Chronic Inflammatory Demyelinating Polyradiculoneuropathy-Like Neuropathy in Heterozygous C9orf72 Mutation: A Case Report

Abstract

Introduction

C9orf72 repeat expansion is usually associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS/FTD overlap. We report an atypical neuromuscular presentation of C9orf72 repeat expansion.

Case Presentation

A 68-year-old patient developed a sensorimotor polyneuropathy with slow continuous worsening over 3 years. Symptoms started in the left foot and slowly extended to all four limbs. Nerve conduction studies were consistent with a non-length-dependent predominantly axonal sensorimotor polyneuropathy, with some additional demyelinating features (proximal temporal dispersion and F-wave latency prolongation). Electro-clinical presentation fulfilled EAN/PNS 2021 criteria for CIDP, but the patient was not responsive to IVIg. RT-PCR revealed a heterozygous pathogenic expansion of the C9orf72 gene. The patient’s father and brother died from ALS. At onset, his brother also had sensorimotor involvement and was misdiagnosed with CIDP.

Conclusion

This case may expand the phenotypic spectrum associated with C9orf72 repeat expansion. The initial phenotype could be a non-length-dependent sensorimotor polyneuropathy with demyelinating features that potentially mimics CIDP.

Introduction

C9orf72 repeat expansion accounts for 40% of familial amyotrophic lateral sclerosis (ALS), 6% of sporadic ALS, 25% of familial frontotemporal dementia (FTD), 2–6% of sporadic FTD, and up to 50% of ALS/FTD pedigrees [1]. Transmission is autosomal dominant. Other atypical neurological phenotypes have been more rarely linked to C9orf72 repeat expansions, such as Parkinsonism and other movement disorders [2]. We report here an atypical neuromuscular presentation of C9orf72 repeat expansion.

Case Report

A 68-year-old man presented with a 3-year history of asymmetric sensory symptoms in the lower limbs, gradually extending up to the knees. He also reported gait difficulties requiring the use of a walking stick, as well as a loss of dexterity in both hands. The patient worked as a farmer. He did not report exposure to industrial toxins or alcohol abuse. The patient’s father and one of his brother died from ALS. His father developed the disease in his early seventies and died 10 years later. His brother developed a distal asymmetric sensorimotor polyneuropathy in his late fifties, initially diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). He was later diagnosed with ALS and died 2 years after symptom onset. No genetic testing had been performed. A sister had mild cognitive symptoms which began in her late sixties, and a second sister was diagnosed with a major neurocognitive disorder, with symptom onset in her mid-sixties.

Thirty-three months after symptom onset (M33), neurological examination showed a mild distal lower limb atrophy, MRC4 weakness of both deltoid, dorsal interosseous, iliopsoas, hamstrings, MRC 4+ weakness of both quadriceps and tibialis anterior muscles and MRC4-/MRC4 weakness of the left/right extensor digitorum brevis. Muscle tone was normal. There was reduced light touch and pinprick sensation in the lower limbs up to the knees, with pain anesthesia in both feet, and reduced light touch and pinprick sensation in the fingers bilaterally. Vibration sense was globally reduced, but testing appeared unreliable. Joint position sense was impaired in both halluces but preserved in both indexes. Deep tendon reflexes were absent in the lower limbs and decreased in the upper limbs, plantar responses were in flexion, and Hoffmann sign was negative. The examination of bulbar functions was normal.

Three nerve conduction studies (NCS) were performed at M12, M22, and M33 (Table 1) and demonstrated a predominantly axonal sensorimotor polyneuropathy. There were also several demyelinating features (F-waves latencies prolongation in upper and lower limbs, slight prolongation of motor distal latencies, motor conduction velocities slowing and abnormal proximal temporal dispersion in lower limbs, Fig. 1). At M33, needle electromyography of the right upper trapezius, deltoid, first dorsal interosseous, and vastus medialis muscles were unremarkable. Needle electromyography of the right tibialis anterior muscle displayed rare fibrillation and fasciculation potentials, increased duration and polyphasic motor unit potentials, and a neurogenic recruitment pattern. Lumbar spine MRI revealed a L5-S1-herniated disc with left S1 nerve root compression. CSF analysis disclosed mild increased protein levels (660 mg/L) with no leukocytes. Lumbosacral plexus MRI, blood tests (vitamin B group, TSH, HbA1c, serum immunofixation with serum light chain quantification, ANA, ANCA, anti-nucleoprotein, and anti-ganglioside antibodies), anti-neural antibodies (against neuronal cell surface and intracellular neuronal antigens) in blood and CSF and full-body CT scan were unremarkable. At M18, a CIDP was suspected, and two courses of IVIg 2 g/kg at 6-week interval did not lead to any objective clinical improvement or stabilization.

Table 1.

Key motor and sensory NCS parameters at 12, 21, and 33 months from symptoms onset

Nerve/sites	12 months					21 months					33 months
	Lat	Amp	Dur	Vel	F lat	Lat	Amp	Dur	Vel	F lat	Lat	Amp	Dur	Vel	F lat
	ms	mV (M) µV (S)	ms	m/s	ms	ms	mV (M) µV (S)	ms	m/s	ms	ms	mV (M) µV (S)	ms	m/s	ms
Motor nerves
R median – recording APB
Wrist (5 cm)	​	​	​	​	​	3.6	9.7	5.9	​	33.1	3.5	10.4	6.7	​	33.2
Elbow	​	​	​	​	​	​	9.9	6.1	48	​	9.2	10.0	6.8	48	​
L median – recording APB
Wrist (5 cm)	​	​	​	​	​	4.8	8.3	6.0	​	33.2	4.7	6.2	7.1	​	33.6
Elbow	​	​	​	​	​	10.3	7.8	6.4	49	​	10.2	5.4	7.5	49	​
R ulnar – recording ADM
Wrist (5 cm)	​	​	​	​	​	2.8	10.1	6.5	​	33.3	2.8	9.5	6.5	​	33.5
Elbow	​	​	​	​	​	7.6	8.6	7.0	51	​	7.5	9.1	7.0	55	​
L ulnar – recording ADM
Wrist, cm	​	​	​	​	​	3.0	10.5	6.1	​	32.5	3.1	9.5	6.1	​	32.2
Elbow	​	​	​	​	​	7.7	9.0	6.6	54	​	7.8	7.2	6.5	53	​
Above elbow	​	​	​	​	​	​	8.0	6.7	45	​	​	​	​	​	​
R tibial – recording AH
Ankle (8 cm)	4.6	1.7	5.8	​	68.3	5.5	2.4	7.0	​	68.5	4.7	2.0	6.4	​	67.4
Popliteal fossa	​	​	​	​	​	​	0.8	26.1	33	​	16.8	0.6	17.5	33	​
L tibial – recording AH
Ankle (8 cm)	4.1	2.1	5.0	​	65.3	​	​	​	​	​	6.9	1.9	3.9	​	66.1
Popliteal fossa	​	​	​	​	​	​	​	​	​	​	18.9	0.9	11.5	33	​
R fibular – recording EDB
Ankle (7 cm)	​	​	​	​	​	5.2	2.1	5.0	​	NR	5.1	2.1	4.9	​	NR
Fibula	​	​	​	​	​	15.2	1.3	12.2	32	​	15.3	1.8	9.6	34	​
Knee	​	​	​	​	​	18.1	1.3	12.5	33	​	17.2	1.8	9.4	47	​
L fibular – recording EDB
Ankle (7 cm)	5.0	0.5	5.0	​	​	​	​	​	​	​	6.3	0.1	6.5	​	NR
Fibula	12.6	0.4	8.0	40	​	​	​	​	​	​	17.0	0.1	25.1	34	​
Sensory nerves
R median – antidromic
Wrist	​	​	​	​	​	​	5.0	​	30	​	​	4.5	​	38	​
L median – antidromic
Wrist	​	​	​	​	​	​	7.7	​	31	​	​	4.2	​	31	​
R ulnar – antidromic
Wrist	​	​	​	​	​	​	10.2	​	46	​	​	​	​	​	​
L ulnar – antidromic
Wrist	​	​	​	​	​	​	7.5	​	45	​	​	​	​	​	​
R radial – antidromic
Forearm	​	​	​	​	​	​	18.4	​	52	​	​	14.8	​	53	​
L radial – antidromic
Forearm	​	​	​	​	​	​	17.4	​	50	​	​	13.6	​	52	​
R sural – antidromic
Calf	​	4.0	​	51	​	​	4.4	​	46	​	​	4.1	​	50	​
L sural – antidromic
Calf	​	6.0	​	47	​	​	6.2	​	44	​	​	4.9	​	51	​

Abnormal values are shown in bold. ADM, abductor digiti minimi; AH, abductor hallucis; APB, abductor policis brevis; Amp, amplitude; Dur, duration; EDB, extensor digitorum brevis; F lat, F-wave latency; L, left; Lat., latency; M, motor; NR, not recordable; R, right; S, sensory; Vel, velocity.

Fig. 1.

Abnormal proximal temporal dispersion in right fibular and tibial nerves at M33. Right fibular (a) and tibial (b) motor NCS at M33. CMAP-negative peak duration increased by 96% in the fibular nerve and 173% in the tibial nerve between distal and proximal stimulations, with no reduction in surface.

According to 2021 EAN/PNS criteria, a diagnosis of typical CIDP could have been considered. However, although the clinical presentation and NCS findings were not consistent with ALS, the highly suggestive family history prompted genetic testing for the four most common mutations associated with familial ALS (C9orf72, SOD1, TARDBP, and FUS). RT-PCR revealed a heterozygous pathogenic GGGCC repeat expansion (145 repeats) of the unstable intron-1 region of the C9orf72 gene. Treatment with riluzole was initiated. At M39, a full neuropsychological evaluation showed a moderate to severe executive dysfunction and a moderate verbal episodic memory impairment. Motor and sensory deficits in the lower limbs progressively worsened over the following 6 months, after which the patient was lost to follow-up.

Discussion

We describe the case of a patient who developed a slowly progressive, asymmetric sensorimotor polyneuropathy likely caused by a heterozygous C9orf72 repeat expansion. The patient exhibited marked asymmetric sensory disturbances in the lower limbs, with relatively slow clinical progression and only mild motor deficits after 3 years. There were no signs of upper motor neuron involvement and only limited lower motor neuron signs. As a result, the revised El Escorial, Awaji, and Gold Coast criteria for ALS were not met. Neuropsychological testing revealed cognitive impairment consistent with that typically observed in motor neuron diseases, particularly those associated with a C9orf72 repeat expansion.

NCS displayed a primarily axonal sensorimotor polyneuropathy. Some motor nerve conduction abnormalities could suggest a superimposed demyelinating process but were most likely attributable to axonal loss. For example, proximal temporal dispersion may occur physiologically in the tibial nerve at the popliteal fossa or in the context of severe underlying axonal loss. Prolonged F-wave latency may result from slowed nerve conduction velocity due to axonal degeneration, or from coexisting spinal or foraminal stenosis. In our patient, lumbar spine MRI revealed a left S1 nerve root compression, which could explain the prolongation of the left tibial nerve F-wave latency. Similarly, mild slowing of motor conduction velocities can be explained by the loss of the fastest-conducting nerve fibers. This case highlights the importance of cautious interpretation of electrophysiological abnormalities, particularly when distinguishing between demyelinating and axonal processes.

As a supportive criterion for CIDP, mild increase in CSF protein should be interpreted with caution, as it can be physiologically elevated in older male patients, particularly in the presence of diabetes or spinal stenosis [3]. Another cause of the patient’s polyneuropathy could be considered, especially to account for the sensory involvement, but an extensive workup did not identify any alternative explanation, with no evidence of a metabolic or dysimmune origin. Moreover, the patient’s brother exhibited a similar phenotype that ultimately progressed to ALS, further supporting the association between the C9orf72 repeat expansion and the patient’s polyneuropathy.

Sensory Involvement in ALS

Subclinical sensory nerve dysfunction has been often reported in ALS patients, suggesting that it may be part of the disease’s spectrum. Reported rates of sensory polyneuropathy in ALS patients range from 13% to 22% [4]. Sensory neuropathy appears to be more frequent in patients with SOD1-ALS; a recent cohort has reported mild sensory involvement in up to 50% of patients [5]. In a recently published retrospective analysis, electrophysiological evidence of sensory polyneuropathy was also found in approximately one-third of patients with C9orf72-ALS [6].

CIDP-Like Presentation in ALS

ALS patients presenting with a CIDP-like phenotype were scarcely described. The first description was made in 2005 [7]. Three patients had an initial presentation compatible with typical CIDP, with various demyelinating conduction abnormalities, including conduction blocks outside compression sites. Postmortem examination in one patient showed endoneurial infiltration of mononuclear cells of the lumbar roots and peripheral nerves, consistent with CIDP. Two patients had a positive family history of ALS, but no genetic mutation was found. More recently, a demyelinating neuropathy with diffuse nerve enlargement and albumin-cytologic dissociation in the CSF was described in a patient with coexisting ALS and a C9orf72 heterozygous repeat expansion [8]. The relationship between ALS and CIDP is still unclear. The key issue is whether those patients truly have an inflammatory neuropathy or if the “demyelinating” NCS finding simply reflect axonal degeneration. For example, motor pseudo-conduction blocks have been described in ALS and likely results from proximal motor axon hypoexcitability due to rapid Wallerian degeneration [9].

This case may broaden the spectrum of neurological syndromes associated with the C9orf72 mutation. The initial phenotype could be a non-length-dependent sensory-motor polyneuropathy with demyelinating features that potentially mimics CIDP. However, as this observation represents an isolated report, the pathogenicity of C9orf72 mutation in this type of polyneuropathy remains uncertain and requires confirmation in larger cases description. In the absence of CIDP treatment response, a thorough family history and genetic testing including ALS more frequent mutations are therefore crucial in this context.

Acknowledgment

We would like to sincerely thank the patient for providing consent and agreeing to participate in this case report.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

V.L.: conceptualization (lead), methodology (lead), investigation (equal), and writing – original draft (lead). V.A.: conceptualization (support), methodology (support), investigation (equal), and writing – original draft (support). A.V.: writing – review and editing (support) and supervision (support). M.T.: writing – review and editing (lead) and supervision (lead).

Funding Statement

The authors received no financial support for the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author.