Enzyme replacement therapy in adult‐onset glycogenosis II: Is quantitative muscle MRI helpful?

Although it has been shown that muscle magnetic resonance imaging (MRI) improves the phenotypic characterization of patients with neuromuscular disorders and allows accurate quantification of muscle and adipose tissue distribution, to date quantitative MRI has not been used to assess the therapeutic response in clinical trials of neuromuscular diseases. We discuss quantitative MRI findings after a 6‐month course of enzyme replacement therapy administered to nine patients with adult‐onset glycogenosis II. Muscle Nerve 40: 122–125, 2009     

Bent spine syndrome as the initial symptom of late‐onset Pompe disease

Introduction: Late‐onset Pompe disease (LOPD) is a rare disorder characterized by progressive proximal muscle weakness and early respiratory insufficiency, for which enzyme replacement therapy (ERT) is available. Methods: Having diagnosed a case of LOPD presenting with bent spine syndrome, we conducted a brief survey in the French centers involved in management of Pompe disease, from which we collected data on 3 other cases. Results: The patients (3 women and 1 man) had a mean age of 64 years (range 51–77 years) and a delay in diagnosis of approximately 10 years (range 8–42 years). At diagnosis, 3 patients already had respiratory symptoms. All had normal or very mildly raised creatine kinase levels and magnetic resonance imaging abnormalities in the paraspinal muscles. They exhibited the most frequent mutation in Pompe disease (c.‐32‐13 T>G). Conclusion: Clinicians should be aware of this atypical presentation of LOPD to enable earlier diagnosis and treatment. Muscle Nerve 56 : 167–170, 2017     

Diagnostic criteria for late‐onset (childhood and adult) pompe disease

The diagnosis of late‐onset (childhood and adult) Pompe disease can often be challenging, as it is a rare disease and the heterogeneous clinical presentation can mimic the presentation of other neuromuscular disorders. The objective was to develop a consensus‐based algorithm for the diagnosis of late‐onset Pompe disease. A systematic literature search was conducted, and an expert panel composed of neuromuscular specialists and individuals with expertise in Pompe disease reviewed the literature and convened for consensus development. An algorithm for the diagnosis of late‐onset Pompe disease was created. Patients presenting with either a limb‐girdle syndrome or dyspnea secondary to diaphragm weakness should undergo further testing, including evaluations of muscle strength, motor function, and pulmonary function. A blood‐based acid α‐glucosidase (GAA) enzyme activity assay is the recommended tool to screen for GAA enzyme deficiency. The diagnosis should be confirmed by a second test: either a second GAA enzyme activity assay in another tissue or GAA gene sequencing. Muscle Nerve 40:149–160, 2009     

Pompe disease,the must‐not‐miss diagnosis: A report of 3 patients

Introduction: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease. Methods: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis. Results: After significant delays in diagnosis, Pompe disease was diagnosed on the basis of the pattern of proximal weakness. Conclusions: Suspicion and recognition of the characteristic symptoms of Pompe disease may improve both the timing and accuracy of the diagnosis, which will improve clinical outcomes and minimize disease progression. Muscle Nerve, 2013     

Both type 1 and type 2a muscle fibers can respond to enzyme therapy in Pompe disease

Muscle weakness is the main symptom of Pompe disease, a lysosomal storage disorder for which major clinical benefits of enzyme replacement therapy (ERT) have been documented recently. Restoration of skeletal muscle function is a challenging goal. Type 2 muscle fibers of mice with Pompe disease have proven resistant to therapy. To investigate the response in humans, we studied muscle biopsies of a severely affected infant before and after 17 months of therapy. Type 1 and 2a fibers were marked with antibodies, and lysosome-associated membrane protein-1 (Lamp1) was used as the lysosomal membrane marker. Quantitative measurements showed a 2.5-3-fold increase of fiber cross-sectional area of both fiber types during therapy and normalization of the Lamp1 signal in approximately 95% of type 1 and approximately 75% of type 2a fibers. The response of both type 1 and 2a muscle fibers in the patient studied herein corroborates the beneficial effects of enzyme therapy seen in patients with Pompe disease.     

Motor function and respiratory capacity in patients with late‐onset pompe disease

Introduction: The relationship between skeletal muscle strength and respiratory dysfunction in Pompe disease has not been examined by quantitative methods. We investigated correlations among lower extremity proximal muscle strength, respiratory function, and motor performance. Methods: Concentric strength of the knee extensor and flexor muscles was measured with a dynamometer, and pulmonary function was evaluated using spirometry in 7 adult patients. The 6‐minute walk test and the 4‐step stair‐climb test were used for assessing aerobic endurance and anaerobic power, respectively. Results: Anaerobic motor performance correlated with strength of both thigh muscles. Respiratory function did not correlate with either muscle strength or motor function performance. Conclusions: Respiratory and lower extremity proximal muscles could be affected differentially by the disease in individual patients. Motor performance is influenced by thigh muscle strength and is less dependent of respiratory capacity in our cohort of ambulatory patients. Muscle Nerve 49:603–606, 2014     

Functional connectivity changes differ in early and late‐onset alzheimer's disease

At a similar stage, patients with early onset Alzheimer's disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late‐onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age‐matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting‐state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso‐lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double‐dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large‐scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes. Hum Brain Mapp 35:2978–2994, 2014. © 2013 Wiley Periodicals, Inc.     

Clinical profiles of late‐onset semantic dementia,compared with early‐onset semantic dementia and late‐onset Alzheimer's disease

Background: Semantic dementia (SD) has been recognized as a representative of dementia with presenile onset; however, recent epidemiological studies have shown that SD also occurs in the elderly. There have been few studies about the differences of clinical profiles between early‐onset SD (EO‐SD) and late‐onset SD (LO‐SD). Age‐associated changes in the brain might cause some additional cognitive and behavioural profiles of LO‐SD in contrast to the typical EO‐SD cases. The aim of the present study was to clarify the characteristics of neuropsychological, and behavioural and psychological symptoms of dementia (BPSD) profiles of LO‐SD patients observed in screening tests in comparison with EO‐SD patients and late‐onset Alzheimer's disease (LO‐AD) patients as controls. Methods: Study participants were LO‐SD (n = 10), EO‐SD (n = 15) and LO‐AD (n = 47). We examined the Mini‐Mental State Examination (MMSE), the Raven's Coloured Progressive Matrices (RCPM), the Short‐Memory Questionnaire (SMQ), the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Results: Both SD groups scored significantly lower than the LO‐AD patients in ‘naming’ of the MMSE. In the ‘construction’ score of the MMSE and the RCPM score, however, the LO‐SD patients as well as the LO‐AD patients were significantly lower than the EO‐SD patients. In the SMQ score, ‘euphoria’ and ‘disinhibition’ scores of the NPI, the SRI total and subscale scores, both SD groups were significantly higher, whereas in the ‘delusion’ score of the NPI, both SD groups were significantly lower than the LO‐AD patients. Conclusions: Visuospatial and constructive skills of LO‐SD patients might be mildly deteriorated compared with EO‐SD patients, whereas other cognitive and behavioural profiles of LO‐SD are similar to EO‐SD. Age‐associated changes in the brain should be considered when we diagnose SD in elderly patients.     

Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy

Pompe's disease (glycogen storage disease type II) is an autosomal recessive myopathy caused by lysosomal alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is currently under development for this disease. We evaluated the morphological changes in muscle tissue of four children with infantile Pompe's disease who received recombinant human alpha-glucosidase from rabbit milk for 72 weeks. The patients were 2.5-8 months of age at entry. Prior to treatment, all patients showed lysosomal glycogen storage in skeletal and smooth muscle cells, vascular endothelium, Schwann cells, and perineurium. The first response to treatment was noticed in vascular endothelium and in peripheral nerves after 12 weeks of treatment at an enzyme dose of 15-20 mg/kg. Increasing the dose to 40 mg/kg led, after 72 weeks of treatment, to a reduction of glycogen storage and substantial improvement of muscle architecture in the least affected patient. Not all patients responded equally well, possibly due to differences in degree of glycogen storage and concomitant muscle pathology at the start of treatment. We conclude that intravenous administration of recombinant human alpha-glucosidase from rabbit milk can improve muscle morphology in classic infantile Pompe's disease when treatment is started before irreversible damage has occurred.     

Changes in nutritional status and body composition during enzyme replacement therapy in adult‐onset type II glycogenosis

Background: In adult glycogen storage disease type II (GSDII), a single‐gene mutation causes reduction of the lysosomal enzyme acid alpha‐glucosidse. This produces a chronic proximal myopathy with respiratory involvement. Enzyme replacement treatment (ERT) has recently become available and is expected to improve muscle strength. This should result in increased lean body mass. In this study we evaluate body composition and nutritional status in GSDII, and assess whether these parameters changed during treatment. Methods: Seventeen patients with late‐onset GSDII, aged 52.6 ± 16.8 years, received ERT for >18 months. Dietary habits and metabolic profiles of glucids, lipids, and proteins were assessed. Body composition was calculated using anthropometry and bioelectrical impedence analysis. Results: On inclusion, we found increased fat mass (FM) in five patients in severe disease stage; all had normal body mass index (BMI). FM correlated inversely, and lean mass (LM) directly, with creatine kinase, prealbumin and albumin levels. After treatment, BMI and FM significantly increased, while LM only showed a trend toward increase. Prealbumin and albumin levels increased as early as after the first months of ERT. Discussion: Body mass index value may underestimate FM in patients in severe stage of disease, due to altered body composition. In severely affected patients, laboratory parameters revealed a relative protein malnutrition, that was reversed by ERT, this reflecting restoration of normal muscle metabolic pathways. Increased BMI may indicate a reduction in energy consumption during exercise or respiration, along with clinical improvement.     

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) in Mallorca: a comparison between late‐ and early‐onset disease

The age of onset (AO) of hereditary ATTR amyloidosis (hATTR) is known to vary between populations, with differing characteristics reported according to AO in endemic/non‐endemic foci. This was a retrospective study of patients with early AO (<50 years) and late AO (≥50 years) hATTR at our center in Mallorca. Data were collected on patient demographics, clinical disease manifestation, and physical symptoms. A total of 95 patients were analyzed, with mean follow‐up of 9 years from diagnosis. The early AO group included 53 patients (33 male) and the late AO group included 42 patients (21 male). Neurologic involvement was the most common initial symptom, although it was significantly more frequent in the late AO vs. early AO group (p = 0.015). Autonomic involvement was observed in 26% of patients in the early AO group, but was rarely observed in the late AO group (5%). During follow up, cardiologic symptoms, renal involvement, and ophthalmologic symptoms were significantly more common in the late AO group (p < 0.05). This retrospective study demonstrates the variation in disease presentation and progression according to AO of hATTR at our Mallorcan center.