White vitreous opacities in five patients with Gaucher disease type 3.

Fundal abnormalities, including preretinal and retinal changes, are a rare finding in patients with the autosomal recessive lysosomal storage disorder Gaucher disease, most often described in patients with the chronic neuronopathic form (type 3). We evaluated whether these ophthalmological findings correlated with other manifestations of type 3 Gaucher disease. Reviewing the records of 40 patients with type 3 Gaucher disease, we identified five with white vitreous opacities and reviewed their clinical course in depth. Each of the patients described decreased visual acuity and "floaters" obstructing their vision. The development and/or progression of these fluffy-appearing white opacities in each patient were tracked longitudinally in the context of their neurological and other clinical findings. It was noted that all five patients shared genotype p.L483P/p.L483P (L444P/L444P) and had significant neurological, oculomotor and bone involvement and two had undergone splenectomy. Enzyme replacement therapy with recombinant glucocerebrosidase did not prevent the development or progression of these ocular opacities. Since preretinal findings, in addition to other neuro-ophthalmological findings, can be a feature of Gaucher disease, it is recommended that patients be monitored by regular eye examinations.

GBA1-associated parkinsonism: new insights and therapeutic opportunities.

PURPOSE OF REVIEW: GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options. RECENT FINDINGS: The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress. SUMMARY: As our understanding of GBA1-associated Parkinson disease increases, new treatment opportunities emerge. MicroRNA profiles are providing examples of both up-regulated and down-regulated proteins related to GBA1 and may provide new therapeutic targets. Chaperone therapy, directed at either misfolded glucocerebrosidase or α-synuclein aggregation, is currently under development and there are several early clinical trials ongoing. Substrate reduction therapy, aimed at lowering the accumulation of metabolic by-products, especially glucosylsphingosine, is also being explored. Basic science insights from the rare disorder Gaucher disease are serving to catapult drug discovery for parkinsonism.

Ophthalmological findings in Gaucher disease.

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the gene GBA1, which encodes the lysosomal protein glucocerebrosidase. Patients with Gaucher disease generally have a variety of clinical manifestations ranging from visceral to neurological involvement and some develop ocular involvement. The most commonly affected organs include the spleen, liver, and bone. Moreover, patients often have hepatosplenomegaly, thrombocytopenia, anemia, and bone involvement related to deficient glucocerebrosidase and the subsequent accumulation of glucosylceramide and glucosylsphingosine in cells. A subset of patients develops neurological manifestations, including seizures, myoclonic epilepsy, and progressive neurodegeneration. Eye involvement tends to be less common and presents with diverse clinical findings. These rare and variable ocular manifestations, involving the vitreous, retina, cornea, uvea, conjunctiva and eye movements, can pose a diagnostic challenge for clinicians, especially those not familiar with the disorder. In this review, we explore the different ophthalmologic findings reported in patients with Gaucher disease, aiming to facilitate diagnosis and expedite treatment for patients presenting with ocular manifestations of this rare disorder.

Five-parameter evaluation of dysphagia: A novel prognostic scale for assessing neurological decline in Gaucher disease type 2.

BACKGROUND: Gaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2. METHODS: A post-hoc analysis of modified barium swallow studies was performed. Six parameters of swallowing were scored in a retrospective chart review of eleven infants with GD2. Mixed effects regression, principal component analysis (PCA), and a transition analysis were used to evaluate swallow function and model disease progression. RESULTS: All patients exhibited impaired swallow function. There was no association between any of the swallow parameters and age, indicating non-linear disease progression. PCA and transition analysis identified five parameters capturing multiple dimensions of swallowing which defined two distinct disease states. CONCLUSION: A five-parameter swallow evaluation was sufficient to identify distinct states of GD2 and model prospective outcomes. This multi-dimensional evaluation could be a useful efficacy parameter for future therapeutic trials in GD2 and other neurodegenerative disorders of infancy.

Rapid neurodevelopmental recovery after ART initiation in an infant with HIV encephalopathy.

While there is ample evidence that antiretroviral therapy (ART) can improve cognitive outcomes in older children living with HIV, encephalopathy in infants has historically been considered an advanced disease presentation with less likelihood of neurodevelopmental recovery on treatment. More recent studies suggest that timely ART can halt encephalopathic disease progression and even lead to symptom resolution. Here we present a case of an HIV-positive infant diagnosed with encephalopathy who experienced impressive and rapid improvement with a multi-disciplinary care approach that included physical and occupational therapy and ART.

Asymmetric Lower Extremity Involvement and Facial Palsy: An Atypical Case of Guillain-Barre Syndrome.

Guillain-Barre syndrome (GBS) represents the most common cause of acute flaccid paralysis and is characterized by muscle weakness frequently accompanied by respiratory and bulbar paralysis which oftentimes can be life-threatening. Early recognition and intervention are essential to prevent potential complications and help hasten recovery. Herein, we report a case of a middle-aged female who presented with nonspecific gastrointestinal symptoms that were shortly followed by a unique combination of new-onset facial diplegia and asymmetric lower extremity areflexia. Treatment with intravenous immunoglobulins (IVIG) was initiated following a prompt diagnosis of GBS was made. Clinicians should always be vigilant about the possibility of GBS in the appropriate clinical setting and be aware of the essentials of management of this potentially treatable disease.

The natural history of type 2 Gaucher disease in the 21st century: A retrospective study.

OBJECTIVE: To gather natural history data to better understand the changing course of type 2 Gaucher disease (GD2) in order to guide future interventional protocols. METHODS: A structured interview was conducted with parents of living or deceased patients with GD2. Retrospective information obtained included disease presentation, progression, medical and surgical history, medications, family history, management, complications, and cause of death, as well as the impact of disease on families. RESULTS: Data from 23 patients were analyzed (20 deceased and 3 living), showing a mean age at death of 19.2 months, ranging from 3 to 55 months. Fourteen patients were treated with enzyme replacement therapy, 2 were treated with substrate reduction therapy, and 3 underwent bone marrow transplantation. Five patients received ambroxol and one was on N-acetylcysteine, both considered experimental treatments. Fifteen patients had gastrostomy tubes placed; 10 underwent tracheostomies. Neurologic disease manifestations included choking episodes, myoclonic jerks, autonomic dysfunction, apnea, seizures, and diminished blinking, all of which worsened as disease progressed. CONCLUSIONS: Current available therapies appear to prolong life but do not alter neurologic manifestations. Despite aggressive therapeutic interventions, GD2 remains a progressive disorder with a devastating prognosis that may benefit from new treatment approaches.