Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation.

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid beta-glucosidase activity. Mutation analysis identified heteroallelism for acid beta-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material approximately 0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed.     

Correlating liver stiffness with disease severity scoring system (DS3) values in Gaucher disease type 1 (GD1) patients

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score.An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values.Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27 years, age range: 4–67 years). The median GD-DS3 score was 4 (range: 1–10.1) and median MRE value was 2.43 kPa (range: 1.30–5.20 kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r = 0.47, p < 0.001 for all scores, r = 0.68, p < 0.001 for complete scores and r = 0.46, p < 0.07 for incomplete scores. The inter-observer variation of bone marrow burden showed only fair agreement with a Kappa coefficient of 0.26.There is a significant positive correlation between increasing liver stiffness and increasing composite GD-DS3 scores. This supports the use of MRE, a non-invasive reproducible quantitative test, as both an additional assessment and independent marker for monitoring disease severity and progression in GD.     

Quality of life and psychological functioning of pediatric and young adult patients with Gaucher disease,type 1

This study examined the health‐related quality of life (HRQoL) and psychological functioning of children and young adults with Gaucher disease, type 1 (GD1). Thirty‐two (17 pediatric, 15 young adult) patients with GD1 and one parent completed age‐appropriate assessments of HRQoL, emotional, and behavioral health. The HRQoL of children with GD1 was compared with a healthy sample and to children diagnosed with Fabry disease (FD; another lysosomal storage disease), while young adults were compared to a healthy sample and to patients with self‐reported chronic illnesses. Children with GD1 reported significantly lower HRQoL across all domains relative to healthy counterparts yet comparable HRQoL compared to children with FD. Young adults reported mildly lower physical functioning than healthy peers, but no differences in HRQoL relative to the chronic illness sample. Parent‐reported symptom severity was associated with poorer HRQOL in children but not young adults. Few group differences in psychological functioning were observed, except young children showed more school problems than the normative average and there was a trend toward internalizing symptoms. Overall, results consistently identified younger patients with GD1 as more affected than older patients in HRQoL and psychological domains. Implementation of psychosocial interventions may be particularly beneficial during early childhood.     

The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease

The effect of enzyme replacement therapy (ERT) on bone crisis and bone pain was investigated in patients with Gaucher disease (GD) type 1 followed over 4 years. Data from the International Collaborative Gaucher Group Gaucher Registry were used. Only patients with bone crisis and/or bone pain data for 1 year prior to ERT, and for each of 3 years after the start of ERT, were included. Bone crises were reported in 17% of patients during the year before starting ERT. The frequencies of bone crises decreased to 5%, <1% and 3% for 1, 2, and 3 years after initiation of treatment, respectively (p < 0.0001). Bone pain followed a similar pattern of response. Bone pain was reported in 49% of patients the year before treatment and decreased to 30% in the first year, 29% in the second year, and 30% in the third year of ERT (p < 0.0001). ERT is associated with a reduction in bone crisis and bone pain in patients with GD type 1 . This study shows that significant improvements in symptoms of skeletal disease are achievable clinical outcomes and treatment goals in GD type 1.     

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near-normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.     

Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: Identification and expression of a novel acid β-glucosidase mutation

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid β-glucosidase activity. Mutation analysis identified heteroallelism for acid β-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material ∼0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed. Am. J. Med. Genet. 84:334–339, 1999. © 1999 Wiley-Liss, Inc.     

Frequency of carriers of chronic (type I) Gaucher disease in Ashkenazi Jews

In this study we estimate the frequency of carriers of chronic (type I) Gaucher disease among Ashkenazi Jews by examining the glucocerebrosidase activity in leukocytes in a population of 635 blood donors (441 Ashkenazi) and 57 obligatory heterozygotes. Estimation using the defect in the enzyme glucocerebrosidase (beta-glucosidase) in leukocytes is complicated by the existence of considerable overlap between enzyme activity in normals and in heterozygotes. The assay was carried out with a natural substrate labeled with 14C. Discriminant analysis was used to establish an optimal cutoff point between the obligatory heterozygotes and normal (non-Ashkenazi) subjects for the purpose of estimating frequency of carriers. Applied to the Ashkenazi group, the cutoff point identified 3.17% as heterozygotes. Corrected for errors in classification, the carrier rate was estimated as 4.67%. This figure is in good agreement with a carrier rate of 4% estimated from the number of known cases of clinical Gaucher disease ascertained in Israel.     

Multipoint mapping of adult onset polycystic kidney disease (PKD1) on chromosome 16.

Analysis of genetic linkage data in 33 adult onset polycystic kidney (ADPKD) families was carried out using probes for the D16S85, D16S84, and D16S94 loci. The data set of 33 families shows no evidence of genetic heterogeneity since one unlinked family was previously excluded. Two point linkage analysis showed maximum likelihood values of the recombination fraction of 0.07 for ADPKD and D16S85 (lod score 18.78), 0.02 for ADPKD and D16S84 (lod score 7.55), and 0.00 for ADPKD and D16S94 (lod score 6.73). Multipoint analysis showed a maximum likelihood order of tel-D16S85-0.06-D16S84-0.02-(PKD1, D16S94)-cen with a multipoint lod score of 32.16. Analysis of rare recombinants lying close to PKD1 gave results consistent with this order.     

Therapeutic approaches to bone pathology in Gaucher disease: past, present and future

Enzyme replacement therapy (ERT) is effective for the treatment of the systemic manifestations of Gaucher disease (GD) and can have a significant impact on skeletal manifestations. Bone involvement is broad and can occur in otherwise clinically asymptomatic individuals. The heterogeneity in GD-related bone disease may implicate multiple pathological processes such as disruption of coordinated bone cell activity, in addition to the physical impact of Gaucher cells causing vascular occlusion. Accumulated data suggests that earlier treatment initiation decreases skeletal complications and that bone disease may require a longer duration of treatment and higher dose than is necessary for organ involvement and hematopoietic manifestations. However, in some patients, bone manifestations persist and even worsen despite ERT, regardless of dose or duration of treatment. Treating skeletal disease should be considered of equal importance as treating visceral and hematologic manifestations. When treatment decisions involve multiple enzyme preparations and other therapeutic modalities such small molecules, the choice should be tailored on an individual basis with continuing evaluation.     

A 47-year-old man with sudden onset of blindness, pleocytosis, and temporary hearing loss. Vogt-Koyanagi-Harada syndrome (Uveomeningoencephalitic syndrome)

The clinicopathologic findings of this patient were typical for Vogt-Koyanagi-Harada syndrome. Clinically, the patient had sudden onset of blindness, pleocytosis, and temporary hearing loss, with no history of eye trauma or surgery. Histopathologically, the choroid and iris showed chronic inflammation, loss of choroidal melanocytes, and dense chorioretinal adhesions. Presence of HLA-DRB1*0405 was consistent with the chronic phase of this syndrome.     

Generalized glycogenosis (Pompe's disease) in an 11-year-old girl]

A case of cardiomegalic glycogenosis in a girl of 11 is described. The autopsy revealed cardial hypertrophy, hepatomegaly and enlargement of the kidneys. Histologically, diffuse accumulation of glycogen in the heart muscle, liver, epithelium of the convoluted tubules of the kidneys and in skeletal muscles was demonstrated. The features of the observation include the long-term course of the disease and combination of cardiomegalic glycogenosis with hepato-renal manifestations of enzymopathies.     

Collagenous fibroma (desmoplastic fibroblastoma): a unique presentation as a goiter in an 88-year-old man

Collagenous fibroma (desmoplastic fibroblastoma) is a recently described entity in the medical literature. This entity has been reported in various locations, including the upper extremities, posterior neck, upper back, lower extremities, abdominal wall, and hip. We report an interesting case of an 88-year-old man who presented with an apparent goiter involving the right anterolateral neck. Histologic studies revealed a well-circumscribed, paucicellular lesion composed of stellate and spindle-shaped fibroblasts separated by bundles of collagen. No mitotic figures, necrosis, or calcification was observed. The stellate and spindle-shaped cells were positive for vimentin and focally positive for desmin, indicating myofibroblastic differentiation. Our case exemplifies the diagnostic difficulties that these tumors may pose from the clinical and radiologic standpoint when they clinically present as a goiter.     

Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (- 13T->G) mutation in a majority of patients and a novel IVS10 (+ 1GT -> CT) mutation

Two newly identified splice site mutations (IVS1 – 13T     

Pulmonary involvement in type 1 Gaucher disease: functional and exercise findings in patients with and without clinical interstitial lung disease

Pulmonary disease is a well-known complication of Type 1 Gaucher disease (GD), although its incidence is not well established and its severity varies. The purpose of this study was to determine the frequency and extent of pulmonary involvement in patients with GD. Pulmonary involvement was assessed by history, physical examination and chest radiograph in 150 consecutive patients with Type 1 GD presenting at a specialized center for genetic diseases. Five patients were noted to have clinical evidence of pulmonary involvement. Full pulmonary function tests were performed in these five patients and in an additional 13 patients randomly selected from the remaining 145. Many of the 18 patients also underwent radionuclide body imaging with 67 Gallium citrate and 111Indium-tagged leucocyte scans, as well as incremental cardiorespiratory exercise tests. Lung biopsies were available in two patients with lung disease, and a second examination of lung tissue was performed in one of these two patients post-mortem. Clinical lung disease was detected in five patients. All five had dyspnea, diffuse infiltrates, restrictive impairment and low single breath CO diffusing capacity (DLCOSB). Two of these patients underwent exercise testing and showed abnormalities consistent with lung disease (ventilatory limitation, excessive ventilation and increased dead space) as well as decreased VO2 max. and anaerobic threshold (AT). In contrast, in the other 13 patients, physical examination, chest radiographs and pulmonary function were normal (except for a low DLCOSB in one patient). Responses on exercise testing (performed in six of the 13 patients) were consistent with a circulatory impairment (decreased VO2 max. and AT). Our study found that <5% of patients with Type 1 GD have clinical interstitial lung disease. In addition, we found that some patients, without evident lung involvement, may experience limitations in physical exertion and are easily fatigued; this is attributable to impaired circulation.