PracticeUpdate

Late-Onset Pompe Disease Linked to Polyneuropathy Early diagnosis may help optimize the chance of stabilizing or

improving the course of disease L ate-onset Pompe disease has been associated with polyneuropathy, according to results of a prospective chart review of six patients. Gauthier Remiche, MD, of the Erasme Hospital in Brussels, Belgium, and col- leagues set out to determine whether late-onset Pompe disease could be asso- ciated with polyneuropathy. “We undertook the study because I was questioning, during routine practice, whether several patients with late-onset Pompe disease might have had polyneu- ropathy without any demonstrated etiology, despite ad hoc work-up," Dr. Remiche told Elsevier’s PracticeUpdate . The team retrospectively assessedmedical records of individuals with late-onset Pompe disease who were followed in their center to assess potential clinical and neurophysi- ological indicators of polyneuropathy. Moreover, they sought the presence of potential etiologies of polyneuropathy and applied international diagnostic cri- teria for late-onset Pompe disease and polyneuropathy. Of the six individuals with late-onset Pompe disease in the database, four exhibited clinical evidence of poly- neuropathy, which was confirmed by electroneuromyography. None of the indi- viduals demonstrated any other common known cause of polyneuropathy. Pompe disease is divided into infantile and late-onset disease. Infantile-onset represents the most severe form and almost invariably leads to death due to cardiorespiratory failure within 1 year. The late-onset variant presents at any time after the age of 1 year, and is characterized by a spectrum of phenotypic variation. It may range from asymptomatic individuals with increased creatinine kinase to muscle cramps and pain syndrome or rigid-spine syndrome. The lower limbs and paraspinal muscles are frequently affected first, followed by respiratory muscles, particularly the dia- phragm, intercostal, and accessorymuscles. Respiratory failure, caused mainly by dia- phragmatic weakness, is the main cause of increased morbidity and mortality. Late-onset Pompe disease presents hetero- geneously andmimics other neuromuscular

diseases, posing a diagnostic challenge. Clinical manifestations vary in terms of organ involvement, age at onset, and severity. Symptoms are often unspecific and may remain mild for decades, such that neither individual nor doctor considers further diagnostic procedures. The disease strikes mainly striated muscle but also involves many other tissues. Early diagnosis may help optimize the chance of improving or at least stabilizing the course of disease using enzymatic replacement therapy. Dr. Remiche explained that late-onset Pompe disease is caused by α-glucosidase lysosomal enzyme deficiency. Though the clinical phenotype of late-onset Pompe disease varies, genetic analysis of the GAA gene, or determination of the level of α-glucosidase enzyme activity in blood, fibroblasts, or muscle tissue, can provide a definitive diagnosis. Though muscle biopsy often reveals a vacuolar myopathy with increased amounts of glycogen, a normal muscle biopsy does not exclude late-onset Pompe disease. Involvement of large nerve fibers has not been depicted but has been shown in mouse models of Pompe disease, glyco- gen accumulation in Schwann cells, and the perineurium of peripheral nerves. Moreover, two individuals with late-onset Pompe disease were reported as suffering from small-fiber neuropathy. Dr. Remiche concluded that polyneuropathy seems overrepresented in individuals with late-onset Pompe disease. A pathophysio- logical basis may be evoked to explain this potentially disabling additional condition in individuals with late-onset Pompe disease. “Our results should be taken with caution since our sample was small and we did not exclude all etiologies of polyneuropathy. For example, we did not perform genetic testing such as a panel for Charcot-Marie- Tooth or /hereditary motor and sensory neuropathy. A physiopathological rationale exists for patients with late-onset Pompe disease to develop polyneuropathy, so this topic should be studied in a large sample. Moreover, the condition could worsen their functional prognosis and could be missed by clinicians if they are unaware of this possibility,” Dr. Remiche concludes. www.practiceupdate.com/c/70780

investigation and have demonstrated encouraging results. Monoclonal antibodies directed against either the serum amyloid P component or amyloidogenic forms of transthyretin constitute another strategy to clear amy- loid deposits. Antisense oligonucleotides such as inotersen or interfering RNA lipid nan- oparticles (patisiran), which bind to wild type and mutated transthyretin mRNA have proved able to reduce transthyretin production by more than 75%. Both inotersen and patisiran proved very effective in two recently completed phase III trials. Both trials reached primary end- points, and multiple measures improved significantly in treated versus untreated participants. Stabilization or improvement occurred in a substantial proportion of treated individuals. Inotersen was administered subcuta- neously once weekly for 15 months. Thrombocytopenia and renal problems required monitoring of platelet and renal function. Patisiran administered intravenously every 3 weeks for 18 months was well tolerated. Infusion-related reactions and peripheral edema were themost relevant side effects. Both treatments were effective, inde- pendent of disease stage, the presence of cardiomyopathy, and type of mutation. Development of such novel therapies is changing the natural history of hATTR neuropathy from a relentlessly progres- sive disorder inexorably leading to death into an effectively treatable disorder. www.practiceupdate.com/c/70781

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