New Keys to Early Diagnosis: Muscle Echogenicity, Nerve Ultrasound Patterns, Electrodiagnostic, and Clinical Parameters in 150 Patients with Hereditary Polyneuropathies

Hereditary neuropathies are of variable genotype and phenotype. With upcoming therapies, there is urgent need for early disease recognition and outcome measures. High-resolution nerve and muscle ultrasound is a dynamic, non-invasive, well-established tool in the field of inflammatory and traumatic neuropathies. In this study, we defined nerve and muscle ultrasound parameters as recognition and progression markers in 150 patients with genetically confirmed hereditary neuropathies, including Charcot-Marie-Tooth (CMT) disease (CMT1A, n = 55; other CMT1/4, n = 28; axonal CMT, n = 15; CMTX, n = 15), hereditary neuropathy with liability to pressure palsies (HNPP, n = 16), hereditary transthyretin-amyloidosis (ATTRv, n = 14), and Fabry’s disease (n = 7). The CMT1A, followed by the CMT1/4 group, had the most homogeneous enlargement of the nerve cross-sectional areas (CSA) in the ultrasound pattern sum (UPSS) and homogeneity score. Entrapment scores were highest in HNPP, ATTRv amyloidosis, and Fabry’s disease patients. In demyelinating neuropathies, the CSA correlated inversely with nerve conduction studies. The muscle echo intensity was significantly highest in the clinically most affected muscles, which was independent from the underlying disease cause and correlated with muscle strength and disease duration. Further correlations were seen with combined clinical (CMTES-2) and electrophysiological (CMTNS-2) scores of disease severity. We conclude that nerve ultrasound is a helpful tool to distinguish different types of hereditary neuropathies by pattern recognition, whereas muscle ultrasound is an objective parameter for disease severity. The implementation of neuromuscular ultrasound might enrich diagnostic procedures both in clinical routines and research.

A Quest to Capture Latent Fabry’s Disease in a High-Risk Subpopulation of FMF.

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disease, associated with mutations in the Mediterranean fever gene (MEFV), and manifests with recurrent episodes of febrile serositis. Fabry’s disease (FD) is an X-linked lysosomal storage disease caused by mutations in the alpha- galactosidase A gene, and presents with a wide range of gastrointestinal, skin, vascular, renal and neurological manifestations. FMF and FD share similar manifestations, which may lead to misdiagnosis of one as the other; mostly FD is misdiagnosed as FMF. Moreover, various overlapping manifestations may stem from comorbidities, commonly coupled to FMF, as well as from colchicine adverse effects, which may add to the diagnostic confusion. Thus, we postulated that screening FMF for FD will lead to the identification of patients falsely diagnosed as FMF, or who suffer from FD that was previously missed.Methods: To find missed FD among FMF population, we performed chemical and genetic analyses for FD in blood samples obtained from a cohort of FMF patients followed in the specialized FMF center of our institution. To increase the likelihood of detecting patients with FD, we enriched the surveyed FMF population with patients exhibiting manifestations shared by patients with FD or who deviate from the typical FMF presentation.Results and conclusions: Of 172 surveyed FMF patients in a cohort derived from a clinic dedicated to FMF, none had FD. Thus, the postulation of increased odds for detecting FD in patients with FMF was not confirmed.

Neuropathic pain in children

Lesions or disease of the somatosensory nervous system can produce neuropathic pain (NP). Typical features include spontaneous or paroxysmal pain, often described as burning, shooting, like electric shocks, or pins and needles. NP does occur in childhood, but age at the time of injury may influence the risk of NP following traumatic nerve injuries. Whilst conditions commonly associated with NP in adults may be less common in childhood (e.g., trigeminal neuralgia), other conditions (e.g., Fabry’s disease and erythromelalgia), may present with pain in childhood and present a diagnostic challenge for paediatric practitioners.

MO050MUTATION TYPES AND ENZYME LEVELS IN FABRY DISEASE IN A MULTICENTER STUDY

Background and Aims Fabry disease is a chronic, progressive and multi-systemic hereditary condition, related to a Xq22 mutation in X chromosome, which results in deficiency of acid alpha-galactosidase, hence reduced capacity of globotriaosylceramide (Gb3) degradation. Gb3 accumulates in lysosomes throughout virtually every organ, thus causing considerable morbidity and mortality. Objectives: To evaluate the types of Fabry disease mutations and enzyme levels of Alpha Galactosidase and Lyso Gb3 in a multicenter study; the RIM FABRY BRASIL PROJECT. Method We conducted a transversal study that consists of data analysis secondary to the multicenter project: Clinical and Epidemiological Analysis of Fabry's Disease in Dialysis Centers in Brazil, “PROJETO RIM FABRY BRASIL”. Included 854 dialysis centers throughout Brazil and 75059 individuals screened using a questionnaire and signing an Informed Consent Form. The data were entered into a computer program (algorithm) that filters the possible carriers of Fabry's disease. The program / algorithm discarded those who probably did not have Fabry's disease and sent blood suspects to filter enzyme dosage and genetic testing of those suspected of the disease. Results 75059 individuals from the RIM FABRY BRASIL project were screened, where 58.37% were men and 41.54% women. 408 individuals with mutations for Fabry disease were identified, including patients with kidney and Family history of the disease, 34.6% men and 65.4% women with a mean age of 42.7 years. 47 different mutations were identified, with a higher prevalence of c.352C> T p.Arg118Cys (24.8%), followed by c.376A> G p.Ser126Gly (13.1%), c.1102G> A p.Ala368Thr ( 7.8%), c.937G> T p.Asp313Tyr (7.8%), c.870G> C p.Met290Ile (7.3%). Alfa GalA dosage was performed in 120 men, with 90% of them showing decreased enzyme and Lyso Gb3 dosage of 320 individuals, (36.2% men and 63.8% women) 72.5% normal and 27.5% increased. Conclusion The most frequent mutations were: c.352C> T p.Arg118Cys, followed by c.376A> G p.Ser126Gly, c.1102G> A p.Ala368Thr, c.937G> T p.Asp313Tyr, c.870G> C p.Met290Ile. 90% of men showed a decrease in the enzyme Alpha GalA and 27.5% of individuals had increased Lyso Gb3.

New α-galactosidase-inhibiting aminohydroxycyclopentanes

A concise and robust synthesis of new cyclopentanoid competitive inhibitors of α-galactosidases related to Fabry's disease and other α-galactosidase related disorders.