Ming-Hong Chang

The ‘hot cross bun’ sign in the patients with spinocerebellar ataxia

Background and purpose:  The ‘hot cross bun’ sign (HCBS), typically seen in the patients with multiple system atrophy, refers to a cruciform hyperintensity in the pons on T2‐weighted MRI. Little is known about its pathological basis and prevalence in other degenerative cerebellar diseases and healthy population. We investigate the frequency of HCBS in the patients with spinocerebellar ataxia (SCA) and healthy controls.

The Mutational Spectrum in a Cohort of Charcot-Marie-Tooth Disease Type 2 among the Han Chinese in Taiwan

Background Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese. Methodology and Principal Findings Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%). Conclusions and Significance This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.

Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese

Background and purposeCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, most clinical, molecular and neuroimaging information has come from Caucasians. Therefore, we investigated the spectrum of NOTCH3 mutations and MRI features in CADASIL patients of Chinese origin on Taiwan.MethodsMutational analysis of NOTCH3 exons 2 to 23 by direct nucleotide sequencing was performed in patients with clinically suspected CADASIL. MRI findings were retrospectively evaluated and scored using a modified Schelten’s scale.ResultsNine different point mutations of NOTCH3 were identified in 21 unrelated patients. Intriguingly, 47.6 % were in exon 11, and 19 % in each of exon 4 and 18. R544C was very common and present in all patients with a mutation in exon 11. Many patients with NOTCH3 R544C share the same haplotype linked to the mutation using markers D19S929 and D19S411, which flank the NOTCH3. The sensitivity of T2-weighted MRI detecting anterior temporal abnormality was only 42.9 %. Furthermore, the neuroimaging evidence of intracerebral hemorrhage (ICH) was present in 23.8 % of the 21 patients.ConclusionsA population-specific mutational spectrum of CADASIL was found in the Chinese patients on Taiwan. The Chinese patients carrying NOTCH3 R544C may descend from a common ancestor. Anterior temporal hyperintensity on T2-weighted MRI may not be a sensitive marker for CADASIL. ICH is a relatively common manifestation of CADASIL in East Asians, especially in the presence of hypertension.

PRRT2 Mutations in Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions in a Taiwanese Cohort

Background Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC. Methodology and Principal Findings We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation. Conclusions and Significance PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.

Risk of Premotor Symptoms in Patients with Newly Diagnosed PD: A Nationwide, Population-Based, Case-Control Study in Taiwan

Background To evaluate the risk of premotor symptoms, namely rapid eye movement behavior disorder (RBD), constipation, and depression among patients with newly diagnosed Parkinson disease (PD). Methods A total of 705 PD patients and 2,820 control subjects were selected from the Taiwan National Health Insurance Research Database. Patients were traced back for a maximum of 14 years to determine the diagnoses of RBD, depression, and constipation. Logistic regression analysis was used to identify risk of premotor symptoms for PD. Moreover, subgroup analyses were performed by dividing the patients into a middle-age onset group (≤ 64 years) and an old-age onset group (≥ 65 years). The associations between these premotor symptoms and age of PD onset were further examined. Results An association was found between a history of premotor symptoms and newly diagnosed PD in which a high occurrence of premotor symptoms was identified in PD patients as compared to selected controls (4.3% vs. 1.2% for RBD, 40.4% vs. 24.0% for constipation, and 13.0% vs. 5.1% for depression). The strength of this association remained statistically significant after adjustment for potential confounders (3.69 fold risk for RBD, 2.36 for constipation, and 2.82 for depression, all p < 0.0001). The average interval between premotor symptoms and PD ranged from 4.5 to 6.2 years. RBD and depression carried higher risks for PD in the middle-age onset group than in the old-age onset group (7.20- vs. 2.24-fold risk for RBD, 6.06 vs. 1.40 for depression). Conclusion The prevalence of premotor symptoms was higher among the PD patients than in the controls. Premotor symptoms appeared to be associated with a higher risk for PD in subjects with an earlier age of onset.

Eye of the tiger-like MRI in parkinsonian variant of multiple system atrophy

Parkinsonian variant of multiple system atrophy (MSA-P) clinically presents as autonomic dysfunction with parkinsonian features. Parkinsonian features include bradykinesia, rigidity, tremor, postural instability and poor levo-dopa response. Neuropathologically, MSA-P is characterized by selective neuronal loss and gliosis mainly affecting the putamen and caudate nucleus, substantia nigra, olivopontocerebellar pathway and intermediolateral cell column of the spinal cord. Therefore, the target of magnetic resonance imaging (MRI) is focused on signal changes or volume reduction on putamen, including putaminal slit, gliosis by diffusion studies and reduction of putaminal volume. There have been no reports describing clinical manifestations of MSA-P with imaging abnormalities over globus pallidus. Here, we describe three patients with typical presentations of MSA-P with autonomic dysfunction and disturbances of axial motor function with minimal appendicular symptoms, including postural instability and gait difficulties. MRI showed symmetrical hyperintensity over the center of globus pallidus surrounded by a mild low-signal rims at T2-weighted image that is similar to that of eye of the tiger sign except for the marked hypointense rims. Dopamine transporter scans showed symmetric reduction of uptake over bilateral basal ganglia. This is the first report concerning these unusual imaging findings in MSA-P patients and we believe there is a subgroup of MSA-P with clinical presentation of axial impairment and symmetrically abnormal signal changes of globus pallidus in MRI.

Occipital lobe seizures related to marked elevation of hemoglobin A1C: Report of two cases

Occipital lobe seizures caused by nonketotic hyperglycemia (NKH) have been reported in only a few cases and are not fully characterized. We report two cases of NKH-related occipital lobe seizures with high hemoglobin A1C (HbA1C), epileptiform electroencephalograph (EEG) and MRI abnormalities. Both patients had moderate hyperglycemia (310-372 mg/dl) and mildly elevated serum osmolarity (295-304 mOsm/kg) but markedly elevated HbA1C (13.8-14.4%). One patient had a clinico-EEG seizure originating from the right occipital region during sleep. The other patient had an interictal epileptiform discharge consisting of unilateral occipital beta activity in sleep. None of the previously reported cases fulfilled the criteria of a nonketotic hyperglycemic hyperosmolar (NKHH) state, or showed any interictal beta paroxysms, spikes, sharp waves, or spike/sharp-slow wave complexes. We suggest that prolonged exposure to uncontrolled hyperglycemia, as indicated by HbA1C, rather than an acute NKHH state is crucial in the development of this peculiar seizure. We also suggest clinicians look for the presence of interictal focal beta paroxysms in addition to the usual epileptiform discharges while reading the EEG of these patients.

Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes

Mutations in MPZ, which encodes myelin protein zero (P0), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes. Nine P0 mutants associated with CMT1 (P0S63F, R98H, R277S, and S233fs), DSS (P0 I30T and R98C), and CMT2 (P0S44F, D75V, and T124M), were investigated. Wild-type and mutant P0 fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization. An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes. Three different intracellular localization patterns of the mutant P0 were observed. Wild-type P0, P0I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P0R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P0S233fs formed aggregates within the ER. Cells expressing mutant P0, as compared with those expressing wild-type P0, demonstrated variable degrees of reduction in the cell adhesiveness. The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors. This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.

Clinical characterization and genetic analysis of a possible novel type of dominant Charcot-Marie-Tooth disease

A family of dominant Charcot-Marie-Tooth disease with eleven members, six of them symptomatic, was characterized clinically and genetically. The ages at onset ranged from 10 to 45 years, and the clinical severity varied from no symptom to being wheelchair-bound. The median motor nerve conduction velocities ranged from 16.5 to 45.7 m/s. Men were more severely affected. The sural nerve biopsies in two patients featured demyelinating changes. No mutation in PMP22, MPZ, GJB1, NEFL, LITAF, EGR2, MFN2, HSP27, HSP22, GADP1, YARS, and DNM2 genes was found in the proband. Haplotype analyzes excluded linkage to the previously reported dominant CMT loci. A genomewide screen with 400 microsatellite markers and multipoint linkage analyzes revealed that the highest LOD score was around 1.6 on chromosome 3q28-q29, suggestive of a weak but possible linkage at this locus. The results of this study implicate the existence of a novel genetic locus for this syndrome.

Spastic paraparesis as a manifestation of metabolic vitamin B12 deficiency

Sirs: Vitamin B12 deficiency may be associated with variable neurological symptoms, including peripheral neuropathy, myelopathy, altered mental status, optic neuropathy, and cerebellar ataxia [1–3]. The myelopathy caused by vitamin B12 deficiency is well known as subacute combined degeneration, which is characterized by lesions in the posterior and lateral columns, always leading to both sensory and motor deficits [4]. Here we describe a 39-year-old man who had metabolic vitamin B12 deficiency but low normal vitamin B12 serum levels and developed a spastic paraparesis without sensory impairment. The 39-year-old man had begun developing progressive spastic paraparesis without sensory symptoms 20 years previously. In the past two months, he had also suffered from sexual and urinary dysfunction with frequent nocturia, occasional urine incontinence, and absence of morning erection. His prenatal and developmental histories were normal. The family history was unremarkable. Neither gastrointestinal disease nor a history of nitrous oxide exposure could be traced. He had been a strict vegetarian because of religious faith since adolescence. Neurological examination revealed mild weakness, marked spasticity of lower limbs with a scissor gait, and hyperactive deep tendon reflexes with bilateral ankle clonus and extensor plantar responses. The mental status, cranial nerves, coordination, and sensory test, including modalities of pinprick, light touch, and proprioception were normal. Laboratory studies demonstrated a normal complete blood cell count, a serum vitamin B12 level of 195 ng/L (reference range 130–785 ng/L), and a folic acid level of 19.5 μg/L (3–17 μg/L). His serum homocysteine level was 30.59 μmole/L (5–14 μmole/L). The serum methylmalonyl acid level was not checked. The results of cerebrospinal fluid studies, including cell counts, glucose, protein, IgG index, oligoclonal banding, anti-HTLV1 antibody titer, and VDRL test, were normal. Serum VDRL and HIV tests, anti-parietal cell antibody titer, and copper level were normal. Magnetic resonance imaging of the brain and spinal cord, nerve conduction studies, and somatosensory evoked potentials of the median and tibial nerves were all normal. The patient was treated with intramuscular injections of cyanocobalamin 1 mg daily for 7 days, weekly for 3 weeks, and monthly thereafter. On the sixth day of therapy, the vitamin B12 serum level increased beyond 1200 ng/L and the serum homocysteine level normalized to 7.38 μmole/L. Three months later, lower limb weakness had recovered fully and spasticity became moderately improved. The nocturia and urinary incontinence disappeared, and he regained daily morning erection as well as a fair sexual function. Five months later, spasticity persisted and transcranial magnetic stimulation study still revealed a mildly prolonged central motor conduction time (Table 1). Spastic paraparesis is uncommon in patients with vitamin B12 deficiency. Healton et al. reported that only seven of 153 episodes of cobalamin deficiency with neurological findings were associated with spastic paraparesis, and all were accompanied by proprioceptive deficits [1]. Diagnosis of metabolic vitamin B12 deficiency in patients with low normal serum vitamin B12 level can be established by elevated serum methylmalonyl acid or homocysteine levels [5–7]. Both metabolites may accumulate when there is impairment of cobalamin-dependent metabolic pathways. In this patient, the diagnosis could be supported by clinical response to vitamin B12 therapy. Other differential diagnosis, including copper deficiency [8, 9], can be excluded by normal laboratory data. Familial spastic paraparesis cannot be totally excluded without a detailed family history but is less likely in light of the remarkable improvement with treatment. This case demonstrates the importance of taking into consideration metabolic vitamin B12 deficiency in people with a low normal serum cobalamin level. It also LETTER TO THE EDITORS