A novel syndromic form of sensory‐motor polyneuropathy is linked to chromosome 22q13.31‐q13.33

To the Editor : Hereditary peripheral neuropathies are the most common inherited diseases of the nervous system (1). Several clinical forms are described with Charcot-Marie-Tooth (CMT) disease being the most common with extensive genetic heterogeneity (2,3). Here, we describe a family with an apparently novel syndrome in which sensorymotor polyneuropathy is associated with microcephaly, mental retardation, ophthalmoplegia and syndactyly. Index is a 46-year-old Saudi male. He was born to healthy first cousin parents and was noted to have syndactyly and strabismus early in infancy. Motor development was normal, but he did have cognitive delays. By 15 years of age, he developed progressive lower extremities weakness and became immobile by 33 years. Weakness of the upper extremities occurred later at the age of 36 years and currently he is challenged to perform even basic hand functions. Sphincter control is normal. He was short (150 cm) and microcephalic (48 cm) on exam. His facies were largely nondysmorphic (Fig. 1a). He was cognitively impaired with an IQ of 47. Ophthalmoparesis was evident particularly on adduction and downward gaze (Fig. 1b). Pupils were not reactive and oculocephalic response was absent. Mild facial weakness was noted and mild dysarthria but no tremor or ataxia. There was wasting of calf muscles with foot drop, but the foot arch was largely normal. Deep tendon reflexes were absent and proprioception, touch and temperature sensation were impaired in a length-dependent pattern. There was bilateral syndactyly (Fig. 1c,d) and severe weakness of the wrist movement and mild wasting of the forearms. MRI brain showed mild non-specific brain atrophy. Electrophysiological tests confirmed significant peripheral neurogenic involvement. The compound muscle action potentials were markedly reduced in amplitude but normal in shape, and the sensory nerve action potentials were absent with surface recording and only obtainable with near nerve recording. The sensory and motor conduction velocities were mildly reduced with a range of 34–46 m/s. Motor unit potentials were neurogenic with clear signs of renervation but no signs of active denervation. Nerve biopsy showed moderately depleted myelinated axons of all fiber size with no onion bulbs. There was no evidence of active axonal degeneration, but there was some attempt of axonal sprouting (Fig. S2). Muscle biopsy showed neurogenic angulated muscle fibers and mild fiber type grouping; however, there was no evidence of ragged red fibers. Case 2 is the 45-year-old brother of Case 1. History was similar. Weakness started at the age of 10, was immobile by the age 25, and lost purposeful use of his hand at the age of 30 years, with additional decreased sensation and incontinence. His ability to swallow has deteriorated at the age of 41 and is on strictly soft diet. Physical examination revealed short stature and microcephaly (50.2 cm) (Fig. 1e). His IQ was 50. There was bilateral exotropia with ophthalmoplegia (Fig. 1f). Facial weakness was evident and gag was difficult to elicit. There was wasting and weakness in forearms and legs with absent reflexes and impaired proprioception. Pain and touch sensation were reduced distally. He had mild webbing of the fingers and two-thirds toe syndactyly (Fig. 1g,h). Conduction studies and EMG were consistent with mainly axonal sensory-motor polyneuropathy with evidence of denervation in upper and lower extremities. Case 3 is the 34-year-old brother of Case 1 who similarly had strabismus and progressive weakness (upper < lower) that started at the age of 20 years, but he is still able to ambulate albeit with great difficulty. He reports normal sensation, but has been incontinent for urine recently.