Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene

Patients.

Patient 1 is a 21-year-old man who, since age 10, has been repeatedly hospitalized for episodes lasting from 5 hours to 3 days. The episodes are characterized by weakness, moderate or severe (at times complete paralysis), involving the extremities and, to a lesser extent, the trunk and head, with dysarthria and dysphagia. Between episodes, the patient shows no disturbance of consciousness, whereas during severe ones, he presents with dyspnea, somnolence (score of 13 on the Glasgow Scale), and frequent yawning. No precipitating factors for these episodes or myotonia have been reported. At age 16, Patient 1 presented with permanent distal mild weakness and atrophy of the upper and lower extremities. The frequency and severity of weakness episodes have remained unchanged.

Patient 2 is the 19-year-old brother of Patient 1, who, at age 12, presented with almost identical episodes of weakness. At age 17, he also presents with weakness and atrophy of the upper and lower extremities distally.

Examinations.

Clinical examination of both patients disclosed muscle atrophy and weakness of the upper and lower extremities distally, loss of tendon reflexes, and pes cavus. The plantar reflexes were extensive in Patient 1 and indifferent in Patient 2. There was mild sensory impairment of the limbs distally. No myotonia, dysmorphic features, or cardiac dysrhythmias were detected.

The laboratory investigation of both patients, including serum calcium and lactic acid levels during and between episodes, anti-acetylcholine receptor antibodies, as well as laboratory tests for collagen disease, primary aldosteronism, thyroid and kidney disease, X-linked adrenoleukodystrophy, Krabbe’s leukodystrophy, and metachromatic leukodystrophy, was normal. In repeated measurements, the serum potassium and muscle enzyme levels were normal in both patients, during and between episodes. The serum potassium level varied from 3.9 to 4.7 mEq/L (normal 3.5 to 5.2 mEq/L), creatine kinase level from 56 to 81 U/L (normal 24 to 190 U/L), lactic dehydrogenase level from 250 to 310 U/L (normal 220 to 450 U/L), and aldolase level from 4.1 to 5.2 U/L (normal 3.1 to 7.6 U/L). The results of lumbar puncture were normal in both patients. Routine and 24-hour EEG recordings between episodes were normal, whereas repeated recordings during episodes showed moderate diffuse slowing (figure 1).

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Figure 1. EEG tracing of Patient 2, showing normal recording between episodes (A) and diffuse slowing during a severe episode (B). Electrode placements were according to the 10–20 system.

Psychometric testing between episodes showed no abnormalities in both patients. The scores were as follows (Patient 1/Patient 2): Wechsler Scale 109/111, Auditory Verbal Learning Test 12/11 (mean normal 12.9), and Complex Figure Test 31/33 (normal range 18 to 36). Psychometric testing was not possible during severe episodes.

The electrophysiological examination in both brothers showed marked reduction of motor and sensory conduction velocities and findings of chronic denervation. No myotonic discharges were detected. Repeated recordings during episodes showed no further changes. Visual evoked potentials and brainstem auditory evoked responses were abnormal (table). Repetitive stimulation and single-fiber electromyography was normal during and between episodes.

The brain MR scan of both patients showed symmetric bilateral hyperintensities of the periventricular white matter in T2-weighted images (figure 2).

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Figure 2. Brain MRI scan of Patient 1, showing symmetric bilateral regions of high-density signal in T2-weighted images in the periventricular white matter.

The patients’ parents are unrelated. The father is healthy, whereas the mother, who is asymptomatic, showed bilateral pes cavus and a moderate reduction of motor and sensory conduction velocities, with findings of denervation (see the table). An X-linked mode of inheritance was considered likely.

DNA analysis.

Genomic DNA was extracted from peripheral blood nucleated cells of the parents and the two patients, using standard methods. The search for mutations in the GJB1 gene was performed using nucleotide sequencing.2 The mother and the two affected sibs showed a C-to-T transition at the position 164 of exon 2, resulting in a substitution of threonine by isoleucine at amino acid position 55 in the first extracellular loop.

Search for mutations in the SCN4A gene, responsible for hyperkalemic periodic paralysis, was performed by single-strand conformation polymorphism (SSCP) of PCR-amplified genomic DNA products obtained with primers specific for all 24 SCN4A exons.5 Search for mutations in the CACLN1A3 gene, responsible for hypokalemic periodic paralysis, was performed by restriction enzyme digest (BbvI) of DNA encoding D2S4 and SSCP analysis of regions of DNA encoding D4S4, D1S4, D3S4, and the cytoplasmic loop between domains 2 and 3, according to a previously described method.6 No mutations were identified in either case.