Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients.

Evidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of parkinsonism. Anthropometric measures, complete neurological assessment, and SSI were examined. Neuropsychiatric evaluation included parts I, II, III, and V of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Wechsler Intelligence Scale for Children (WISC-children). Molecular analysis of the acid GBA gene was performed, and SSI was calculated. Sixteen GD patients (66.6%) had parkinsonian features with a male to female ratio of 1:1. Their mean age was 15.69 ± 5.62 (range, 12-26). They were all on enzyme replacement therapy (ERT) with a dose of 60 U/kg/2 weeks. Twelve GD patients were phenotypically type 3 (75%). Thirteen GD patients with parkinsonian features (81.25%) had L483P mutation. GD patients with parkinsonian features had higher SSI (P < 0.001), lower cognitive functions (P = 0.007), and more significant depressive symptoms (P = 0.031). Logistic regression analysis revealed that GD genotype (P = 0.003), GD type (P = 0.006), and cognitive functions (P = 0.03) were the only significant independent factors for the development of parkinsonian features among GD patients. With the increased life span and improved somatic manifestations of type 3GD on ERT, these patients can live to develop parkinsonism. Cognitive decline and depression can be early predictors of parkinsonism among GD population.

Direct and indirect effects of the SARS-CoV-2 pandemic on Gaucher Disease patients in Spain: Time to reconsider home-based therapies?

OBJECTIVE: An analysis of the SARS-CoV-2 pandemic impact in the Spanish Gaucher Disease (GD) community is presented here. PATIENTS & METHODS: The Spanish GD foundation (FEETEF) surveyed 113 GD patients from March 30 to April 27; all patients provided a verbal consent. RESULTS: 110 surveys were analyzed. The median age was 47 years old (y.o.), 31 patients were ≥ 60 y.o.; and 34% of patients reported comorbidities. 46% (51/110) of patients were treated by enzyme replacement therapy (ERT), 48 of them at hospitals; 45.1% (45/110) were on substrate reduction therapy (SRT) and 9% (10/110) receive no therapy. 25% (11/48) of ERT-hospital-based patients reported therapy interruptions, while SRT-patients did not report missing doses. No bone crises were reported. However, 50% (55/110) of patients reported being worried about their predisposition to a severe SARS-COV-2 infection and 29% (16/55) of them took anxiolytics or antidepressants for this. While 6 patients reported to have contact with an infected person, another two confirmed SARS-CoV-2 infections were reported in splenectomyzed patients, one of them (a 79-year-old diabetic) died. CONCLUSIONS: One quarter of the patients treated at hospitals reported dose interruptions. Home-based therapy may need to be considered in order to minimize the impact of the COVID-19 pandemic.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Attitudes of Individuals with Gaucher Disease toward Substrate Reduction Therapies.

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapies (ERTs). More recently, oral substrate reduction therapies (SRTs) were approved for treatment of GD. Although both therapies alleviate disease symptoms, attitudes toward SRTs and patient perceptions of health while using SRT have not been well established. Electronic surveys were administered to adults with GD and asked about treatment history, attitudes toward SRTs, and perception of health while using SRTs as compared to ERTs, if applicable to the participant. ERT users that were offered treatment with SRTs cited potential side effects, wanting more research on SRTs, and satisfaction with their current treatment regimen as reasons for declining SRTs. SRT users expressed convenience and less invasiveness as reasons for choosing SRTs. Additionally, those using SRTs most often perceived their health to be similar to when they previously used ERT. Participant responses illustrate that attitudes toward SRTs can be variable and that one particular treatment may not be ideal for all patients with GD depending on individual perceptions of factors such as convenience, invasiveness, or side effects. Thus, individuals with GD should be counseled adequately by healthcare providers about both ERTs and SRTs for treatment of GD now that SRTs are clinically available.

Patients' perspectives on newborn screening for later-onset lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are an individually rare but collectively common group of hereditary, progressive, multi-systemic disorders. Recent technological advances have brought newborn screening (NBS) for LSDs to attention in the United States. However, many LSD symptoms present in later childhood or adulthood, with a wide spectrum of severity. Because late-onset symptoms stray from the traditional NBS model, healthcare providers have expressed concerns about potential harm to patients and/or their families. In this study, 47 individuals with Fabry disease (FD), 22 with Gaucher disease (GD), and 22 with late-onset Pompe disease (LOPD) were surveyed regarding how their life might have been impacted by NBS. Of the 91 participants, none had symptoms at birth and 42 (46.7%) were symptom-free until adulthood. Over half (52.8%) were diagnosed ≥5years from symptom onset; of these, significantly more had FD (60%) or LOPD (63.6%) than GD (23.8%). However, length of diagnostic odyssey was not significantly correlated with opinion on NBS. Most participants either strongly agreed (45%) or agreed (33.3%) with NBS for their condition, with no significant differences between diseases. Opinions on NBS were correlated with participants' opinions on whether NBS would have resulted in better current health, but uncorrelated with disease severity or current life satisfaction. Significantly more participants with FD (42.6%) and LOPD (63.6%) than GD (13.6%) felt they would have greater life satisfaction had they been diagnosed as a newborn (p=0.007). Almost half (41%) of participants would have made different life decisions, including lifestyle, financial, and reproductive decisions. Regarding potential harm, participants were most concerned about insurability and least concerned about removal of children's autonomy. In conclusion, NBS is highly approved of among individuals with LSDs themselves, as it would significantly eliminate diagnostic odysseys and potentially alter life planning.

The cognitive profile of type 1 Gaucher disease patients.

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain.

Family caregivers of rare disease: A survey on health-related quality of life in family caregivers for Gaucher disease patients in China.

BACKGROUND: Rare diseases affect the health-related quality of life (HRQoL) of patients and their family caregivers (FCs). However, limited evidence is available on the HRQoL of FCs of patients with Gaucher disease (GD). This study aimed to assess HRQoL and related factors among FCs of patients with GD in China. METHODS: A cross-sectional online survey was conducted with 49 FCs recruited by convenience sampling. Participants completed the Medical Outcome Study Short Form-36 (SF-36), Zung's Self-Rating Anxiety Scale, Zung's Self-Rating Depression Scale, the Multi-dimensional Scale of Perceived Social Support, the Herth Hope Index, and a questionnaire about FCs' and patients' sociodemographic characteristics. Single-sample t tests, one-way analysis of variance, and multivariate linear regression analysis were used to analyze the data analysis. RESULTS: Participating FCs had significantly lower scores in all eight SF-36 domains compared with the general population in China (p < 0.01). FCs' gender, education, daily care time, anxiety, and the perceived disease severity of patients were significant predictors of SF-36 physical component summary scores. Caregiving help from others, anxiety, perceived disease severity, and medical insurance type were significant predictors of SF-36 mental component summary scores. CONCLUSION: The findings showed FCs of patients with GD had lower HRQoL. There is an urgent need to address the health concerns of FCs of people with rare diseases including their HRQoL.

Living with Gaucher disease: Emotional health, psychosocial needs and concerns of individuals with Gaucher disease.

Gaucher disease (GD) is the most common hereditary lysosomal storage disorder. Of the three variants of GD, type 1 accounts for 90% of cases. Patients with GD suffer from multiple medical symptoms and conditions. Clinical features of type 1 GD include hepatosplenomegaly; hematologic complications such as anemia and thrombocytopenia; and skeletal disease leading to avascular necrosis, osteopenia, and osteosclerosis. GD has unique features as a chronic illness: the disorder often presents with mild symptoms, and is frequently diagnosed in later childhood or adulthood. The treatment, enzyme replacement therapy (ERT), is efficacious. However, that same effective treatment is intrusive, expensive, and requires that patients restructure their work and personal schedules. Since the age of presentation can be anywhere between infancy and the eighth decade, the diagnostic process can be prolonged and stressful. The success of ERT notwithstanding, GD patients show distinct psychological complications [Packman et al. (2006); J Inherit Metab Dis 29:99-105]. In the present study, we describe the concerns, needs, challenges and positive effects of GD from the patients' perspective using in depth interviews of 28 individual affected by GD. Five core themes emerge: (1) difficulty coping with the diagnosis; (2) impact of pain on work, career, and recreational activities; (3) insurance concerns; (4) psychological distress (e.g., mood changes and anxiety); and (5) positive effects-strengthened family and social relationships and positive outlook. Our results highlight and expand awareness of the psychological and social needs of GD patients. This study calls for a collaborative, multidisciplinary effort in treating these patients and their families.

Psychological aspects of patients with Fabry disease.

The Minnesota Muliphasic Personality Inventory (MMPI-2) is widely used in chronic illness and chronic pain populations to assess psychological functioning. We report the results of the first investigation using the MMPI-2 to assess psychological aspects of patients with Fabry disease. Fabry disease, an X-linked lysosomal storage disorder, is a multisystem progressive disease affecting the kidney, heart, and central nervous system, and is particularly associated with chronic symptoms including pain. In this study, 28 patients with Fabry disease completed the MMPI-2 and a background questionnaire. Fabry disease patients scored significantly higher than the MMPI-2 normative sample on seven clinical scales (Hs, D, Hy, Pd, Pa, Pt, Sc) and two validity scales (L, F). Individuals with elevated scores on the Hs, D, and Hy scales tend to have somatic complaints, sadness, and emotional distress. Under stress, they may experience an increase in physical symptoms. Elevated Pd, Pa, Pt, and Sc scales suggest social maladjustment, suspiciousness, and feelings of isolation. An elevated L scale suggests defensiveness; a high score on F suggests emotional turmoil. When compared with cohorts of patients with Gaucher disease (GD), chronic heart disease (CRHD), and chronic pain, the Fabry disease patients had significantly higher scores than GD patients and CRHD patients on numerous clinical (Hs, D, Si), and validity (F) scales underscoring the relative amount of suffering and pain experienced by Fabry disease patients. No significant differences on any MMPI-2 scales were found between the Fabry disease patients and the pain patients, suggesting that Fabry disease patients may be comparable to pain patient populations.

Psychiatric manifestations in Egyptian Gaucher patients on enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) may include psychiatric symptoms as a part of its wide spectrum of manifestations, with several reports describing its association with mood or psychotic symptoms. We investigated the presence of psychiatric manifestations in an Egyptian sample of Gaucher Disease (GD) patients. METHODS: Our sample consisted of 22 GD patients (diagnosed by low glucocerebrosidase (GBA) activity in leukocytes or fibroblasts and molecular analysis by full (GBA) gene sequencing). 13 patients were classified as GD type 1 and 9 patients as GD type 3. We assessed the presence of psychiatric symptoms using the Mini-international neuropsychiatric interview (M.I.N·I) and the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) tools. Arabic versions were used. RESULTS: The results showed that 41% of the sample had psychiatric disorders, with the most common being depression. None was receiving any form of psychiatric treatment. We found no statistically significant association between the presence of psychiatric disorders and any of the clinical variables of GD, its phenotype, or genotype. CONCLUSION: The current results suggest that GD patients are susceptible to psychiatric disorders. However, these results need to be replicated on a wider scale. These findings are of ultimate importance, considering the lack of integrated services addressing both the medical and psychological aspects of inborn errors of metabolism in many countries.

Neurological evaluation of patients with Gaucher disease diagnosed as type 1.

Type 1 Gaucher disease (GD1) is characterised by lack of central nervous system involvement; however, there are several reports of associated neurological manifestations. The aim of this study was to systematically evaluate neurological manifestations in 31 patients with GD1 (12 males and 19 females; mean age 39.4 (range 5-77) years). Participants underwent a complete neurological examination and cognitive tests. Investigation of symptoms and medication intake, and motor and sensory electroneurograms were obtained. 30.7% of adult patients had neurological deficits, including psychomotor delay, parkinsonism, dementia, impaired saccadic ocular movements and peripheral nerve dysfunction. Three patients were redefined as type 3 GD. Electrodiagnosis was performed on 15 patients; 26.7% had reduced amplitude and/or abnormal waveforms in at least three nerves, 33.3% had a mild reduction in amplitude of two nerves and 40% had amplitude reduction in one nerve. Patients with three or more affected nerves had additional neurological symptoms. Our results demonstrate that neurological alterations occur in patients diagnosed with GD1, and subclinical peripheral neuropathy is a frequent finding.

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

Intravenous enzyme replacement therapy: better in home or hospital?

This article evaluates satisfaction with enzyme replacement therapy (ERT) at home and at hospital in adult patients with Fabry and Gaucher diseases. A questionnaire was developed and sent to 34 patients with Fabry disease who were receiving ERT with agalsidase alfa (Replagal) and to 49 patients with type I Gaucher disease who were receiving ERT with glucocerebrosidase (Cerezyme). Of the 45 returned questionnaires, 20 were from patients with Fabry disease and 25 from patients with Gaucher disease. Hospital treatment visits were reported as stressful by 18 patients (40%), whereas only 4 (9%) patients reported that home therapy was stressful. Both groups of patients adjusted well to receiving home-based therapy. Nearly all of the patients with Fabry disease (19 patients, 95%) and Gaucher disease (21 patients, 84%) preferred home-based therapy. Treatment in the home was reported as more comfortable, less stressful, more effective and had less impact on family life. Only 4 (9%) patients chose to continue receiving infusions in hospital. The majority of patients with Fabry disease and Gaucher disease found home-based therapy to be more convenient and less stressful than hospital-based therapy.

Color Discrimination in Patients with Gaucher Disease and Parkinson Disease.

BACKGROUND: Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the ß-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. OBJECTIVE: The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. METHODS: The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. RESULTS: Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. CONCLUSIONS: These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients.

Medical conditions in Ashkenazi schizophrenic pedigrees.

To limit the genetic heterogeneity of schizophrenia, this study focused on the widely extended pedigrees of Ashkenazi Jewish schizophrenia probands. The hypothesis posed is that the increased prevalence among the Ashkenazim of the rare lysosomal enzyme disorders, Tay Sachs disease (TDS), caused by low levels of hexosaminidase A, and Gaucher's disease (GD), caused by low levels of glucocerebrosidase, might contribute to the demonstrated increased vulnerability to schizophrenia in this ethnic group. Signs and symptoms characterizing the candidate illnesses were systematically queried by the family history method. Rates and relative risks for symptoms characterizing these disorders and for several nonautosomal illnesses associated with TSD and/or GD (i.e., amyotrophic lateral sclerosis and Hodgkin's disease, leukemia and lymphoma) are significantly elevated in the schizophrenia pedigrees, compared to controls. The conditions with elevated rates and risks have been associated with chromosomal regions 1q21 and 15q23-q24. These areas are suggested as candidate regions for future targeted deoxyribonucleic acid (DNA) research in schizophrenia.

The effect of search procedures on utility elicitations.

OBJECTIVE: Elicited preferences for health states vary among scaling methods, manners of describing health states, and other features of the elicitation process. The authors examined the effects of changing the search procedure for a subject's utility on mean utility values. METHODS: A randomized controlled trial of two search procedures (titration and "ping-pong") using two otherwise identical computer programs that describe health states related to Gaucher's disease, then measuring subjects' preferences. SETTING: Paid, healthy volunteers recruited from the community through advertisements. RESULTS: The mean time tradeoff (TTO) and standard gamble (SG) utility values for life with severe anemia and splenomegaly and life with chronic bone pain from Gaucher's disease were between 0.10 and 0.15 higher with the titration search procedure than with the ping-pong procedure. Effects of the search procedure were additive with variability due to scaling methods, resulting in mean differences in utility ratings for the same health state of as much as 0.28 among procedures and scaling methods. Effects of search procedures on utility values persisted on repeated testing at week 2 and week 3; there was no evidence of convergence to a single "true" utility value over time. CONCLUSIONS: The procedure used to search for subjects' utility values strongly influences the results of preference-assessment experiments. Effects of search procedures persist on repeated testing. The results suggest that utility values are heavily influenced by, if not created during, the process of elicitation. Thus, utility values elicited using different search procedures may not be directly comparable.

Gaucher disease (type III): intellectual profile.

In 20 patients with Gaucher disease type III (Norrbottnian variant), long-term intellectual prognoses were analyzed on the basis of psychometric tests which were performed on an average of five tests per patient. Intellectual delay was not found to be characteristic of the early stages of the disease. Slow regression occurred through childhood and adolescence. Patients splenectomized at an early stage averaged lower IQ scores in the long-term than those in whom the spleen had been spared as long as possible. These data added to other evidence of increased neurologic and other organ impairment after splenectomy, support the view that the spleen should not be removed in other than emergent situations.

Collaborative research.

Our experience of collaborative research "the process of working with others in pursuit of scientific discovery" has been a most rewarding experience. The nurses and physicians have developed mutual respect and appreciation of the value of each other's practice, and true collaboration has emerged. The relationships between the nurses and physicians have developed over time and have been supported by our visionary Associate Director for Nursing, Kathryn McKeon. Throughout this process of collaboration, we've grown to appreciate each others strengths and recognize what each discipline has to offer. We have also learned that when we work together, it is the patient who ultimately benefits most. The neurologists' holistic approach to patient care and their respect for nursing practice have greatly contributed to the establishment of truly collaborative research.

Gaucher's disease: a pilot study of the symptomatic responses to enzyme replacement therapy.

Symptomatic responses to enzyme replacement therapy were studied in 12 patients with an inherited lipid storage disorder (Type 1 Gaucher's disease) in order to determine the impact of treatment on perceptions of well being. Before each intravenous infusion of enzyme, patients were asked to comment on the presence or absence of disease-specific symptoms presented in questionnaire format. Symptoms were grouped into five major categories: bleeding abnormalities, chronic fatigue, gastrointestinal complaints, bone pain and psychosocial function. Each reported symptom was discussed in detail with the clinic nurse coordinator and documented in the medical record. After six months of enzyme replacement therapy, each patient's chart was reviewed and changes in the frequency of disease-specific symptoms over time were evaluated. The major subjective changes included a decrease in the frequency and severity of nosebleeds, reduced bruising, increased vigor and energy level, visible reduction in abdominal girth, increased self-esteem and enhanced self-image. Patients frequently described relief of their symptoms well before changes were confirmed by objective laboratory measurements. These observations may prove useful in the comprehensive management of patients with Gaucher's disease as they recover from a chronic, debilitating illness while receiving enzyme replacement therapy. The extent and ease with which these patients can achieve a state of normal, healthy function is unknown at the present time and will require further study.