Chronic Neuronopathic Gaucher Disease Research Articles

A review of type 3 Gaucher disease: unique neurological manifestations and advances in treatment.

Gaucher disease (GD) is a rare lysosomal storage disease that is caused by mutations in the GBA gene. It is classified into three main phenotypes according to the patient's clinical presentation. Of these, chronic neuronopathic GD (GD3) is characterized by progressive neurological damage. Understanding the unique neurological manifestations of GD3 has important diagnostic and therapeutic implications. Our article summarizes the neurological symptoms specific to GD3 and related therapeutic advances, and it highlights the relevance of the gene to clinical symptoms, so as to provide a reference for the diagnosis and treatment of GD3.

Kyphoscoliosis in Egyptian patients with chronic neuronopathic Gaucher disease over 16 years: Part of disease phenotype or a marker of disease severity

Kyphoscoliosis in Egyptian patients with chronic neuronopathic Gaucher disease over 16 years: Part of disease phenotype or a marker of disease severity

ХИРУРГИЧЕСКОЕ ЛЕЧЕНИЕ ТЯЖЕЛОЙ КИФОСКОЛИОТИЧЕСКОЙ ДЕФОРМАЦИИ ПОЗВОНОЧНИКА У ДВЕНАДЦАТИЛЕТНЕЙ ПАЦИЕНТКИ С БОЛЕЗНЬЮ ГОШЕ 3-го ТИПА: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Gaucher disease (GD) is an autosomal recessive genetic disease characterized by the accumulation of glucocerebroside in the lysosomes of macrophages of the reticuloendothelial system with the development of cytopenia, hepatosplenomegaly, bone lesions, and, in some cases, neurological disorders. Skeletal manifestations vary in severity and usually affect long bones with clinical presentation of bone pain, bone crises, avascular necrosis, decreased bone mineral density, and pathological fractures. Involvement of the spine and chest in the form of their deformities has an unclear mechanism of development and is mostly applied in neuronopathic forms of the disease, in particular, the type 3 GD. The authors represent a unique clinical case of successful treatment of severe kyphoscoliotic deformity in an adolescent with the type 3 GD. The routine monitoring of the spine in patients with chronic neuronopathic GD is necessary in order to perform the timely surgical intervention and to prevent the progression of the spinal deformity and neurological deficit.

Neuropathological Features of Gaucher Disease and Gaucher Disease with Parkinsonism.

Deficient acid β-glucocerebrosidase activity due to biallelic mutations in GBA1 results in Gaucher disease (GD). Patients with this lysosomal storage disorder exhibit a wide range of associated manifestations, spanning from virtually asymptomatic adults to infants with severe neurodegeneration. While type 1 GD (GD1) is considered non-neuronopathic, a small subset of patients develop parkinsonian features. Variants in GBA1 are also an important risk factor for several common Lewy body disorders (LBDs). Neuropathological examinations of patients with GD, including those who developed LBDs, are rare. GD primarily affects macrophages, and perivascular infiltration of Gaucher macrophages is the most common neuropathologic finding. However, the frequency of these clusters and the affected anatomical region varies. GD affects astrocytes, and, in neuronopathic GD, neurons in cerebral cortical layers 3 and 5, layer 4b of the calcarine cortex, and hippocampal regions CA2–4. In addition, several reports describe selective degeneration of the cerebellar dentate nucleus in chronic neuronopathic GD. GD1 is characterized by astrogliosis without prominent neuronal loss. In GD-LBD, widespread Lewy body pathology is seen, often involving hippocampal regions CA2–4. Additional neuropathological examinations in GD are sorely needed to clarify disease-specific patterns and elucidate causative mechanisms relevant to GD, and potentially to more common neurodegenerative diseases.

EEG abnormalities in patients with chronic neuronopathic Gaucher disease: A retrospective review

The clinical phenotype of Gaucher disease type 3 (GD3), a neuronopathic lysosomal storage disorder, encompasses a wide array of neurological manifestations including neuro-ophthalmological findings, developmental delay, and seizures including progressive myoclonic epilepsy. Electroencephalography (EEG) is a widely available tool used to identify abnormalities in cerebral function, as well as epileptiform abnormalities indicating an increased risk of seizures. We characterized the EEG findings in GD3, reviewing 67 patients with 293 EEGs collected over nearly 50 years. Over 93% of patients had some form of EEG abnormality, most consisting of background slowing (90%), followed by interictal epileptiform discharges (IEDs) (54%), and photoparoxysmal responses (25%). The seven patients without background slowing were all under age 14 (mean 6.7 years). There was a history of seizures in 37% of this cohort; only 30% of these had IEDs on EEG. Conversely, only 56% of patients with IEDs had a history of seizures. These observed EEG abnormalities document an important aspect of the natural history of GD3 and could potentially assist in identifying neurological involvement in a patient with subtle clinical findings. Additionally, this comprehensive description of longitudinal EEG data provides essential baseline data for understanding central nervous system involvement in neuronopathic GD.

Scoliosis in chronic neuronopathic Gaucher disease: Characterization in the treatment era

Intraoperative monitoring (IOM) using somatosensory-evoked potentials (SSEPs) plays an important role in reducing iatrogenic neurologic deficits during corrective pediatric idiopathic procedures for scoliosis. However, for unknown reasons, recent reports have cited that the sensitivity of SSEPs to detect neurologic deficits has decreased, in some to be less than 50%. This current trend, which is coincident with the addition of transcranial motor-evoked potentials, is surprising given that SSEPs are robust, reproducible responses that were previously shown to have sensitivity and specificity of >90%.Our primary aim was to assess whether SSEPs alone can detect impending neurologic deficits with similar sensitivity and specificity as originally reported. Our secondary aim was to estimate the potential predictive value of adding transcranial motor-evoked potentials to SSEP monitoring in idiopathic scoliosis procedures.This was a retrospective review to analyze the efficacy of SSEP monitoring in the group of pediatric instrumented scoliosis fusion cases.We retrospectively reviewed all consecutive cases of patients who underwent idiopathic scoliosis surgery between 1999 and 2009 at Children’s Hospital of Pittsburgh. We identified 477 patients who had the surgery with SSEP monitoring alone. Exclusion criteria included any patients with neuromuscular disorders or unreliable SSEP monitoring. Patients who had incomplete neurophysiology data or incomplete postoperative records were also excluded.Major outcomes measured were clinically significant postoperative sensory or motor deficits, as well as significant intraoperative SSEP changes.Continuous interleaved upper- and lower-extremity SSEPs were obtained throughout the duration of all procedures. We considered a persistent 50% reduction in primary somatosensory cortical amplitude or a prolongation of response latency by >10% from baseline to be significant. Persistent changes represent significant deviation in SSEP amplitude or latency in more than two consecutive averaged trials. Patients were classified into one of four categories with respect to SSEP monitoring: true positive, false positive, true negative, and false negative. The sensitivity, specificity, positive predictive value, and negative predictive value were then calculated accordingly.Our review of 477 idiopathic scoliosis surgeries monitored using SSEPs alone revealed a new deficit rate of 0.63% with no cases of permanent injury. Sensitivity = 95.0%, specificity = 99.8%, positive predictive value = 95%, negative predictive value = 99.8%. Using evidence-based epidemiologic measures, we calculated that the number needed to treat was 1,587 patients for one intervention to be performed that would have been missed by SSEP monitoring alone. In addition, the number needed to harm, which represents the increase in false positives with the addition of transcranial electrical motor-evoked potentials, was 200.SSEP monitoring alone during idiopathic scoliosis continues to be a highly reliable method for the detection and prevention of iatrogenic injury. Our results confirm the high sensitivity and specificity of SSEP monitoring alone published in earlier literature. As such, we suggest the continued use of SSEP alone in idiopathic scoliosis surgeries. At this time we do not believe there are sufficient data to support the addition of MEP monitoring, although more studies and revised criteria for the use of MEP may provide added value for its use in the future.

Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease

Pathological mutations in GBA, encoding lysosomal glucocerebrosidase (GCase), cause Gaucher disease (GD). GD is a multi-system disease with great phenotypic variation between individuals. It has been classified into type 1 with primarily peripheral involvement and types 2 and 3 with varying degrees of neurological involvement. GD is characterized by decreased GCase activity and subsequent accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Current murine models of neuronopathic GD mostly replicate the severe aspects of the neurological symptoms developing rapid progression and early lethality, thus presenting a short window for therapeutic testing. In order to develop a model of chronic neuronopathic GD, we reduced GCase in the central nervous system (CNS) of a mild GD mouse model (GbaD409V/D409V) via intracerebroventricular administration of an adeno-associated virus encoding a microRNA to Gba (AAV-GFP-miR-Gba). GbaD409V/D409V mice have significantly reduced GCase activity and increased substrate accumulation in the CNS. Phenotypically, these mice partially recapitulate features of mild type 1 GD. Their neurological examination reveals cognitive impairment with normal motor features. Administration of AAV-GFP-miR-Gba into GbaD409V/D409V pups in the CNS caused progressive lipid substrate accumulation. Phenotypically, AAV1-GFP-miR-Gba-treated mice were indistinguishable from their littermates until 10 weeks of age, when they started developing progressive neurological impairments, including hyperactivity, abnormal gait, and head retroflexion. Importantly, these impairments can be prevented by simultaneous administration of a miR-resistant GBA, demonstrating that the pathological effects are specifically due to Gba mRNA reduction. This novel model of neuronopathic GD offers several advantages over current models including slower progression of neurological complications and an increased lifespan, which make it more amenable for therapeutic testing.

AB120. Cholelithiasis in a Filipino child with chronic neuronopathic Gaucher disease: report of a case

AB120. Cholelithiasis in a Filipino child with chronic neuronopathic Gaucher disease: report of a case

Saccadic Impairments in Patients with the Norrbottnian Form of Gaucher's Disease Type 3.

Chronic neuronopathic Gaucher's disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3. To characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique. Horizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41.1 ± 11.0 years; modified severity scoring tool (mSST): 9.3 ± 5.4; Montreal Cognitive Assessment (MoCA): 24.0 ± 4.2] and age-matched controls were analyzed using EyeBrain T2, a head-mounted binocular eye tracker. Systematic clinical assessment included the mSST, a valid tool for monitoring the neurological progression in GD3 and MoCA. In Norrbottnian GD3 patients, gain, peak, and average velocity (107.5°/s ± 41.8 vs. 283.9°/s ± 17.0; p = 0.0009) of horizontal saccades were reduced compared to healthy controls (HCs). Regarding vertical saccades, only the average velocity of downward saccades was decreased (128.6°/s ± 63.4 vs. 244.1°/s ± 50.8; p = 0.004). Vertical and horizontal saccadic latencies were increased (294.3 ms ± 37.0 vs. 236.5 ms ± 22.4; p = 0.005) and the latency of horizontal reflexive saccades was correlated with the mSST score (R2 = 0.80; p = 0.003). The latency of antisaccades showed association to MoCA score (R2 = 0.70; p = 0.009). GD3 patients made more errors in the antisaccade task (41.5 ± 27.6% vs. 5.2 ± 5.8%; p = 0.005), and the error rate tended to correlate with the cognitive function measured in MoCA score (p = 0.06). The mean age of 41 years of our GD3 cohort reflects the increased life expectancy of patients in the Norrbottnian area compared to other GD3 cohorts. Marked impairment of horizontal saccades was evident in all patients, whereas vertical saccades showed distinct impairment of downward velocity. Latency of reflexive saccades was associated with the severity of neurological symptoms. Increased latency and error rate in the antisaccade task were linked to cognitive impairment. The assessment of saccades provides markers for neurological and neuropsychological involvement in Norrbottnian GD3.

Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report

BackgroundThe variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood–brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood–brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.Case presentationWe report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.ConclusionsThis case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease

Gaucher disease (OMIM #230800) is caused by β-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T>C (NM_000157.3) GBA mutation) who at 16years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

Bilateral symmetrical cortical osteolytic lesions in two patients with Gaucher disease

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder characterized by the reduced or absent activity of glucocerebrosidase. The disease is split into three types. Type 3, or chronic neuronopathic GD, manifests with heterogeneous clinical presentations. Skeletal manifestations of GD can include abnormal bone remodeling resulting in the characteristic Erlenmeyer flask deformities, painful bone crises, osteopenia, and an increased frequency of fractures. Osteolytic lesions can also occur but are rare and tend to be large, expanding intramedullary lesions with cortical thinning. We present two adolescent patients with type 3 GD who developed bilateral symmetrical cortical osteolytic lesions. The lesions in both cases demonstrate predominant cortical scalloping with fairly indolent growth. Neither patient manifests some of the more common bony manifestations of GD--bone crises or osteonecrosis. These atypical and unique skeletal findings in two unrelated probands with type 3 GD further expand the extent of phenotypic variation encountered in this single gene disorder.

Cognitive Outcome in Treated Patients with Chronic Neuronopathic Gaucher Disease

To investigate the spectrum and prevalence of cognitive deficits among children with type 3 (chronic neuronopathic) Gaucher disease (GD). A case review study identified 32 children (male/female; 17:15) with type 3 GD who had received enzyme replacement therapy (ERT) or a bone marrow transplant. The diagnosis of GD was established by enzymatic assay and DNA testing. Subjects were assessed with standard neuropsychological testing, and data from the most recent evaluation were included. Neuropsychometric assessments demonstrated a wide spectrum of full-scale IQ scores ranging from 39 to 124 (mean 75). About 60% of subjects had intellectual skills below average. There were significant discrepancies between verbal and performance IQ, with a range between -6 and 38 points (P = .02). This gap was more prominent in older subjects, with better performance in the verbal areas. No correlation was observed between intelligence measures and genotype or the extent of systemic involvement. The dosage, age at initiation, and the length of ERT had no significant effect on IQ scores. In type 3 GD, cognitive deficits, characterized by visual-spatial dysfunction, are common but underappreciated and appear resistant to ERT.

Brain Involvement—The Ultimate Challenge

Lysosomal storage disorders (LSDs) typically present with a spectrum of phenotypes. More severe disease in terms of progression and complications is usually seen in patients with early neuronopathic manifestations. The primary central nervous system (CNS) pathology has traditionally been thought to be caused mainly by intracerebral storage of undegraded substrates of the deficient lysosomal enzymes. Visceral organs such as the liver, spleen, and kidney are easily reached by IV administration of enzyme replacement therapy. These therapies can overcome and prevent local substrate accumulation, whereas avascular tissues, such as cartilage and cornea, are not within reach for circulating enzymes. The brain presents a particular challenge, as the blood‐brain barrier (in health) prevents therapeutic enzymes from entering brain parenchyma. Despite this, some clinical indications of (partial) CNS progression/prevention effects of various “systemic-intended” enzyme replacement therapies in neuronopathic patients, especially with Gaucher disease, mucopolysaccharidosis (MPS) I, and MPS II, have been observed. As a result, additional adapted ideas regarding the possible etiopathology of CNS manifestations in LSDs have emerged. Among these are questioning whether the blood‐brain barrier is “leaky” in some LSDs, whether secondary damage to the brain can be a consequence of systemic disease (eg, hypoxia in MPS with sleep apneas), and whether aggregation of mutated proteins could cause disruption of neuronal cell function. New management approaches have also emerged. Among them is earlier and higher doses of IV enzyme replacement therapy. One concern with this treatment is that antigenicity may play a more important role in neuronopathic patients since they often have more nonsense mutations. The impact of antigenicity and immune response, especially in the CNS, to repeated delivery of exogenous proteins must be studied in more detail in animal models (MPS IIIA, MPS I). Another approach is the development of strategies to bypass the blood‐brain barrier, specifically targeting therapeutic enzymes to the CNS and peripheral nervous system. Lonser et al 1 recently published an approach with “direct convective delivery” of glucocerebrosidase in the CNS of 1 patient with chronic neuronopathic Gaucher disease. Other pharmacologic delivery techniques have been investigated, but they are limited in how they can be used clinically. Yet other therapeutic strategies—such as substrate reduction therapy, enzyme enhancement with chaperones, or gene therapy—have the theoretical potential to be effective in the brain but may have to be combined with enzyme replacement therapy. It is clear that specific advanced pathophysiologic changes (eg, neuronal cell loss, ectopic dendritogenesis) are not reversible; hence, early diagnosis, referral, intervention, and prevention are essential. The success of old and new therapeutic strategies depends on a small and early time window critical for intervention. In addition, timely and adequate use of supportive therapies and interventions is needed (eg, positive pressure ventilation in MPS, antiepileptic agents in Gaucher disease). Systematic and collaborative research in this field is warranted. Therefore, natural history studies, with a focus on manifestation and progression of neurologic signs and symptoms, as well as new techniques to examine and measure “neuronopathic disease,” are needed.

GAUCHER DISEASE AND MISCELLANEOUS

Abstract Introduction: The most common subtype of Gaucher disease is the non‐neuronopathic form with only visceral symptoms. At the opposite end of the spectrum is chronic neuronopathic Gaucher disease with severe neurological symptoms and typically a decreased life span. Methods: We report 15 patients (median age at manifestation, 1.2 years) with chronic neuronopathic Gaucher disease and 20 patients with non‐neuronopathic Gaucher disease (median age at manifestation, 3.0 years). Results: In most patients with chronic neuronopathic Gaucher disease (12 out of 15), the 1448T‐C mutation was found, whereas in 18 out of 20 patients with non‐neuronopathic Gaucher disease the mutation identified was N370S. At initial presentation, patients with chronic neuronopathic Gaucher disease had significantly higher chitotriosidase levels (median, 21 307 versus 5611 nmol/ml/hour). Thirteen of these patients had a strabismus, all patients suffered from saccade initiation failure, and eight of the nine patients assessed showed abnormal brainstem auditory evoked response (BAER) (none of these were found in patients with non‐neuronopathic disease). Three of the patients with neuronopathic disease had multifocal myoclonic epilepsy. Additionally, in ten of these patients pulmonary manifestation was seen (versus three of the patients with non‐neuronopathic Gaucher disease). After treatment with enzyme replacement therapy (60–120 IU/kg) for between 18 months and 8 years, three of the children with chronic neuronopathic Gaucher disease experienced an improvement in BAER. Eight out of the nine patients with bone pain before enzyme replacement therapy had no pain. The patients with non‐neuronopathic Gaucher disease received 60 IU/kg or less to maintain their therapy response and were observed for 3–13 years. Conclusion: Neurological manifestations are often associated with chitotriosidase activities greater than 20 000. In patients with chronic neuronopathic Gaucher disease, a higher dose between 60 and 120 IU/kg bodyweight may be required to reduce the visceral manifestations of disease.