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, 40 (3), 304-12

Distal Hereditary Motor Neuropathy in Korean Patients With a Small Heat Shock Protein 27 Mutation

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Distal Hereditary Motor Neuropathy in Korean Patients With a Small Heat Shock Protein 27 Mutation

Ki Wha Chung et al. Exp Mol Med.

Abstract

Distal hereditary motor neuropathy (dHMN) is a heterogeneous disorder characterized by degeneration of motor nerves in the absence of sensory abnormalities. Recently, mutations in the small heat shock protein 27 (HSP27) gene were found to cause dHMN type II or Charcot-Marie-Tooth disease type 2F (CMT2F). The authors studied 151 Korean axonal CMT or dHMN families, and found a large Korean dHMN type II family with the Ser135Phe mutation in HSP27. This mutation was inherited in an autosomal dominant manner, and was well associated with familial members with the dHMN phenotype. This mutation site is located in the alpha-crystallin domain and is highly conserved between different species. The frequency of this HSP27 mutation in Koreans was 0.6%. Magnetic resonance imaging analysis revealed that fatty infiltrations tended to progressively extend distal to proximal muscles in lower extremities. In addition, fatty infiltrations in thigh muscles progressed to affect posterior and anterior compartments but to lesser extents in medial compartment, which differs from CMT1A patients presenting with severe involvements of posterior and medial compartments but less involvement of anterior compartment. The authors describe the clinical and neuroimaging findings of the first Korean dHMN patients with the HSP27 Ser135Phe mutation. To our knowledge, this is the first report of the neuroimaging findings of dHMN type II.

Figures

Figure 1
Figure 1
Pedigree of the HSP27 Ser135Phe mutation in the dHMN family. The open symbols represent unaffected members (□, ○) and filled symbols affected members (■, ●). Half-filled symbol (◘) indicates an unaffected individual harboring the Ser135Phe mutation. Asterisks (*) indicate that a DNA sample was available.
Figure 2
Figure 2
Identification of the HSP27 Ser135Phe mutation. (A) Sequencing chromatograms showing the C404T (Ser135Phe) mutation in HSP27 exon 2. Exons were amplified by standard PCR and sequenced using an ABI 3100 automatic sequencer. (B) Conservation of an amino acid at the Ser135Phe mutation site in different species. Multiple alignments of HSP27 proteins were performed using the ClustalX 1.83 program. The mutation is located on the Hsp20-α-crystallin domain.
Figure 3
Figure 3
T1-weighted magnetic resonance images (MRI) of the thighs and legs of a patient (V-30) with 15 years disease duration (A-C), and of patient IV-28 with 40 years disease duration (D-F). (A) Anterior coronal thigh image through femoral heads showing subtle fatty infiltration of the vastus muscle group. (B) Middle third axial thigh image showing subtle fatty infiltration of the posterior (BF, biceps femoris; Sm, semimembranosus; and St, semitendinosus) and anterior compartments, but preservation of the sartorius (Sr) and rectus femoris (RF) muscles. Medial compartments are intact. (C) Middle-third axial calf muscle image, showing severe fatty atrophy of the four compartment muscle groups, but a lower degree of anterolateral compartment muscle involvement. (D) Anterior coronal thigh image through femoral heads, showing marked and symmetric hyperintensity, indicative of fatty atrophy of the tensor fasciae latae (TFL) and vastus lateralis muscles, but sparing the gracilis (Gr) and sartorius (Sr) muscles. (E) Middle axial thigh image showing severe fatty atrophy of the posterior compartment and vastus muscle groups of the anterior compartment. Moderate fatty infiltration of the medial compartment and rectus femoris is shown (RF). The preservation of the gracilis (Gr) muscle was noted at this level. (F) Middle third axial calf image showing extensive fatty infiltrations of all four compartments. For comparative purposes the MR images of her daughter with a short disease duration are included (A-C), relatively severe thigh muscle involvements were evident in the mother.
Figure 4
Figure 4
T1-weighted MRI of upper and mid thighs, and legs according to disease progress, i.e., less than 20 years disease duration (A-F) and more than 20 years diseases duration (G-L). Posterior and anterior compartment muscle groups, especially vastus muscles groups, were severely involved in terms of total fatty atrophy, though fatty infiltration in the rectus femoris and sartorius thigh muscles was limited. Gracilis muscle was preserved despite of long disease duration (G-L). In the lower leg, deep and superficial posterior compartments were more severely affected by fatty atrophy than the anterior and extensor digitorum muscle group. However, total fatty atrophy was pronounced in those with a long disease duration, demonstrating the progressive nature of the disease.

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