Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.

Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.

Nemaline myopathy is among the most common congenital myopathies. We describe for the first time a novel double de novo mutation in two adjacent codons resulting in two amino acid changes E74D and H75Y in the ACTA1 gene. The hypotonic male infant was the first son of healthy unrelated parents with no family history of neuromuscular disorders. Pregnancy was complicated: decreased fetal movements were noted on the 25th week of gestation, premature labour pains were present from the 29th week onwards and because of breech presentation a Caesarian section was carried out in the 39th week. The patient presented with multiple congenital fractures and joint contractures. He was dependent on ventilatory support until his death at 2 months. Muscle biopsy revealed severely atrophic and rounded muscle fibers with considerable variation in diameter and pronounced disorganization of the myofibers. Electron microscopy indicated a distinct disturbance of the myofibrillar architecture and nemaline rods. In view of previously described cases carrying different single missense mutations of the amino acid residues E74 or H75, we suggest that the particular genotype E74D/H75Y is compatible with the severity of the patient's phenotype. The possibility of germ cell mosaicism should be taken into account in genetic counseling.