Su Jin Hwang

A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease

AbstractA wide range of phenotypes have been reported in autosomal recessive (AR) Charcot-Marie-Tooth disease (CMT) patients carrying mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene, such as axonal, demyelinating, and intermediate forms of AR CMT. There have been very few reports of GDAP1 mutations in autosomal dominant (AD) CMT. Here, we report an AD CMT family with a novel Q218E mutation in the GDAP1 gene. The mutation was located within the well-conserved glutathione S-transferase (GST) core region and co-segregated with the affected members in the pedigree. The affected AD CMT individuals had a later disease onset and much milder phenotypes than the AR CMT patients, and the histopathologic examination revealed both axonal degeneration and demyelination.

Distal hereditary motor neuropathy in Korean patients with a small heat shock protein 27 mutation

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 α-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.

Early-onset stroke associated with a mutation in mitofusin 2.

Mitofusin 2 ( MFN2 ) gene encodes an outer mitochondrial membrane protein which plays a central role in mitochondrial fusion.1 Mutations in the MFN2 gene have recently been reported to cause up to 33% of axonal peripheral neuropathies which in some cases involved the CNS.2,3 Since an initial study, which linked MFN2 mutations with Charcot-Marie-Tooth disease type 2A (CMT2A),4 MFN2 mutations have also been found in CMT with optic atrophy (CMT6).5 MFN2 prevents cell death following DNA damage and K+ deprivation induced apoptosis beyond its role of mitochondrial fusion.6 Furthermore, it has been reported that mitochondrial fusion defect is an early event of ischemic stroke.7 We report a case with early-onset stroke putatively caused by a novel MFN2 mutation. To our knowledge, no previous report has been published concerning CNS involvement without peripheral neuropathy caused by MFN2 mutations. ### Case reports. #### Patient 1. The proband was admitted at 12 years of age because of sudden development of vomiting and gait ataxia. She did not show any delay in developmental milestones. In tandem gait, she kept veering to the right side, and showed marked intention tremor. Laboratory examinations disclosed elevated plasma lactate (42.6 mg/dL; normal: 7.4–27.1 mg/dL) and pyruvate levels (0.78 mg/dL; normal: 0.30–0.70 mg/dL). The ratio of lactate/pyruvate was 54.6 (normal: 10–20). In addition, her hemoglobin …

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

AbstractCharcot-Marie-Tooth disease (CMT) is classified into demyelinating neuropathy (CMT1) and axonal neuropathy (CMT2). Mutations in the neurofilament light chain polypeptide (NEFL) gene are present in CMT2E and CMT1F neuropathies. Two types of Pro22 mutations have been previously reported: Pro22Ser in CMT2E with giant axons, and Pro22Thr in CMT1F. In this study, we identified another Pro22 mutation, Pro22Arg, in a Korean CMT1 family. An investigation to identify the clinical and pathological characteristics of the Pro22Arg revealed that it is associated with demyelinating neuropathy features in CMT1F. Histopathological findings showed onion bulb formations but no giant axons. It appears that the Pro22 mutations may influence not only the Thr-Pro phosphorylation site by proline-directed protein kinases but also other structural alteration of the NEFL protein in a different way.

A MELAS syndrome family harboring two mutations in mitochondrial genome

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous mitochondrial disorder with variable clinical symptoms. Here, from the sequencing of the entire mitochondrial genome, we report a Korean MELAS family harboring two homoplasmic missense mutations, which were reported 9957T > C (Phe251Leu) transition mutation in the cytochrome c oxidase subunit 3 (COX3) gene and a novel 13849A > C (Asn505His) transversion mutation in the NADH dehydrogenase subunit 5 (ND5) gene. Neither of these mutations was found in 205 normal controls. Both mutations were identified from the proband and his mother, but not his father. The patients showed cataract symptom in addition to MELAS phenotype. We believe that the 9957T > C mutation is pathogenic, however, the 13849A > C mutation is of unclear significance. It is likely that the 13849A > C mutation might function as the secondary mutation which increase the expressivity of overlapping phenotypes of MELAS and cataract. This study also demonstrates the importance of full sequencing of mtDNA for the molecular genetic understanding of mitochondrial disorders.

A Family Harboring CMT1A Duplication and HNPP Deletion

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.

PO5.34 Different Clinical and Electrophysiological Characteristics between CMT1A and CMTX Patients

hands according to neurophysiological criteria. Mean nerve conduction velocities from digit to C1, C2, C3 and C4 were 53.0±10.2 ms, 47.9±7.3, 38.2±8.6 ms, and 38.0±8.8 ms respectively. Mean segmental nerve conduction velocities of C1 C2, C2 C3 and C3 C4 are 41.8±16.9 m/s, 23.4±13.3 and 36.5±11.0 m/s respectively with a minimum value from C2 C3; which represents the segment of median nerve across the carpal ligament. When compared with C2-C3 segment there is a significant difference of nerve conduction velocities of C1 C2 (p < 0.001) and C3 C4 (p = 0.001). Median sensory nerve action potentials (MSNAP) at C1, C2, C3 and C4 were 1.3±8.5, 6.6±3.8, 8.1±5.1mV and 9.7±5.5mV respectively. Median motor distal latency is negatively correlated (r = .552) to NCV of C2 C3 segment (p < 0.01). Conclusions: The maximum slowing of median sensory nerve conduction velocity was obtained across the distal segment of carpal ligament.

PO5.26 Characteristics of the Proximal Lower Limb MRI in Korean Charcot-Marie-Tooth Patients with Demyelinating Neuropathy and Axonal Neuropathy

diagnostic criteria for demyelinated nerves were fulfilled in 5 (38%). Albuminocytologic dissociation of CSF in 6. No autoantibody was detected in all tested patients. Conclusions: Sensory symptoms of Ab and Ad fibers transmitting vibratory sense and sharp pain with symmetric centrifugal patterns of trunk and limbs, decreased SNAPs, absent H-reflex suggest pathology as demyelinating sensory polyneuropathy, not ganglionopathy. However, albuminocytologic dissociation, multiple combination of demyelinating NCS and minor weakness in most patients suggest sensory fiber myelinspecific disease, triggered by virus or bacteria, as superantigen, or by activation of primed CD4 T helperor memory-cell by molecular mimicrying antigen.

PO7.9 Phenotypes of 117 Korean Patients with Mitochondrial Disorders

Background: Ventilatory failure is a common and potentially lifethreatening complication of myotonic dystrophy. It usually parallels the muscular manifestations, but there are some cases that ventilatory failure is a presenting symptom without limb weakness. In that case, muscular dysfunction alone is insufficient to account for the ventilatory failure. Case report: A 34-year-old man with history of diabetes and hypercholesterolemia presented to the hospital with a 2-month history of gradually progressive hypersomnia and supine dyspnea. In the emergency room, he was cyanotic and confused, so he was intubated and admitted to intensive care unit. He was obese (BMI: 32.7) and had facial features characteristic of myotonic dystrophy including frontal boldness, hatched face, without ptosis, facial drooping and limb atrophy. Neurologic examination demonstrated mild generalized weakness (MRC grade IV+) and percussion myotonia. Deep tendon reflex were hypoactive, and sensation was normal. Arterial blood gas analysis demonstrated severe hypoxia and hypercapnia with a respiratory acidosis. No cardiac, pulmonary and pharmacologic causes were identified. Pulmonary function tests revealed a severe restrictive ventilatory insufficiency. Electromyography showed myotonic discharges and genetic analysis showed classic phenotype of myotonic dystrophy type 1. Polysomnographic study revealed sleep apnea of central origin. He responded to ventrilatory support with BIPAP. Conclusions: We report a case of myotonic dystrophay presenting with ventilatory failure without significant limb weakness or any provocative challenge such as anesthesia or surgery. The PFT and polysomnographic findings support that this patient’s respiratory dysfunction was due to dual origin central and peripheral.

PO5.44 Evaluation of Quality of Life in Korean Charcot-Marie-Tooth Patients

Background: To investigate the correlation between the slowing of median nerve conduction velocity at the segment of forearm (fMCV) and the severity of the entrapment neuropathy in CTS, and to explore the possible pathogenesis of the slowed fMCV. Methods: Consecutive 66 CTS patients (126 hands) that satisfied the diagnostic criteria were enrolled and the ageand gender-matched 96 volunteers (96 non-dominant hands) were served as controls. Routine nerve conduction studies were performed. The distal motor latency (DML) of median nerve and thenar compound muscle action potentials amplitude (CMAP) were taken as indications of CTS severity, and the correlation between the severity and fMCV was analyzed. Results: As to ulnar nerve, there is no difference of motor and sensory conduction between patients group and controls. In the patient group, the median distal motor latency DML (ms) was 5.0±1.3, significantly longer (P= 0.000); the CMAP amplitude (mV) of abductor pollicis brevis was 7.3±2.9, decreased significantly (P= 0.000); the wpMCV (m/s) was 22.2±7.3, slowed significantly (P= 0.000); the fMCV (m/s) was 53.7±5.5, slowed significantly (P= 0.000), compared with the controls; and there was a significantly negative correlation between the fMCV and DML (r = 0.35, P< 0.01, n = 126) and positive correlation between fMCV and CMAP amplitude (r = 0.18, P< 0.05, n = 96). Conclusions: The conduction abnormalities of median nerve at the segment of forearm may be associated with the lesion severity in the patient with CTS, in which the pathogenesis may be retrograde axonal degeneration.