Clinical features associated with maternal uniparental disomy for chromosome 6.

BACKGROUND: Maternal uniparental disomy for chromosome 6 (upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat) has been previously reported to cause intrauterine growth restriction (IUGR), but the specific clinical phenotype has not been defined. Based on clinical data from two new cases and patients from the literature, specific phenotypes and mechanisms will be discussed further. CASE PRESENTATION: In case 1, a maternal isodisomy mixed with a heterodisomy was found on chromosome 6, including a regional absence of heterozygosity between 6q23.3 and 6q27. In case 2, a homozygous SCUBE3 mutation and upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat, involving the 6p21.1-25.1 region were found. Clinical data related to upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat were also reviewed. Of all the 21 reported cases with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat (including our 2 cases), 18 (85.7%) presented IUGR. CONCLUSIONS: The phenotypes of the two newly identified patients with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat further suggest that IUGR is associated with upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat and case 2 is the first reported upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat patient with a homozygous SCUBE3 gene mutation. However, the specific phenotypes involved in upd(Cajaiba MM, Witchel S, Madan-Khetarpal S, Hoover J, Hoffner L, Macpherson T, et al. Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings. Am J Med Genet Part A. 2011;155 A(8):1996-2002.)mat and the related mechanisms need to be further studied.

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.

An unusual presentation of fucosidosis in a Chinese boy: a case report and literature review (childhood fucosidosis).

BACKGROUND: Fucosidosis is one of the rare autosomal recessive lysosomal storage diseases (LSDs) attributed to FUCA1 variants causing the deficiency of α-L-fucosidase in vivo. Α-L-fucosidase deficiency will cause excessive accumulation of fucosylated glycoproteins and glycolipids, which eventually leads to dysfunction in all tissue systems and presents with multiple symptoms. Fucosidosis is a rare disease which is approximately 120 cases have been reported worldwide (Wang, L. et al., J Int Med Res 48, 1-6, 2020). The number of reported cases in China is no more than 10 (Zhang, X. et al., J Int Med Res 49:3000605211005975, 2021). CASE PRESENTATION: The patient was an 8-year-old Chinese boy who presented with postnatal motor retardation, intellectual disability, short stature, language development retardation, coarse facial features, hepatomegaly, and diffuse angiokeratoma of both palms. His genetic testing showed the presence of a homozygous pathogenic variant (c.671delC) in the FUCA1 gene. In addition, the enzymatic activity of α-L-fucosidase was low. Ultimately, the patient was diagnosed with fucosidosis. CONCLUSIONS: Fucosidosis is a rare lysosomal storage disease because of FUCA1 variants that cause the deficiency of α-L-fucosidase in vivo. An explicit diagnosis requires a combination of clinical manifestations, imaging examination, genetic testing and enzyme activity analysis. Early diagnosis plays an important role in fucosidosis.

Case Report: Mucolipidosis II and III Alpha/Beta Caused by Pathogenic Variants in the GNPTAB Gene (Mucolipidosis).

Objective: This study aimed to improve the cognition of mucolipidosis (ML) II and III alpha/beta by analyzing the clinical manifestations of two patients. Methods: The clinical, biochemical, and molecular data of two clinical cases associated with ML II and III alpha/beta were analyzed and compared with other case reports of ML II and III alpha/beta. Results: The first patient was a 14-month-old girl who was hospitalized because of abnormal postnatal coarse facial features. The child had no abnormal birth history, but developed multiple abnormalities such as psychomotor retardation, abnormal facial features, bilateral limb muscle hypotonia, and genital abnormalities. The X-ray of the spine revealed multiple bone malformations. Brain magnetic resonance imaging (MRI) showed delayed myelination. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1364C>T and c.1284+1G>T) in the GNPTAB gene. The second patient was an 18-month-old boy who was hospitalized for recurrent respiratory tract infections. The patient was a high-risk preterm infant with postnatal psychomotor retardation, language development retardation, intellectual disability, and coarse facial features. X-ray showed multiple bone malformations. Craniocerebral ultrasound showed bilateral ventricle widening. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1284+1G>T and c.483delT) in the same gene. Conclusions: ML II and III alpha/beta are rare autosomal-recessive lysosomal storage diseases that are attributed to GNPTAB variants that cause N-acetylglucosamine-1-phosphotransferase deficiency, finally leading to multiple clinical signs and symptoms. A proper ML II and/or III alpha/beta diagnosis requires a combined analysis of a patient's clinical manifestations, imaging examination, enzymatic analysis, and genetic testing results. Ultimately, genetic counseling is essential for this disease.