Charcot-Marie-Tooth type 2CC misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). CASE REPORT: A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. INTERPRETATION: Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

Proximal weakness involvement in the first Italian case of Charcot-Marie-Tooth 2CC harboring a novel frameshift variant in NEFH.

Charcot-Marie-Tooth (CMT) diseases are a clinically and genetically heterogeneous group of disorders. Different variants in the neurofilament heavy chain (NEFH) gene have been described to cause the CMT2CC subtype. Here we report the first Italian patient affected by CMT2CC, harboring a novel variant in NEFH. In describing our patient, we also reviewed previously CMT2CC individuals, and suggested to consider NEFH variant if patients have an axonal sensory-motor neuropathy with a prominent proximal muscles involvement with early requirement of walking aids or wheelchair, remembering a motor neuron disorder.

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.

The purpose of this research is to explore the underlying genes of Charcot-Marie-Tooth (CMT). Technologies such as electrophysiological testing and gene sequencing have been applied. We identified a novel variant NEFH c.2215C>T(p.P739S)(HGNC:7737) in a heterozygous state, which was considered to be pathogenic for CMT2CC(OMIM:616924).The proband and his brothers presented with muscle atrophy of hand and calf and moderately decreased conduction velocities. By whole exome sequencing analysis, we found the novel missense pathogenic variant in the proband, his brother and mother. This report broadened current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with NEFH. In addition, the proband carried other five variants {HSPD1c.695C>A (p.S232X), FLNCc.1073A>G (p.N358S), GUSBc.323C>A (p.P108Q), ACY1 c.1063-1G>A and APTX c.484-2A>T}, which have not been reported until now. The NEFH c.2215C>T (p.P739S) give us a new understanding of CMT, which might provide new therapeutic targets in the future.

Axonal Charcot-Marie-Tooth neuropathy concurrent with distal and proximal weakness by translational elongation of the 3' UTR in NEFH.

Mutations in the NEFH gene encoding the heavy neurofilament protein are usually associated with neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS). Recently, frameshift variants in NEFH (p.Asp1004Glnfs*58 and p.Pro1008Alafs*56) have been reported to be the underlying cause of axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC). The frameshift mutation resulted in a stop loss and translation of a cryptic amyloidogenic element (CAE) encoded by the 3' untranslated region (UTR). This study also identified a de novo c.3015_3027dup frameshift mutation predicting p.Lys1010Glnfs*57 in NEFH from a CMT2 family with an atypical clinical symptom of prominent proximal weakness. This mutation is located near the previously reported frameshift mutations, suggesting a mutational hotspot. Lower limb magnetic resonance imaging (MRI) revealed marked hyperintense signal changes in the thigh muscles compared with those in the calf muscles. Therefore, this study suggests that the stop loss and translational elongations by the 3' UTR of the NEFH mutations may be a relatively frequent genetic cause of axonal peripheral neuropathy with the specific characteristics of proximal dominant weakness.