Fucosidosis: clinical and molecular findings of Turkish patients.

BACKGROUND: Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a novel homozygous pathogenic variant and atypical clinical findings and summarized the clinical and molecular features of Turkish patients reported in the literature and present. CASE: The patient was born to consangineous parents at the 28th week of gestation. He had developmental delay that was attributed to prematurity. At he age of 2.5 years, brain magnetic resonans imaging revealed hyperintensities of symmetrical periventricular, subcortical, centrum semiovale and corona radiata regions on T2 and FLAIR weighted images. He developed seizures and showed developmental regression at he age of 3,5 years. Beside, coarse facial features and hepatomegaly were detected on phsyical examination. Lysosomal enzyme analysis revelaed alfa fucosidase deficiency and molecular genetic analysis identified a novel homozygous pathogenic p. Lys431 fs variant in FUCA1 gene. CONCLUSIONS: In Turkish patients no distinguishable clinical and radiologic finding could be established. Molecular analysis was performed in few patients. Increasing of molecular and biochemical facilities might enable to make diagnosis and increase the prevalence of the disease in countries with high rate of consanguineous marriages. Moreover, it will provide genetic counseling, and enlighten the therapeutic effects of hematopoietic stem cell transplantation.

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.

Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report.

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

The Identification of a Novel Fucosidosis-Associated FUCA1 Mutation: A Case of a 5-Year-Old Polish Girl with Two Additional Rare Chromosomal Aberrations and Affected DNA Methylation Patterns.

Fucosidosis is a rare neurodegenerative autosomal recessive disorder, which manifests as progressive neurological and psychomotor deterioration, growth retardation, skin and skeletal abnormalities, intellectual disability and coarsening of facial features. It is caused by biallelic mutations in FUCA1 encoding the α-L-fucosidase enzyme, which in turn is responsible for degradation of fucose-containing glycoproteins and glycolipids. FUCA1 mutations lead to severe reduction or even loss of α-L-fucosidase enzyme activity. This results in incomplete breakdown of fucose-containing compounds leading to their deposition in different tissues and, consequently, disease progression. To date, 36 pathogenic variants in FUCA1 associated with fucosidosis have been documented. Among these are three splice site variants. Here, we report a novel fucosidosis-related 9-base-pair deletion (NG_013346.1:g.10233_10241delACAGGTAAG) affecting the exon 3/intron 3 junction within a FUCA1 sequence. This novel pathogenic variant was identified in a five-year-old Polish girl with a well-defined pattern of fucosidosis symptoms. Since it is postulated that other genetic, nongenetic or environmental factors can also contribute to fucosidosis pathogenesis, we performed further analysis and found two rare de novo chromosomal aberrations in the girl's genome involving a 15q11.1-11.2 microdeletion and an Xq22.2 gain. These abnormalities were associated with genome-wide changes in DNA methylation status in the epigenome of blood cells.

Fucosidosis-Clinical Manifestation, Long-Term Outcomes, and Genetic Profile-Review and Case Series.

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described-one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype-phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases.

Tandem mass spectrometry-based multiplex assays for α-mannosidosis and fucosidosis.

Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using dried blood spots (DBS) on newborn screening cards, have garnered much attention due to its sensitivity, high precision, and the capability to screen for an unprecedented number of diseases in a single assay. Herein we report the development of MS/MS-based enzyme assays for the diagnosis of α-mannosidosis and fucosidosis. These new protocols are able to distinguish untreated patients from random newborns, carriers and a post-bone marrow transplant patient. We have successfully multiplexed the α-mannosidosis assay with a multiplex MS/MS assay for the screening and diagnosis of other LSDs, namely Fabry, Pompe, MPS I, Gaucher, Niemann-Pick-A/B, and Krabbe diseases. Additionally, we also multiplexed the fucosidosis NBS assay with a 5-plex assay that tests for MPS-II, MPS-IIIB, MPS-IVA, MPS-VI and MPS-VII.

A novel homozygous frameshift mutation in the FUCA1 gene causes both severe and mild fucosidosis.

AIMS: Fucosidosis is a rare autosomal recessive lysosomal storage disorder caused by α-L-fucosidase deficiency as a result of FUCA1 gene mutations. Here, we studied clinical features and the molecular basis of fucosidosis in a family from Iran, including two probands and nine family members. METHODS: DNA sample of two probands were screened for gene defects using a next generation sequencing technique. The sequencing processes were performed on an Illumina Hiseq 4000 platform. Sequence reads were analysed using BWA-GATK. RESULTS: Next generation sequencing revealed a frameshift mutation caused by 2 bp deletion (c.837_838 delTG; p.Cys279) in the FUCA1 gene. The identified mutation was tested in all participants. Homozygous patients had almost all the complications associated with fucosidosis, while heterozygous carriers were unaffected. CONCLUSIONS: The variant c.837_838 delTG; p.Cys279 has not been reported previously and is predicted to be pathogenic due to a premature stop codon.

Late diagnosis of fucosidosis in a child with progressive fixed dystonia, bilateral pallidal lesions and red spots on the skin.

Fucosidosis is a rare lysosomal storage disease. A 14-year-old girl is presented, with recurrent infections, progressive dystonic movement disorder and mental retardation with onset in early childhood. The clinical picture was also marked by mild morphologic features, but absent dysostosis multiplex and organomegaly. MRI images at 6.5 years of age were reminiscent of pallidal iron deposition ("eye-of-the-tiger" sign) seen in neurodegeneration with brain iron accumulation (NBIA) disorders. Progressively spreading angiokeratoma corporis diffusum led to the correct diagnosis. This case extends the scope of clinical and neuroradiological manifestations of fucosidosis.

A case of fucosidosis type II: diagnosed with dysmorphological and radiological findings.

Fucosidosis is a rare autosomal recessive lysosomal storage disorder in which fucose-containing glycolipids, glycoproteins and oligosaccharides accumulate in tissues, as a result of a deficiency of α-L-fucosidase. In this report we describe clinical, dysmorphological and radiological findings of a boy with this disorder. Developmental delay, skeletal deformities and mild coarsening of the face began at two years of age. Clinical signs typical for fucosidosis evolved over time. Psychomotor deterioration progressed slowly. At age 12, he could not walk without help; he was admitted to the hospital with intellectual disability, short stature and coarse facial features. A skeletal survey showed dysostosis multiplex. Cranial MRI demonstrated high intensities on the periventricular white matter and low intensities on the basal ganglia on T2-weighted images. Despite the absence of angiokeratoma on the skin, type II fucosidosis with clinical, dysmorphological and radiological signs was suspected. The diagnosis was established on the basis of severely decreased activity of α-L-fucosidase in the leukocytes. The natural history and specific dysmorphic and radiological findings should, even in the absence of angiokeratoma, assist in the differential diagnosis of this rare condition when lysosomal storage disorders are suspected, particularly in populations in which consanguineous marriages are common.

Oligosaccharide analysis in urine by maldi-tof mass spectrometry for the diagnosis of lysosomal storage diseases.

BACKGROUND: There are 45 known genetic diseases that impair the lysosomal degradation of macromolecules. The loss of a single lysosomal hydrolase leads to the accumulation of its undegraded substrates in tissues and increases of related glycoconjugates in urine, some of which can be detected by screening of free oligosaccharides (FOS) in urine. Traditional 1-dimensional TLC for urine oligosaccharide analysis has limited analytical specificity and sensitivity. We developed fast and robust urinary FOS and glycoaminoacid analyses by MALDI-time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry for the diagnosis of oligosaccharidoses and other lysosomal storage diseases. METHODS: The FOS in urine equivalent to 0.09 mg creatinine were purified through sequential passage over a Sep-Pak C18 column and a carbograph column and were then permethylated. MALDI-TOF/TOF was used to analyze the permethylated FOS. We studied urine samples from individuals in 7 different age groups ranging from 0-1 months to ≥ 17 years as well as urine from known patients with different lysosomal storage diseases. RESULTS: We identified diagnostic urinary FOS patterns for α-mannosidosis, galactosialidosis, mucolipidosis type II/III, sialidosis, α-fucosidosis, aspartylglucosaminuria (AGU), Pompe disease, Gaucher disease, and GM1 and GM2 gangliosidosis. Interestingly, the increase in urinary FOS characteristic of lysosomal storage diseases relative to normal FOS appeared to correlate with the disease severity. CONCLUSIONS: The analysis of urinary FOS by MALDI-TOF/TOF is a powerful tool for first-tier screening of oligosaccharidoses and lysosomal storage diseases.

High proportion of mannosidosis and fucosidosis among lysosomal storage diseases in Cuba.

Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of populational occurrence of LSDs; they have been conducted predominantly on Caucasian populations. We studied the occurrence of LSDs in Cuba. Data from individuals who had been referred to the Institute of Neurology and Neurosurgery in Havana from hospitals all over the country between January 1990 and December 2005 were analyzed. This institute was the only laboratory to provide enzyme-based diagnostic testing for 19 LSDs in Cuba during this period. Occurrence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. The combined occurrence of LSDs in Cuba was 5.6 per 100,000, lower than that reported in other studies conducted on Caucasian populations. The most frequent individual LSDs were: mucopolysaccharidosis type I (1.01 per 100,000) and, surprisingly, alpha-mannosidosis (0.72 per 100,000) and fucosidosis (0.62 per 100,000). These findings may be related to specific genetic characteristics and admixture of the Cuban population. This is the first comprehensive study of the occurrence of LSDs in Cuba. We conclude that the epidemiology of these diseases can vary regionally, and we stress the need for similar surveys in other Latin American countries.

Lysosomal disorders associated with leukoencephalopathy.

Metachromatic leukodystrophy and Krabbe's disease are among the most widely recognized causes of leukodystrophy. However, white matter changes have been described in several other lysosomal storage disorders. These conditions are summarized and those associated with hypomyelination are reviewed in more detail.

Towards a selected reaction monitoring mass spectrometry fingerprint approach for the screening of oligosaccharidoses.

The oligosaccharidoses are a group of metabolic disorders resulting from a deficiency in enzymes responsible for the catabolism of protein bound oligosaccharides and are typified by the accumulation of corresponding sugars in the urine. Screening is typically accomplished using thin layer chromatography. However, analyte specificity can be a problem and thus complicate interpretation of results. For this reason we developed a mixed mode liquid chromatography tandem mass spectrometry assay for the screening of the oligosaccharidoses which potentially mitigates many of the problems associated with thin layer chromatography. Samples from patients previously diagnosed with I-Cell disease, mannosidosis, Pompe, galactosialidosis, and fucosidosis were derivatized with 3-methyl-1-phenyl-2-pyrazolin-5-one and subjected to analysis by liquid chromatography tandem mass spectrometry. Results were compared to normal control samples. Preliminary results suggest that each oligosaccharidoses produces a unique selected reaction monitoring fingerprint and that the developed method may be an effective screening and diagnostic tool for these disorders.

Fucosidosis in a domestic shorthair cat.

This paper documents the first reported case of fucosidosis in a cat. The cat presented with signs of forebrain and cerebellar dysfunction and a magnetic resonance imaging scan of the brain suggested a degenerative or metabolic disease process. A fine needle aspirate of grossly normal lymph nodes revealed vacuolated lymphocytes and a renal biopsy of an irregular shaped kidney identified vacuolated tubular epithelial cells. A white cell lysosomal enzyme screen revealed negligible α-fucosidase activity. Fucosidosis should be considered in the differential diagnosis of young cats with cerebellar dysfunction and must be added to the list of lysosomal storage diseases affecting the cat.

Phenotypic spectrum of fucosidosis in Tunisia.

Fucosidosis (OMIM 230000) is a rare autosomal recessive lysosomal disorder due to deficient α-L-fucosidase activity(EC 3.2.1.51), leading to the accumulation of fucose-containing glycolipids and glycoproteins in various tissues. This study contained the largest ever Tunisian survey of fucosidosis patients, diagnosed during the period 1987-2007. The clinical pictures and outcomes of these patients are compared with literature data. Ten patients (8 boys and 2 girls) from six unrelated families were diagnosed at a mean age of 29 ± 10.3 months. Six of the patients were diagnosed as having the more severe phenotype. The other four cases presented the low progressive phenotype. This distinction was determined by the presence or absence of angiokeratoma and age of death. For all of the patients in our survey, early motor development was more severely delayed than described in the literature. Six patients presented psychomotor decline during the second year of life. Clinical features consist of variable mental retardation (all patients), progressive spastic quadriplegia (6/10 cases), coarse facies (9/10 cases), growth retardation (7/9 cases), visceromegaly (3 cases), angiokeratoma corporis diffusum (4 cases), recurrent bronchopneumonias (all cases), seizures (4 cases) and variable degrees of dysostosis multiplex (all cases). Portal cavernoma, never described in the literature, was observed in one patient. The outcomes were severe in this survey, probably owing to restricted health care; death occurred in 6 of the 10 patients before age 10 years, following recurrent pulmonary infections and neurological deterioration. No intrafamilial variability was noted in the multiplex families. The clinical presentation and outcomes of some of these patients were consistent with the continuous clinical spectrum of severity in fucosidosis attested by most clinical studies.

Fucosidosis: MRI and MRS findings.

Fucosidosis is a rare, autosomal recessive lysosomal storage disease in which fucose-containing glycolipids, glycoproteins, and oligosaccharides accumulate in tissues as a consequence of alpha-L: -fucosidase enzyme deficiency. We present the MR imaging findings of diffuse white-matter hyperintensity and pallidal curvilinear streak hyperintensity in a 6-year-old Caucasian girl with a diagnosis of fucosidosis based on cDNA isolated from skin fibroblasts. This report also includes the MRS findings of a decreased N-acetylaspartate/choline ratio together with an abnormal peak at 3.8 ppm which expand the knowledge of the neuroradiological spectrum of this rare disease.