Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes

Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first

Neuroinflammatory disease as an isolated manifestation of hemophagocytic lymphohistiocytosis

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected inPRF1in 23 patients (61%),RAB27Ain 10 (26%),UNC13Din 3 (8%),LYSTin 1 (3%), andSTXBP2in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome