previously healthy 14-year-old male patient had leg pain after the age of nine, and was admitted with short stature, mild coarse face, pectus deformity, digital stiffness, scoliosis, genu valgum and mitral valve prolapse. He did not have intellectual disability or corneal clouding. Radiographs showed irregularities in the acetabular roof and proximal epiphyses of the femur and irregularities in the end plates of vertebral bodies. A novel homozygous missense variant in the exon 5 of GNPTG, c.316G > T, confirmed the diagnosis of ML- IIIγ. Juvenile idiopathic arthritis (JIA), progressive pseudorheumatoid dysplasia (PPRD), ML-II, ML-IIIαβ, galactosialidosis and mucopolysaccharidosis should be considered in the differential diagnosis. ML-IIIγ should be kept in mind in populations with high consanguineous marriage rates or with possible founder effect, in patients with short stature and skeletal destruction. Genetic tests should be planned for a definitive diagnosis.

We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase (GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces β-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease.