Approximately 20% of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the superoxide dismutase 1 gene (SOD1). More than 160 mutations have been reported.[1-3]
A 63-year-old man developed insidious onset of lower facial weakness. The initial symptom was difficulty speaking. One year later. he noticed difficulty smiling and handling food in the mouth due to weakness in his cheeks. No laterality of symptoms was reported, and neurological examination showed no tongue or limb involvement. Two years after onset, he noted progressive left hand weakness and loss of dexterity. Examination demonstrated bilateral lower facial weakness and atrophy, sparing the frontalis muscle. There were no tongue fasciculations. Articulation was normal except for labial consonants. There was a positive jaw jerk. The remainder of the cranial nerve examination was normal. There was mild distal left upper extremity atrophy and weakness. In the lower limbs, tone was increased, but power was normal. Reflexes were brisk in all limbs. The Hoffman sign was absent, and plantar reflexes were extensor.
A first cousin on his father's side died of ALS. Blood tests and cerebrospinal fluid were unremarkable. MRI scan of brain and spine were normal. Electrodiagnostic studies supported a diagnosis of motor neuronopathy. Needle examination revealed chronic neurogenic changes in the face, widespread and frequent polymorphic fasciculation potentials in the limbs, less frequent fasciculation potentials in the paraspinal and trapezius muscles, and very mild and patchy neurogenic abnormalities in the limbs. Nerve conduction studies were normal except for a mild ulnar neuropathy at the left elbow. Central motor conduction times showed prolonged latency in the upper left limb. Sequencing of SOD1 revealed a heterozygous T>C point mutation resulting in the substitution of Isoleucine for Threonine at amino acid 113 (Ile113Thr).
In the following 6 months, the patient developed spasticity and widespread fasciculations in all limbs. He did not develop emotional lability. He died 3 years after symptom onset.
The Ile113Thr mutation was among the first SOD1 mutations described and is the third most common SOD1 mutation. Its penetrance was shown to be low in fALS families making it plausible that the proband's cousin, who died of ALS, also had this mutation and that both the patient's father and uncle were obligate carriers who did not develop ALS (Figure 1). Previous reports of the SOD1 Ile113Thr mutation indicate a mean age of onset of 57.8 ± 15.1 years and a disease duration of 4.2 ± 2.5 years, which are both compatible with the described patient. This mutation has been linked recently to a patient with ALS/FTD, another very atypical finding for SOD1 ALS.
In a previous report, a patient with the SOD1 A4V mutation presented with facial diplegia, but this also involved upper face muscles and was accompanied by dysarthria, dysphagia, and unilateral vocal cord paralysis. The striking feature of the patient reported here is that the facial diplegia was the only finding for the first 2 years.
In summary, this atypical presentation for a common SOD1 fALS mutation expands the known clinical spectrum of this mutation.
Pietro Fratta, MD1,2
Michael G. Hanna, MD2
Elizabeth M.C. Fisher, PhD1,2
Katie Sidle, MD2
1Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
2MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom