Qualitative Study of the Patient Experience with Venglustat for Gaucher Disease Type 3 in a Phase 2 Open-Label, Multicenter, Multinational Study (LEAP).

INTRODUCTION: Gaucher disease type 3 (GD3) is a genetic, progressive lysosomal storage disorder characterized by visceral manifestations and chronic neurologic symptoms (e.g., horizontal ophthalmoplegia/supranuclear gaze palsy, ataxia, dystonia). The investigational agent venglustat is being studied in combination with imiglucerase as potential treatment for systemic and neuronopathic manifestations of GD3 in a single-arm, open-label, phase 2 trial (LEAP; N = 11). To understand perceived changes in GD3 symptoms from the perspectives of patients, caregivers, and clinicians, we conducted a qualitative case study of selected LEAP participants. METHODS: Four patients in LEAP (age range, 20-28 years), four of their caregivers, and three clinicians involved in LEAP were interviewed individually by moderators using semi-structured guides. Clinicians' perceptions were based on observation of interviewed patients and those in LEAP who were not interviewed, as well as information provided by other staff involved in LEAP, patients, and caregivers. RESULTS: Reported changes in GD3 symptoms varied among patients and among reporters. Only eye movement was spontaneously mentioned as improved by at least one patient, caregiver, and clinical expert. Symptom improvement also varied in terms of time to improvement. Within the first weeks, improvements were seen in understanding new information or complex instructions, remembering the weekday, eye movement, tremor, and seizures. Changes in alertness, engagement and responsiveness, memory, and concentration appeared after months or a year. Most caregivers and all clinical experts reported greater patient independence (e.g., increased ability to perform activities of daily living or travel independently during the trial) as a perceived treatment effect on a GD3 impact. For one patient who perceived benefits from venglustat therapy, pharmacokinetic analyses during LEAP found low to undetectable venglustat levels in their plasma and cerebrospinal fluid. CONCLUSION: Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02843035.

The diagnostic journey for patients with late-onset GM2 Gangliosidoses.

Late-onset forms of GM2 gangliosidosis-mainly, Tay-Sachs disease and Sandhoff disease-are under-recognized in clinical practice. In these rare lysosomal storage disorders, deficiency of ß-hexosaminidase A results in excessive accumulation of GM2 ganglioside primarily within neurons, leading to cell death and progressive neurodegenerative symptoms, including ataxia, dysarthria, muscle weakness, tremors, atrophy, and psychosis. Presentation is variable and often mimics more common neurodegenerative disorders. We conducted semi-structured interviews on GM2 gangliosidoses diagnosis and treatment with five experts, 30 neurologists, and 28 patients and caregivers. Symptom onset occurred during adolescence/early adulthood in 92% of patients (median age: 14 years). Patients first visited a healthcare provider at a median age of 20 years and received a GM2 diagnosis at a median age of 26 years. Nearly all patients reported problems with their legs and balance starting from symptom onset. Problems with memory, attention span, speech and fatigue were reported more after diagnosis. Patients visited an average of eight healthcare providers before receiving a diagnosis; 64% were diagnosed by a neurologist. Four neurologists (13%) in our sample were aware that there are late-onset forms of GM2 gangliosidosis. The path to diagnosis is long for this late-onset form of a classically fatal infantile disease.

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

The mutation pattern of mitochondrial DNA (mtDNA) in mainland Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) has been rarely reported, though previous data suggested that the mutation pattern of MELAS could be different among geographically localized populations. We presented the results of comprehensive mtDNA mutation analysis in 92 unrelated Chinese patients with MELAS (85 with classic MELAS and 7 with MELAS/Leigh syndrome (LS) overlap syndrome). The mtDNA A3243G mutation was the most common causal genotype in this patient group (79/92 and 85.9%). The second common gene mutation was G13513A (7/92 and 7.6%). Additionally, we identified T10191C (p.S45P) in ND3, A11470C (p. K237N) in ND4, T13046C (p.M237T) in ND5 and a large-scale deletion (13025-13033:14417-14425) involving partial ND5 and ND6 subunits of complex I in one patient each. Among them, A11470C, T13046C and the single deletion were novel mutations. In summary, patients with mutations affecting mitochondrially encoded complex I (MTND) reached 12.0% (11/92) in this group. It is noteworthy that all seven patients with MELAS/LS overlap syndrome were associated with MTND mutations. Our data emphasize the important role of MTND mutations in the pathogenicity of MELAS, especially MELAS/LS overlap syndrome.

Childhood chronic inflammatory demyelinating polyneuropathy with nonuniform pathologic features.

Nonuniform pathologic changes in chronic inflammatory demyelinating polyneuropathy were previously reported only in adult humans. We analyzed the pathologic features of 12 children, aged 2-17 years, with chronic inflammatory demyelinating polyneuropathy. Six patients manifested a preceding illness. Five patients presented a chronic, monophasic course, and seven presented a relapsing-remitting course. Three patients exhibited multiple cranial-nerve involvement. Five of 12 (41.7%) patients presented nonuniform features. Two subtypes of nonuniform lesions were revealed. One exhibited varying myelinated fiber content between nerve fascicles, and one exhibited onion bulbs involving a variable number of fascicles. Macrophages were evident in 11 patients, and the number of CD3-positive T cells in the nonuniform group was greater compared with the uniform group (P = 0.045). Our results demonstrate that childhood chronic inflammatory demyelinating polyneuropathy exhibits pathologically nonuniform features, thus providing more evidence to assist in differential diagnoses of pediatric patients. However, clinical and electrophysiologic features, as well as responses to treatment, were similar in the nonuniform and uniform groups.

[The clinical and pathological characteristics of a patient with glycogen storage disease IV].

OBJECTIVE: To report the clinical and pathological characteristics of one patient with glycogen storage disease IV (Anderson disease). METHODS: The patient was received detailed clinical examinations, ultrasound, electromyography, head MRI and muscle biopsy. RESULTS: The onset of the 22 years old male patient was 7 yrs. The main symptoms were intolerance and fatigue in proximal limbs muscular movement, cardiopalmus by chance. Abdominal ultrasound examinations showed cirrhosis, portal hypertension, splenomegaly. Echocardiogram showed left ventricular myohypertrophia, mild mitral and tricuspid valve insufficiency. Electrophysiology study revealed widespread myogenic changes. Cranial MRI, MRA and MRS were normal. Muscle biopsy showed basophilic intracytoplasmic material in a lot of fibers deposits, which was intensively PAS-positive material and partially resistant to diastase digestion. In the electron microscope, the storage material consisted of filamentous and finely granular material. CONCLUSIONS: There was the first case of glycogen storage disease IV reported in our country, mainly involved skeletal muscle, liver, spleen and cardiac muscle.

The overlap of corticobasal degeneration and Alzheimer changes: an autopsy case.

The aspects of various neurodegenerative diseases can be observed overlapping with each other during autopsy. Corticobasal degeneration (CBD) is a rare neurodegenerative disease, whereas Alzheimer disease (AD) is the most common cause of dementia. In this article, we present the combination of CBD and AD in an autopsy case. The patient, an 82-year-old right-handed woman developed asymmetrical parkinsonism, visuospatial dysfunction and memory loss, as well as subsequent non-influent aphasia over the past 10 years. The autopsy revealed characteristic CBD-related pathology, ballooned neurons, globose tangles and astrocytic plaques, mainly in the frontal cortex and basal ganglia. The Alzheimer-related pathology was also present concomitantly. Senile plagues deposited diffusively throughout the hippocampus and neocortices. Neurofibrillary tangles (NFTs) were more confined to the hippocampus. The autopsy demonstrated pathological overlap of CBD and AD, which therefore explained the clinical early development of dementia and parkinsonism. We should suspect the concurrence of various neurodegenerative disorders in any case with atypical or complex clinical manifestations. Tau pathology is a prominent feature in both CBD and AD. Such a combination would be a clue for the pathogenesis of various tauopathies.

Clincial and pathological study of distal motor neuropathy with N88S mutation in BSCL2.

Seipinopathy is an autosomal dominant inherited distal motor neuropathy caused by Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene mutations. We describe a Chinese family with seipinopathy in which nine patients from four successive generations were involved. The onset of age was from 13 to 40 years. Among them six were distal hereditary motor neuropathy type II with predominant weakness of lower extremities, while one of them was accompanied by pyramidal signs. The other three women were distal hereditary motor neuropathy type V with predominant atrophy of hands. Electrophysiological results in one patient demonstrated reduction of amplitude of compound muscle action potentials. Sural nerve biopsy showed loss of large myelinated fibers and fiber regeneration. Gene analysis revealed a heterozygous 263A-->G mutation in BSCL2 gene resulting in amino acid substitutions in N88S. This report suggests that a different type of distal hereditary motor neuropathy could exist within one family carrying N88S mutations. The axonal degeneration of sensory nerves appeared also in the disease.

Tubular aggregates in paralysis periodica paramyotonica with T704M mutation of SCN4A.

T704M mutations in SCN4A have recently been identified in families with paralysis periodica paramyotonica. Here we report the pathological features of intracellular tubular aggregates (TAs) on muscle biopsy in one family with T704M mutations of SCN4A. Tau, dysferlin and ubiquitin were all expressed in areas of tubule accumulation. These observations confirmed that TAs were associated with T704M mutations of SCN4A in paralysis periodica paramyotonica. Some proteins can mislocate in the TAs.

[Rheumatoid leptomeningitis: a case report and literature review].

To report the clinical, radiological and neuropathological findings of a patient with rheumatoid meningitis. The patient was a 71-year-old Chinese man with a two-year history of rheumatoid arthritis and no other significant medical history, who presented to our hospital recurrent weakness of his left extremities, dysarthria and a continuous bilateral hand tremor. Cerebrospinal fluid (CSF) and serum examinations were normal apart from a mildly raised serum perinuclear antineutrophil cytoplasmic autoantibody (p-ANCA). Brain magnetic resonance imaging (MRI) showed leptomeningeal enhancement in both frontal and parietal lobes, in addition to several old white matter infarcts. Meningeal biopsy showed numerous infiltrating macrophages and lymphocytes within the leptomeninges. The patient responded clinically and radiologically to corticosteroid and cyclophosphamide therapy. The patient subsequently developed herpes zoster over his left chest as a complication of his immunosuppressive treatment. His cyclophosphamide was ceased and intravenous immunoglobulin (IVIG) therapy was commenced, with good clinical response to both the herpes zoster and meningitis. According to the result of the biopsy, aseptic meningitis was considered the MRI results and the patient's clinical history were given, and a diagnosis of rheumatoid meningitis was made. The patient was p-ANCA positive. Although there was no evidence for cerebral vasculitis on biopsy, it remains a possibility that the patient's recurrent minor cerebral infarcts visible on MRI were vasculitic in nature.