Family 1. The proband, a 17-year-old male, was admitted to our hospital on July 25, 2018 after experiencing acute onset of profound dysarthria, chorea-choreiform movements, and confusion. His abnormal movements and confusion resolved over the course of several hours, but the slurred speech remained. In the following two days, he experienced two episodes of similar symptoms and recovered after few hours, but no triggering factors were identified.
A review of the patient’s past records revealed that he had experienced an episode of weakness in all four limbs at the age of 12. The episode was of sudden onset and resolved completely over the course of three hours without special treatment. He was evaluated at once with head CT scanning and no abnormalities were found in the first episode.
His physical examination was notable for his pes cavus when he arrived in our department. A detailed pedigree of other family members revealed that the patient’s mother, maternal grandfather, three maternal aunts, and so on also had pes cavus deformities, although none reported sudden onset of weakness or dysarthria episodes.
His neurological examination revealed the atrophy of his distal lower extremities, mild weakness of ankle dorsi- and plantar-flexion, absent deep tendon reflexes in the lower extremities, and negative bilateral Babinski signs.
Polymerase chain reaction (PCR) for Coxsackievirus IgG was positive in the serum but negative for Coxsackievirus IgM. The rest of the routine serum analyses were within the normal range. A serum lactic acid exercise test was applied to exclude mitochondrial encephalomyopathy. Serum lactic acid before exercise was 3.49 mmol/L(0.63~2.44 mmol/L), 3.73 mmol/L after exercise, and 6.75 mmol/L 30 minutes after exercise. Cell count, protein, glucose, and chloride were normal in the cerebrospinal fluid (CSF). CSF and the serum were negative for antibodies against AMPAR1 and AMPAR2, NMDAR, GABABR, LGI1, and Caspr2. A wide range of abnormalities in slow waves was found on the electroencephalograms (EEG). A brain diffusion-weighted magnetic resonance imaging (DWI) obtained on July 24, 2018 showed hyperintensities in the splenium of the corpus callosum and posterior subcortical white matter (Fig. 1-A). MR angiography (MRA) and MR spectroscopy (MRS) were normal. Two weeks later, a second MRI performed on August 6, 2018 showed only minor white matter lesions in the splenium of the corpus callosum and posterior periventricular areas. MRS was normal (Fig. 1-B). NCV data demonstrated a moderate to severe sensorimotor polyneuropathy with mixed demyelinating and axonal features at both upper and lower extremities. Genetic testing showed a c.425G>A (p. Arg 142 Glu) hemizygous point mutation in GJB1. His mother, older maternal aunt and her daughter, as well as a younger maternal aunt, who all had pes cavus also had the same point mutations in GJB1 (Fig. 2). CMTX1 coexistence with reversible posterior leukoencephalopathy was thus diagnosed by his family history, brain MRI, NCV data, and GJB1 mutation.
Intravenous methylprednisolone (500 mg/day for 3 days) followed by oral prednisolone (1 mg/kg/day) was administered because acute demyelinative encephalitis was diagnosed at arrival. Prednisolone was tapered when reversible posterior leukoencephalopathy was confirmed. The patient’s slurred speech improved without episode onset of chorea-choreiform movements and confusion when he was discharged on August 7, 2018. He had recovered to his baseline and symptoms of peripheral neuropathy remained at a 3-month outpatient follow-up.
Family 2. The proband, a 15-year-old male, presented with acute onset of dysarthria, weakness, and numbness in all four limbs on February 16, 2018. In 2 hours, his symptoms had improved but he experienced another two episodes with similar symptoms and recovered after a few hours on the next day. The initial brain MRI DWI on February 17, 2018 showed hyperintensities in both posterior periventricular areas and subcortical white matter of occipital and parietal lobe (Fig. 3-A); MRA and MRS were normal. A possible diagnosis of adrenoleukodystrophy was made when he was admitted to our hospital on March 3, 2018. His physical examination was normal except for pes cavus and diminished deep tendon reflexes in all extremities. The patient’s mother, maternal grandfather, aunt and her daughter also had pes cavus (Fig. 4). His routine serum and CSF analyses were within normal range. The serum of very-long-chain fatty acids, adrenal cortical hormones, and adrenal gland CT with enhancement were checked to exclude adrenoleukodystrophy and all were normal. The findings in EEGs were unremarkable. NCV indicated slight axonal sensorimotor neuropathy at lower extremities. Eighteen days later, a second MRI performed on March 6, 2018 showed normal (Fig. 3-B). Whole-exome sequencing of this patient showed a c.563 C>T (p. Thr 188 Ile) hemizygous point mutation in GJB1.
He had recovered to his baseline without episodes of dysarthria, weakness, and numbness with no special treatment when he was discharged on March 13, 2018. He presented normal at a 3-month outpatient follow-up.
Family 3. The proband, an 18-year-old male, presented with acute onset of left arm weakness on January 24, 2019. Within 20 hours, his symptoms had gradually improved, but he experienced new symptoms as dizziness, weakness and numbness in all four limbs, difficulties in raising head and opening mouth, dysarthria, and dysphagia with normal CT scanning on 11AM, January 25, 2019 and recovered after treatment in local hospital in a few hours. He had another two episodes with similar symptoms and recovered in a few hours on January 25 and 26. The brain MRI DWI on January 26, 2019 indicated hyperintensities in both posterior periventricular areas (Fig. 5-A). He was admitted to our hospital with diagnosis of adrenoleukodystrophy on January 29, 2019. He fell from a 2-meter height in the middle of December, 2018 and was treated in the hospital with diagnosis of abdominal injury, spleen and left kidney contusion, and both lumbar transverse process fracture. His physical examination was normal except for diminished deep tendon reflexes in all extremities.
His neurological examination revealed pes cavus, horizontal nystagmus on both eyes, atrophy in his hands and distal lower extremities, normal muscle strength, and absent deep tendon reflexes in all extremities. The finger-nose test and heel–knee test showed mild dysmetria on right limbs when closing eyes. The Romberg sign was positive, no matter when opening or closing eyes. NCV findings were suggestive of sensorimotor polyneuropathy at both upper and lower extremities. Genetic testing showed a c.103G>C (p. Val 35 Leu) hemizygous point mutation in GJB1. His great-grandmother, grandmother’s brother and grandfather who had pes cavus also had the same point mutations in GJB1 (Fig. 6).
He had recovered to his baseline without special treatment when he was discharged on January 31, 2019. He presented a normal brain MRI DWI within 2 weeks (on February 11, 2019, Fig. 5-B) and within one month (February 26, 2019, Fig. 5-C) during outpatient follow-up.
Electrophysiological characteristics in these three male probands were shown in Table 1 and 2. Motor nerve conduction velocities (MNCV) and sensory nerve conduction velocities (SNCV) were severely reduced in lower limbs as well as upper limbs in case 1 and case 3; however, MNCV and SNCV in case 2 were almost within normal range. Markedly low amplitude of sensory and motor responses were found at both peroneal nerves in case 1 and case 3. Long latency was detected in most motor nerves in the three cases.