Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. Ann Neurol 2013;74:914–919

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Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early-and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat-and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal). K E Y W O R D Samyloid, neuropathy, small fiber, tafamidis, transplantation, transthyretin | 93 FINSTERER ET al. eyes, the gastrointestinal tract, the kidneys, and the skin. ATTRm amyloidosis is resistant to immunotherapy. Though ATTRm-related polyneuropathy or TTR-CA may occur without affection of another tissue, a variable combination of organ affection (multiorgan involvement) is the most frequent phenotype. This review aims at summarizing and discussing previous and recent findings concerning the clinical presentation, genetic background, pathogenesis, diagnosis, treatment, and outcome of ATTRm-related polyneuropathy. | ME THODSData for this review were identified by searches of MEDLINE for references of relevant articles. Search terms applied were "transthyretin," "gene," "TTR-FAP," or "mutation," combined with "neuropathy," "hereditary," "autonomic," "small fiber neuropathy," and "polyneuropathy." Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were randomized controlled trials (RCTs), observational studies with controls, case series, and case reports. Only original articles about humans, and published between 1966 and 2018 were included. Reviews, editorials, and letters were not considered. Reference lists of retrieved studies were checked for reports of additional studies. Websites checked for additional, particularly geneti...

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.MethodsWe recruited patients, collected clinical data and conducted whole-exome sequencing (WES, n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin.ResultsIn the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal dominant trait and less frequently with autosomal recessive inheritance.ConclusionsA detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, either by variants in CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.