Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation

Abstract

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (GJB1) mutations. We herein report a 25-year-old Japanese man with disorientation, right hemiparesis, and dysarthria. Brain magnetic resonance imaging (MRI) showed high signal intensities in the bilateral cerebral white matter on diffusion-weighted imaging. He had experienced 2 episodes of transient central nervous system symptoms (at 7 and 13 years old). A genetic analysis identified a novel GJB1 mutation, c.169C＞T, p.Gln57*. MRI abnormalities shifted from the cerebral white matter to the corpus callosum and had disappeared at the five-month follow-up. Transient changes between these lesions may indicate CMTX1.

Introduction

Charcot-Marie-Tooth disease (CMT) is a genetic disorder that shows peripheral neuropathy. The most common form of CMT, CMT1A, is inherited in an autosomal-dominant manner and is caused by heterozygous duplication or a point mutation of the peripheral myelin protein 22 (PMP22) gene (1).

X-linked CMT (CMTX) is the second-most common form, accounting for 7-15% of cases of CMT occurrences (2,3). To date, six forms of CMTX have been reported (4). CMTX type 1 (CMTX1) accounts for 90% of all CMTX cases and causes demyelinating neuropathy or axonopathy. Occasionally, CMTX1 patients repeatedly show transient central nervous system (CNS) dysfunctions and cerebral lesions on magnetic resonance imaging (MRI) (5-7).

We herein report a patient with CMTX1 caused by a novel gap-junction beta 1 (GJB1) mutation who showed spatial fluctuation of cerebral lesions on MRI during a short follow-up period.

Case Report

A 25-year-old Japanese man had a history of 2 bouts of CNS symptoms. At seven years old, he had experienced a first attack consisting of dysesthesia of the right upper extremity, urinary incontinence, and dysarthria after influenza vaccination. Head MRI had shown high signal intensities in the bilateral cerebral white matter of the parietal and occipital lobes and the splenium of the corpus callosum on T2-weighted imaging (Fig. 1A). Acute disseminated encephalomyelitis (ADEM) had been suspected, and intravenous methylprednisolone (IVMP) therapy followed by oral steroids had been administered. The CNS symptoms had immediately improved.

Figure 1.

Brain MRI findings from the first attack to the current attack. (A) A T2-weighted image from the first attack at 7 years old is shown. High signal intensities on T2-weighted images are shown with white arrows. (B-G) Images from the current attack at 25 years old are shown: DWI (B), ADC map (C), T2-weighted image (D), and Gd-DTPA-enhanced image (E). High signal intensities on DWI were seen in the deep white matter. The lesions had low signal intensities on the ADC map, indicating cytotoxic edema. Follow-up MRI is shown as DWI two weeks later (F) and five months later (G). Two weeks later, the high signal intensity had shifted from the white matter to the corpus callosum (white arrow). Five months later, these lesions had returned to normal.

The second attack occurred at 13 years old. Muscle weakness and dysesthesia of the left side of the body and dysarthria had appeared after a streptococcal infection. MRI had shown high signal intensities in the corpus callosum and white matter of the parietal lobes on diffusion-weighted imaging (DWI) and T2-weighted imaging. Recurrence of ADEM had been suspected, so IVMP therapy had been administered. The CNS symptoms had improved within an hour of the start of the initial steroid infusion.

In the present attack, the patient reported feeling sensory disturbance and dysarthria upon waking and was admitted to his local hospital. DWI showed high signal intensities in the bilateral cerebral white matter (Fig. 1B). In accordance with previous reports, the lesions showed low signal intensities on apparent diffusion coefficient (ADC) mapping (Fig. 1C) (8,9). In addition, the lesions showed faint high signal intensities on T2-weighted imaging (Fig. 1D) and were not enhanced by gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA) (Fig. 1E). The following day, his symptoms worsened with the addition of mild muscle weakness in his right upper and lower extremities. IVMP therapy was administered because its effectiveness could not be excluded based on experiences with his previous attacks. At that point, he was referred to our hospital.

A neurological examination showed disorientation and right hemiparesis without pathological reflexes. His tendon reflexes were totally diminished, and the vibratory senses of lower extremities were reduced. He also had pes caves. A laboratory examination showed no abnormalities in blood cell counts, electrolytes, the liver or renal function, or the coagulation system. Anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative. Very-long-chain fatty acids and enzyme activities of arylsulfatase and galactocerebrosidase in leukocytes were normal. A cerebrospinal fluid analysis showed no abnormal findings in cell counts, total protein or glucose levels, oligoclonal bands, Interleukin-6, or myelin basic protein.

In a nerve conduction study, compound muscle action potentials of the tibial nerves were not evoked (Fig. 2). The right motor nerve conduction velocities of the median and ulnar nerves were reduced to 34.5 m/s (normal range; 47.9-67.5 m/s) and 35.2 m/s (normal range; 48.5-68.9 m/s), respectively.

Figure 2.

Findings of the nerve conduction study. Both the median and ulnar nerves showed a decrease in conduction velocity. Action potentials of the tibial, peroneal, and sural nerves were not evoked. CMAP: compound muscle action potential, NCV: nerve conduction velocity, SNAP: sensory nerve action potential

A review of family history interviews revealed that his brother had been diagnosed with CMT, and his mother had a dropped foot (Fig. 3A). After obtaining informed consent from the patient, we performed a DNA analysis by target sequencing using the Ion Proton next-generation sequencer system (Life Technologies, Tokyo, Japan). This target sequencing analysis analyzed the coding regions and flanking splice regions of 100 genes, including PMP22, myelin protein zero (MPZ), and ganglioside-induced differentiation-associated protein 1 (GDAP1), which are causative for CMT, hereditary motor neuropathy, and hereditary sensory and autonomic neuropathy. We found a C-to-T variation at nucleotide position 169 of the GJB1 gene (Accession #NM_001097642.3), resulting in an amino acid change from glutamine to a stop codon at position 57.

Figure 3.

Family pedigree (A) and results of a genetic analysis (B). (A) Squares indicate males; circles, females; open symbols, unaffected members; closed symbols, affected members; cross-out symbol, deceased member. The arrow indicates a proband. (B) A genetic analysis using Sanger sequencing showed a single-base substitution in the GJB1 gene. The proband (III-3) and his brother (III-4) had the mutation, and his mother (II-4) had the heterozygous mutation. His father (II-3) did not have the mutation.

This c.169C＞T, p.Gln57*, nonsense mutation is novel; therefore, we performed a DNA analysis of the patient and family members by Sanger sequencing (Fig. 3B). The affected family members (the proband's mother and brother) had the same mutation, whereas the healthy father did not. We diagnosed the present patient with CMTX1 with a novel GJB1 mutation.

His symptoms immediately improved. Follow-up MRI after two weeks showed that the high signal intensities of the white matter on DWI had disappeared, while a high signal intensity appeared in the splenium of the corpus callosum (Fig. 1F). Five months later, the splenial lesion on DWI had disappeared entirely (Fig. 1G).

Discussion

Mutations in GJB1 cause CMTX1, with more than 400 having been reported (4). GJB1 encodes a gap-junction protein called connexin 32 (Cx32) (7). Cx32 is expressed in myelinating Schwann cells and oligodendrocytes (10). Several CMTX1 cases are reported to have developed CNS symptoms, including dysarthria, dysphagia, hemiplegia, tetraplegia, sensory disturbance, ataxia, and cranial nerve palsy (4). CNS symptoms often occur as the initial manifestation of CMTX1 and can be independent of the severity and duration of peripheral neuropathy. While most CNS symptoms improve within hours to weeks, head MRI abnormalities return to normal on a time scale ranging from nine days to two years (11).

Factors reported to induce CNS attack include a fever, high-altitude travel, exercise, and hyperventilation (12). The colocalization of Cx32 and Cx47 in oligodendrocytes may be responsible for the CNS involvement that occurs under these stress conditions (10). Brain lesions often extend symmetrically from the corpus callosum to the white matter of the parieto-occipital and temporo-occipital lobes (4,11), but few reports have described a change in the lesion site over a short period of time. Metabolic diseases (such as adrenoleukodystrophy) and inflammatory diseases (such as ADEM) must be differentiated. In the present case, IVMP was administered on suspicion of recurrent ADEM. In another CMTX1 case, intravenous immunoglobulin was administered because atypical chronic inflammatory demyelinating polyneuropathy was suspected (13). However, CNS symptoms of CMTX1 spontaneously resolve.

It is thought that mutant Cx32 reduces the number of functioning gap junctions between oligodendrocytes and astrocytes, resulting in impaired fluid exchange and high signals on DWI (10). The mainstay of CMTX1 treatment is supportive care, such as physical therapy and pain management. Patients diagnosed with CMTX1 are recommended to avoid factors that may induce CNS involvement.

A systematic review by Tian et al. found that, of the 46 CMTX1 cases that experienced transient neurological symptoms, the majority had missense mutations in GJB1, with only 3 having nonsense mutations (6,13-15) (Table). Although a novel genetic mutation was identified in the present case, the clinical presentation was similar to that of previously reported cases. CMTX1 is thought to have similar clinical manifestations, regardless of the type of mutation. The GJB1 p.Gln57* mutation segregated with the disease-associated symptoms in this family. This is the second case report of a patient with repeated transient CNS symptoms and confirmed segregation of a GJB1 mutation causing conversion to a stop codon (4,13). Women are affected by milder CMTX1 symptoms than men (5,7), and the proband's mother's symptoms were consistent with this tendency. In addition, clinical symptoms may differ among men in the same family, suggesting that cryptic genetic variation may modify disease severity.

Table.

Clinical Features of CMTX1 Patients with GJB1 Nonsense Mutations and CNS Symptoms.

No. (Ref)	Age	Sex	Mutation	Trigger	CNS symptoms	MRI findings	Tx, outcome
1 (13)	15	M	Trp133*	Vomiting and diarrhea	Numbness of Lt face and arm, paresis of Lt arm, and dysphagia for several hours	DWI/T2 high signal in the posterior portion of the centrum semiovale and the splenium of the CC	IVIG (s/atypical CIDP), improved
2 (13)	No.1’s mother	F	Trp133*	None	None	Not available	IVIG (s/CIDP), improved
3 (14)	12	M	Trp132*	None	Monoparesis, dysarthria for 1 hour	Not available	None, improved
	16			None	Same	Not available	None, improved
	21			None	Same	Not available	None, improved
	28			None	Same	DWI/T2 high signal in the bilateral deep WM and the splenium of the CC	None, improved
4 (15)	21	M	Glu186*	None	Repeated Lt hemiparesis for one week	DWI/T2 high signal in the WM of the FP corona radiata and the corpus callosum	Aspirin and dipyridamole (s/recurrent ischemic stroke), improved
	23			exercise	Lt hemiparesis and dysarthria	DWI/T2 high signal in the WM of the FP CR and the CC	None, improved
5 (This case)	7	M	Gln57*	Vaccination	Dysesthesia of the Rt upper extremity, urinary incontinence, and dysarthria	T2 high signal in the bilateral deep WM and the splenium of the CC	IVMP (s/ADEM), improved
	13			Infection	Hemiparesis, dysesthesia, dysarthria	DWI/T2 high signal in the WM around the parietal lobe and the CC	IVMP (s/ADEM), improved
	25			None	Sensory disturbance and dysarthria	DWI/T2 high signal in the WM of PO lobes	IVMP (s/ADEM), improved
6 (III-4)	No.5’s brother	M	Gln57*	None	None	Not available	None
7 (II-4)	No.5’s mother	F	Gln57*	None	None	Not available	None

ADEM: acute disseminated encephalomyelitis, CC: corpus callosum, CIDP: chonic inflammatory demyelinating polyneuropathy, CR: corona radiata, FP: frontoparietal, Lt: left, IVIG: intravenous immunoglobulin, PO: parieto-occipital, Rt: right, s/: suspected, Tx: Treatment, WM: white matter

When patients develop transient CNS involvement and reversible MRI abnormalities fluctuating between the cerebral white matter and corpus callosum, it is important to consider the possibility of CMTX1 by evaluating peripheral neuropathy and collecting family history information.

The authors state that they have no Conflict of Interest (COI).