IllnessMucopolysaccharidoses, differential diagnosis II

NGS +

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases. In MPS patients, deficiencies or malfunctions of certain lysosomal enzymes result in the accumulation of mucopolysaccharides/glycosaminoglycans in many cell types and tissues. MPS patients have many similar symptoms, such as multiple organ involvement, "coarse" facial features and skeletal abnormalities, especially joint problems. Other findings include short stature, cardiac and respiratory irregularities, hepatosplenomegaly and/or neurologic abnormalities. The severity of different MPS varies widely among affected individuals, even among those with the same MPS type and even within the same family. In most MPS cases, affected newborns appear normal, with symptoms becoming apparent at 1-2 years of age. In MPS VII, nearly half of pregnancies are complicated by none-immune hydrops fetalis. Early symptoms may include frequent infections, growth retardation or minor developmental delays. Mild forms of these disorders may not become apparent until childhood or adolescence. Most often, MPS are progressive disorders. Depending on the type and severity, affected individuals may experience deterioration in physical and mental functioning.

Hurler syndrome (MPS 1-H) is the most severe form, it is caused by deficiency of the enzyme alpha-L-iduronidase. Symptoms present between 6-24 months of age with developmental delays and recurrent infections. Other problems may include corneal opacities, large tongue, severe scoliosis and joint stiffness. Mental development regresses at about 2 years of age. Scheie syndrome (MPS 1-S) is the mildest form of MPS, it is caused by alpha-L-iduronidase deficiency. These patients have normal intelligence, height and life expectancy. Symptoms begin with stiff joints, carpal tunnel syndrome, aortic regurgitation and corneal opacification at about 5 years of age. Hurler-Scheie syndrome (MPS-IH/S) is extremely rare and represents a less severe form of Hurler syndrome, but a more severe form than Scheie syndrome. Affected individuals may develop coarse facial features, joint stiffness, short stature, corneal opacities, hepatosplenomegaly as well as skeletal and cardiac abnormalities with normal intelligence or mild to moderate intellectual disability between the ages of 3-6 years. Hunter syndrome (MPS II) usually presents between 2-4 years of age with growth retardation, joint stiffness and coarsening of facial features. Affected children may have macrocephaly, a short neck and broad chest, delayed tooth eruption, hearing loss and hepatosplenomegaly. In the mild form (MPS IIB), intelligence may be normal or only mildly impaired; in the more severe form (MPS IIA), profound intellectual disability becomes apparent in late childhood. The 4 subtypes of Sanfilippo syndrome (MPS III) are distinguished by different enzyme deficiencies. Early symptoms of MPS III include hyperactivity, sleep disturbances and delayed arriving at the developmental milestones. All forms are characterized by mental retardation, progressive loss of previously acquired skills and hearing loss, seizures, unsteady gait and aggressive behavior. Morquio syndrome (MPS IV) occurs in 2 forms due to deficiencies in the enzymes N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. The deficiencies result in impaired skeletal development as well as additional symptoms, usually with normal intelligence. The features of MPS IV-B are usually fewer and milder than those of MPS IV-A. Major symptoms include growth retardation, a protruding lower face, abnormally short neck, genu valgum, kyphoscoliosis, abnormal epiphyses and/or a protruding pectus carinatum. Maroteaux-Lamy syndrome (MPS VI) is characterized by a deficiency of N-acetylgalactosamine-4-sulfatase, the symptoms vary widely among affected individuals including coarse facial features, umbilical hernia, pectus carinatum, joint contractures, corneal opacities and heptasplenomegaly. Skeletal malformations and heart disease may occur, intelligence is usually normal. Sly syndrome (MPS VII) is characterized by beta-glucuronidase deficiency, and symptoms can vary widely as well. Affected individuals may have normal intelligence or mild to severe mental retardation, skeletal abnormalities are common, as are hernias, corneal opacities, hydrocephalus, short stature, heart disease and sometimes coarse facial features. Hyaluronidase deficiency (MPS IX) is an extremely rare form. Symptoms include mild short stature, cysts, frequent ear infections, cleft palate and development of soft-tissue masses. With the exception of Hunter syndrome (X-linked), all MPS are inherited as autosomal recessive traits. The diagnostic yield in MPS is low (<1-25%), even using very comprehensive gene panels.

References: https://www.ncbi.nlm.nih.gov/books/NBK1162/

https://www.ncbi.nlm.nih.gov/books/NBK1274/

https://www.ncbi.nlm.nih.gov/books/NBK546574/

https://www.ncbi.nlm.nih.gov/books/NBK148668/

https://www.ncbi.nlm.nih.gov/books/NBK164500/

• Allelic: Charcot-Marie-Tooth disease, axonal, type 2V (NAGLU)
• Allelic: Lewy body dementia, susceptibility to (GBA)
• Allelic: Parkinson disease 24, AD, susceptibility to (PSAP)
• Allelic: Parkinson disease, late-onset, susceptibility to (GBA)
• Allelic: Retinitis pigmentosa 73 (HGSNAT)
• Combined SAP deficiency (PSAP)
• Fabry disease (GLA)
• Fabry disease, cardiac variant (GLA)
• GM1-gangliosidosis type I-III (GLB1)
• Gaucher disease, atypical (PSAP)
• Gaucher disease, perinatal lethal (GBA)
• Gaucher disease, type I, II, III, IIIC (GBA)
• Krabbe disease, atypical (PSAP)
• Mannosidosis, alpha-, types I + II (MAN2B1)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Mucolipidosis II alpha/beta (GNPTAB)
• Mucolipidosis III alpha/beta (GNPTAB)
• Mucolipidosis IV (MCOLN1)
• Mucopolysaccharidosis type II, Hunter syndrome (IDS)
• Mucopolysaccharidosis type IIIA, Sanfilippo A (SGSH)
• Mucopolysaccharidosis type IIIB, Sanfilippo B (NAGLU)
• Mucopolysaccharidosis type IIIC, Sanfilippo C (HGSNAT)
• Mucopolysaccharidosis type IIID, Sanfilippo syndrome D (GNS)
• Mucopolysaccharidosis type IVA (GALNS)
• Mucopolysaccharidosis type IVB, Morquio (GLB1)
• Mucopolysaccharidosis type IX (HYAL1)
• Mucopolysaccharidosis type Ih/s, Hurler-Scheie syndrome+ Is, Scheie syndrome (IDUA)
• Mucopolysaccharidosis type VI, Maroteaux-Lamy (ARSB)
• Mucopolysaccharidosis type VII, Sly syndrome (GUSB)
• Mucopolysaccharidosis type X (ARSK)
• Mucopolysaccharidosis-plus syndrome (VPS33A)
• Multiple sulfatase deficiency (SUMF1)
• Osteoarthritis with mild chondrodysplasia (COL2A1)
• Schimke immunoosseous dysplasia (SMARCAL1)
• Sialidosis, type I (NEU1)
• Sialidosis, type II (NEU1)
• Smith-Magenis syndrome (RAI1)
• Spondyloepiphyseal dysplasia tarda (TRAPPC2)