Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

Abstract

Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Figure 1

CMT pedigrees with a DNM2 mutation. Open/filled/half-filled diamond = unaffected/affected/probably affected; ‘?’ within diamond = CMT-status unknown; slashed diamonds = deceased; n, normal allele; m, mutant allele; ‘?’ at left upper side of diamond, blood cell counts unknown; * = neutropaenia; £ = normal number of white blood cells but only one measurement; § = cataract. The arrow indicates the propositus. The gender is not shown to preserve confidentiality.

Figure 2

Cataract in a DNM2-mutated CMT patient. Presence of nuclear cataract in combination with cortical cataract in the left eye of patient III.4 of family CMT-48 at the age of 45 years.

Figure 3

Blood cell counts in patients of two DNM2-mutated CMT families with neutropaenia. For each patient of family CMT-48 and CMT-310 the number of white blood cells (WBC; black dots) and neutrophils (grey squares) is shown in (A), and the number of red blood cells (RBC; asterisks for males and triangles for females) and platelets (grey dots) is indicated in (B). The horizontal lines indicate the lower normal limit(s) for the different blood cells. Patients with normal blood cell counts are underlined.

Figure 4

Somatosensory-evoked potentials in the three DNM2-mutated patients belonging to family CMT-103. Median nerve sensory potentials obtained between digitIII and wrist, and somatosensory-evoked potentials obtained after stimulation of the median nerve at the wrist, in patient I.2 (A, B), in patient II.2 (C, D) and in patient II.3 (E, F) of family CMT-103. N2 represents the N20 response.

Figure 5

Sural nerve biopsy of index patient of CMT family H20 with DNM2 mutation. (A) Semi-thin section of sural nerve showing diffuse loss of large myelinated fibres, and many clusters of myelinated and unmyelinated fibres. A thickly myelinated fibre is indicated by an arrow. Thionin Basic Fuchsin, magnification bar = 50 μm. (B) Teased fibres with focal myelin thickenings are shown. Magnification bar = 50 μm. (C) Electronmicrograph showing clusters of unmyelinated fibres and two clusters of flattened Schwann cell processes (asterisk). Magnification bar = 1 μm. (D) Clusters of myelinated and unmyelinated fibres and two fibres with broad Schmidt–Lanterman incisures (asterisk). Magnification bar = 10 μm.