Cranial Nerve Involvement With Diplopia as Presenting Feature of CMT1H Caused by Recurring FBLN5 Variant

ABSTRACT

Background and Aims

CMT1H is a rare, autosomal dominant, demyelinating subtype of CMT caused by variants in FBLN5. Symptomatic cranial nerve involvement has never been reported in patients with CMT1H.

Case Report

We report a 45‐year‐old woman with a history of long‐standing diplopia. On examination, she had bilateral limitation of eye abduction, with double vision in all directions of gaze, particularly horizontally. She was unable to heel‐walk, had mild lower limb distal weakness, decreased tendon reflexes with absent Achilles reflexes, reduced distal vibration sense, pes cavus, and hammertoes. A dominant family history was noted. Brain MRI revealed bilateral contrast enhancement and thickening of cranial nerves III through XII. Genetic testing with whole exome sequencing revealed a known, recurring, heterozygous, likely pathogenic missense variant in FBLN5 [c.1117C>T; p. (Arg373Cys)], consistent with a diagnosis of CMT1H.

Interpretation

This is the first reported case of FBLN5‐related CMT1H with symptomatic cranial nerve involvement, expanding the known phenotypic spectrum of the disease.

1. Background and Aims

Charcot‐Marie‐Tooth disease (CMT) is a group of hereditary peripheral neuropathies characterized by progressive distal muscle weakness, atrophy, and sensory loss, most often with onset during childhood. Although CMT typically affects the peripheral nerves, cranial nerve involvement has been reported on rare occasions. Such involvement is more commonly asymptomatic. When symptomatic, manifestations are generally subtle and may be overlooked [1].

FBLN5 encodes fibulin‐5, an extracellular matrix protein involved in elastic fiber assembly, tissue homeostasis, and embryonic development. Pathogenic variants in FBLN5 have been associated with cutis laxa, age‐related macular degeneration, and CMT type 1H (CMT1H). CMT1H is a rare, autosomal dominant, demyelinating subtype of CMT, typically presenting in the third to fifth decade of life with mild to moderate progression and relatively preserved function [2].

Herein, we report a unique case of genetically confirmed CMT1H in a patient who presented with diplopia associated with radiological evidence of bilateral cranial nerve involvement. To the best of our knowledge, this represents the first reported case of symptomatic cranial nerve involvement in FBLN5‐related CMT, thereby expanding the phenotypic spectrum of this rare disease.

2. Case Report

We present the case of a 45‐year‐old woman with a 5‐year history of long‐standing visual disturbances, initially manifesting as nonspecific visual complaints and later evolving into persistent diplopia. There was no previous history of strabismus during childhood nor adulthood. She was first evaluated at the age of 42 in a neuromuscular outpatient clinic, where brain and orbital MRI revealed pathological contrast enhancement and thickening of cranial nerves III through XII bilaterally (Figure 1A–C). Based on these findings, she was admitted for further investigation.

FIGURE 1.

(A–C) 3D T1 black blood post contrast administration (A and B axial, C coronal) images revealing bilateral enhancement and thickening of cranial nerves III (A, arrows), V (B, arrows) and VII–VIII (C, arrows). (D) Hyperintensity and thickening of lumbar‐sacral roots and lumbosacral plexus (D, arrows) shown on maximum intensity projection (MIP) coronal reconstruction of 3D T2 with fat suppression sequence. (E) Pes cavus and hammer toes. (F) Family tree showing dominant inheritance (F, arrow indicates index patient). (G) Sanger sequencing chromatogram, showing the FBLN5 c.1117C>T, p. (Arg373Cys) variant (G, arrow). (H) Hess screen confirmed the presence of a partial abduction deficit in either eye.

On admission, neurological examination showed bilateral limitation of eye abduction, most prominent toward the right with diplopia in all directions of gaze, particularly horizontally (Video S1, segment 1). A mild esotropia of the right eye was present in the neutral position. The remaining cranial nerves were normal. Mild distal weakness was noted in toe flexion and extension, alongside decreased tendon reflexes and absence of Achilles reflexes. Upper limb strength was normal. Vibration sense was reduced in the toes, but touch, pinprick and position sense were normal. Musculoskeletal abnormalities were present, including pes cavus and hammertoes (Figure 1D). She was unable to walk on her heels, but her gait was otherwise normal (Video S1, segment 2). Her CMT Neuropathy Score was 7. Further history revealed that she had never been able to run properly, an observation also reported in her sister, who experienced frequent falls. Similar musculoskeletal features were present in her mother and maternal grandmother (Figure 1E). There was no evidence of hyperelastic skin on general examination nor age‐related macular degeneration on ophthalmological examination. We note that at this point a Hess test was not performed as part of the ophthalmological assessment.

Additional investigations revealed mildly elevated cerebrospinal fluid (CSF) protein levels (73 mg/dL), symmetrical thickening of the lumbosacral nerve roots on spinal MRI (Figure 1F), and a demyelinating sensorimotor polyneuropathy with uniform slowing of velocities, no evidence of conduction block, and chronic neurogenic changes on electrophysiological studies (Table 1). Extensive screening for infectious, autoimmune, neoplastic, and paraneoplastic causes was unremarkable, including tests for thyroid ophthalmopathy and myasthenia gravis. Given the clinical phenotype and positive family history, genetic testing for CMT1A and hereditary neuropathy with liability to pressure palsies (HNPP) (PMP22 duplication/deletion) was performed with multiplex ligation‐dependent probe amplification (MLPA), but came back negative.

TABLE 1.

Electrophysiological findings of the patient with CMT1H caused by the recurring c.1117C>T, p. (Arg373Cys) FBLN5 variant, revealing a demyelinating sensorimotor polyneuropathy with chronic neurogenic changes.

Nerve conduction studies
Limbs	Nerves	Motor conduction			Sensory conduction
		Amp (mV)	CV (m/s)	DL (ms)	Amp (μV)	CV (m/s)	DL (ms)
Upper	Median	4.8	23.6	8.1	0.0	—	—
	Ulnar	4.1	25.5	6.0	0.0	—	—
	Radial	—	—	—	6.7	29.4	3.1
Lower	Common peroneal	0.6	18.2	8.6	—	—	—
	Sural	—	—	—	0.0	—	—

Needle electromyography
Limbs	Muscle	Spontaneous activity		Recruitment	Motor unit potential
		Positive waves	Fibs		Form	Amp	Duration
Upper	Biceps	None	None	Mildly reduced	NL	NL	NL
	1st DI	None	None	Mildly reduced	NL	High	NL
Lower	Anterior tibial	None	None	Moderately reduced	NL	High	NL
	Gastrocnemius	None	None	Moderately reduced	NL	High	NL

Abbreviations: 1st DI, first dorsal interosseous; Amp, amplitude; CV, conduction velocity; DL, distal latency; Fibs, fibrillation potentials; NL, normal.

Three months later, the patient was re‐admitted and treated with a 3‐day course of intravenous corticosteroids, without clinical improvement. She was discharged and underwent further genetic evaluation with whole exome sequencing, which revealed a known, recurring, heterozygous, likely pathogenic missense variant in FBLN5 (NM_006329.4): c.1117C>T, p. (Arg373Cys), confirmed by Sanger sequencing (Figure 1G). This finding established a diagnosis of CMT1H. Genetic counseling was offered to the patient and her family. At follow‐up 2 years later, the patient's condition remained mild without significant changes. At this time, a Hess test was performed by an ophthalmologist with special expertise in strabismus, which confirmed the presence of a partial abduction deficit in either eye (Figure 1H).

3. Interpretation

CMT1H, a rare form of demyelinating CMT first described in 2011, is characterized by late‐onset (third to fifth decade), relatively mild motor involvement and prominent sensory disturbances. It is most often caused by a recurring variant in FBLN5, the c.1117C>T, p. (Arg373Cys) variant [2]. Carriers of this variant can have a mild CMT phenotype, as observed in our patient [2]. Neither the presence of cranial nerve involvement nor a presentation with diplopia has ever been reported in patients with CMT1H.

Cranial nerve involvement is a rare manifestation of CMT and has been primarily observed in demyelinating forms of the disease, including common subtypes, such as CMT1A and HNPP, but also rare subtypes, such as CMT1D and CMT1E [1]. MRI usually reveals cranial nerve enlargement and/or enhancement, as observed in our patient. In a large case series, thickening and enhancement of cranial nerves on MRI were detected in 20% of patients with hereditary neuropathies and were inconsistently associated with clinical deficits [1].

Although more commonly asymptomatic, cranial nerve involvement in patients with CMT can also be symptomatic. More often this involves the vestibulocochlear nerve, usually affected bilaterally, followed by the trigeminal nerve [1]. However, rare cases with long‐standing diplopia, resembling our patient, have also been reported in both common and rare CMT subtypes, such as CMT1A and CMT1D [1, 3]. These cases had a presentation more consistent with a partial oculomotor palsy.

It would be of some interest to screen larger case series of patients with CMT1H for cranial nerve involvement on MRI. If asymptomatic cranial nerve enlargement and/or enhancement was shown to be relatively prevalent in these patients, it could be used in the future as a potential red flag, raising suspicion of this rare form of demyelinating CMT caused by FBLN5 variants.

The presence of elevated cerebrospinal fluid (CSF) protein levels in the absence of pleocytosis has often been found when sought in patients with demyelinating forms of CMT [4]. Similarly, symmetrical thickening of the lumbosacral nerve roots on spinal MRI is a documented feature of demyelinating CMT [5]. The above, therefore, despite also being characteristic of chronic inflammatory demyelinating polyradiculoneuropathy, represent findings consistent with CMT1H, a demyelinating form of CMT.

In conclusion, we have presented a case of CMT1H with diplopia as the presenting symptom, associated with radiological evidence of cranial nerve involvement. To the best of our knowledge, this is the first reported case of FBLN5‐related CMT1H with symptomatic cranial nerve involvement, expanding the known phenotypic spectrum of the disease. This case highlights the diagnostic importance of next‐generation sequencing, particularly in patients with non‐classical features or strong family history with negative results from routine genetic panels.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Video S1: Video showing bilaterally restricted eye abduction, most prominent toward the right (segment 1), and difficulty walking on heels (segment 2).

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.