The Proband's brother is a 58-year-old man who presented with appendicular and low back pain with progressive reduced manual dexterity and imbalance since childhood. Due to work-related difficulties and a clinical suspicion of CMT neuropathy, he was referred to the neuromuscular clinic for specialist evaluation. He had elective carpal tunnel decompression surgeries at a private clinical facility (data not available for review) and underwent magnetic resonance imaging of the lumbar spine with and without contrast at an external facility that showed broad-based disk bulge, bilateral facet joint degeneration changes, and mild-to-moderate bilateral neuroforaminal narrowing at the L4-L5 and L5-S1 levels, associated with Grade 1 L5-S1 anterior spondylolisthesis. Prior to his initial neuromuscular clinic evaluation, he underwent lumbar epidural spinal injections at a private practice pain clinic that improved the pain and numbness in his feet. He mentioned that his older sister had been diagnosed with CMT neuropathy as a teenager.
Examination revealed muscle atrophy of the hands, feet, and distal legs with high arched feet and high steppage gait. Confrontational strength testing based on the MRC scale showed finger abduction, adduction and extension (4/5), ankle plantarflexion (3/5), and ankle dorsiflexion (2/5) weakness bilaterally. All other muscle groups were normal. Sensory examination revealed subjectively decreased proprioception and absent vibratory sense at the hallux with decreased light touch and pinprick sensation below the knees bilaterally. Myotactic stretch reflexes were absent at the ankles and normal elsewhere.
Comprehensive laboratory tests for acquired causes of polyneuropathy (comprehensive metabolic panel; complete blood count with differentials; hemoglobin A1c; thyroid function tests; vitamins B1, B6, B12, and D levels; serum electrophoresis; serum immunofixation; Lyme disease serology; autoimmune neuropathy panel [antiganglioside IgG/IgM, anti-myelin-associated glycoprotein IgM; and anti-sulfate-3-glucuronyl paragloboside IgM antibodies]), and 24-hour urine heavy metal screen was normal. EDX studies (Table 1) demonstrated a moderately severe, chronic length-dependent predominantly axonal sensorimotor polyneuropathy with some demyelinating features and no conduction block, as seen in DI-CMTB.
To evaluate a clinical suspicion of autosomal dominant CMT neuropathy in our patients, the Hereditary Neuropathy genetic test panel was performed by GeneDx (Gaithersburg, Maryland) using oral rinse specimens. Using genomic DNA from the submitted specimens, the coding regions and splice junctions of the genes in the panel were enriched via GeneDx's proprietary-targeted capture system. These targeted regions were sequenced simultaneously using massively parallel (NextGen) sequencing on an Illumina platform using pair-end reads. Bi-directional sequence was assembled, aligned to reference gene sequences based on human genome build GRCh37/UCSC hg19, and analyzed for sequence variants.
Genetic testing identified a heterozygous missense point mutation in exon 15 of the DNM2 gene (c.1609 G>A) on chromosome 19, resulting in substitution of glycine 537 to serine (p.Gly537Ser) in the Proband and her brother (see arrow, Figure 2). This is a non-conservative amino acid substitution, which likely impacts the highly conserved PH domain protein structure and function based on GeneDx's in silico analysis. Importantly, a different amino acid substitution at the same position, c.1609 G>T (p.Gly573Cys),   and the same point mutation in a nearby residue, c.1597 G>T (p.Gly533Cys),   are associated with DNM2-related disorders. As the mutation had neither been previously published as a pathologic variant nor reported as a benign variant, it was initially classified as a variant of undetermined significance.
Due to our high index of suspicion that this mutation was pathogenically significant based on the clinical phenotypes that were consistent with CMT neuropathy and the potential impact of the mutation on secondary protein structure or function, the patients' undiagnosed symptomatic mother and asymptomatic father underwent targeted genetic testing. Their mother possessed the same heterozygous missense DNM2 point mutation which was absent in their father (Figure 2), supporting our inference that DNM2 (c.1609 G>A) is causative of DI-CMTB in this family cohort.
During follow-up neuromuscular clinic visits over the next 2-3 years, the Proband (case 1) reported increased falls despite wearing AFOs; worsening pain in multiple joints, including her hips and knees; progressive weakness in her hands with reduced dexterity; and persistent paresthesias in her feet, adequately treated with Gabapentin. Her brother (case 2) reported worsening hand and leg strength and progressive difficulty standing for prolonged periods and walking. He decided against using AFOs due to perceived discomfort and walked cautiously to prevent falls without using ambulatory aids.