Jiangxi Xiao

Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome

SummaryLeigh syndrome is the most common mitochondrial disorder in children characterized by necrotic lesions in the central nervous system. Both mitochondrial DNA (mtDNA) and nuclear DNA defects in the mitochondrial respiratory chain can lead to this disease. To characterize the clinical and genetic traits of Leigh or Leigh-like syndrome patients in China, 124 unrelated cases were collected between 1992 and 2005. Seventy-seven cases (62.1%) met the typical criteria of Leigh syndrome, including symmetrical bilateral abnormal signals in the basal ganglia, thalamus and brain stem, etc. Other cases (37.9%) belonged to Leigh-like syndrome with atypical clinical or radiological manifestations. Late-onset patients accounted for 20.2%, which is more than previously reported. Movement disorder was the most common symptoms in our patients. Thirty-two patients (25.8%) were confirmed to carry mutant genes. Among them, six cases (4.8%) have been demonstrated to have point mutations in mitochondrial DNA. Two separate patients were detected to have mutations on A8344G and A3243G. The T8993G point mutation was identified in one patient and T8993C in one other patient. SURF1 mutations associated with cytochrome-c oxidase deficiency were identified in 25 patients (20.2%). Four unreported variations have been identified in SURF1 gene from three patients. G604C was found in 22 patients. Only one patient had C214T mutation in the pyruvate dehydrogenase E1α subunit gene. In the remaining 92 patients (74.2%), a specific molecular dysfunction or underlying metabolic abnormality could not be identified.

Magnetic resonance imaging changes of thigh muscles in myopathy with antibodies to signal recognition particle

OBJECTIVE The aim of this study was to evaluate muscle MRI changes and the role of MRI in monitoring therapy in patients with myopathy associated with antibodies to signal recognition particle (anti-SRP myopathy). METHODS We identified 12 patients with anti-SRP myopathy [6 females and 6 males; mean age of onset 38.5 years (s.d. 12.4), mean duration 22.8 months (s.d. 20.6). The main symptoms were proximal limb muscle weakness. Mean serum creatine kinase levels were moderately increased. Muscle biopsies revealed necrotizing myopathy in all patients, with obvious connective tissue proliferation in five patients and a single focus of lymphocytic infiltration in the endomysium in one. The myositis disease activity assessment (MYOACT) visual analogue scales scores were assessed. Muscle MRI was performed through the thighs. All patients were treated with corticosteroids and other immunosuppressive drugs. RESULTS MRI revealed fatty infiltration and oedema in the thigh muscles of all 12 patients. Prominent fatty infiltration was present in 4 of the 12 patients. The hamstrings and adductor magnus were the most severely infiltrated and the quadriceps femoris the least. Obvious oedema was observed in 10 of the 12 patients, the most severely affected muscles being the vastus lateralis, rectus femoris, biceps femoris and adductor magnus, with relative sparing of the vastus intermedius. The degree of oedema was not correlated with creatine kinase levels or MYOACT scores. The four patients with striking fatty infiltration were refractory to therapy. CONCLUSION MRI of the thigh muscles shows a distinct pattern of oedema and fatty infiltration and can be used to monitor the treatment of patients with anti-SRP myopathy.

Progression and variation of fatty infiltration of the thigh muscles in Duchenne muscular dystrophy, a muscle magnetic resonance imaging study

The purpose of this study was to assess the progression and variation of fatty infiltration of the thigh muscles of Duchenne muscular dystrophy patients. Muscle magnetic resonance imaging was used to measure the degree of fatty infiltration of the thigh muscles of 171 boys with Duchenne muscular dystrophy (mean age, 6.09 ± 2.30 years). Fatty infiltration was assigned using a modified Mercuris scale 0-5 (normal-severe). The gluteus maximus and adductor magnus were affected in patients less than two years old, followed by the biceps femoris. Quadriceps and semimembranosus were first affected at the age of five to six years; the sartorius, gracilis and adductor longus remained apparently unaffected until seven years of age. Fatty infiltration of all the thigh muscles developed rapidly after seven years of age. The standard deviation of the fatty infiltration scores ranged from 2.41 to 4.87 before five years old, and from 6.84 to 11.66 between six and ten years old. This study provides evidence of highly variable degrees of fatty infiltration in children of different ages with Duchenne muscular dystrophy, and indicates that fatty infiltration progresses more quickly after seven years of age. These findings may be beneficial for the selection of therapeutic regimens and the analysis of future clinical trials.

The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small artery disease caused by NOTCH3 gene mutation. Here we report clinical, pathological and genetic profiles of 29 newly-diagnosed CADASIL patients, evaluation of the CADASIL scale in Chinese CADASIL patients, and reanalysis of all reported mainland Chinese patients with identified NOTCH3 gene mutation. We found two novel mutations (p.C134G and p.C291Y) and 13 reported NOTCH3 mutations in the newly-diagnosed group. CADASIL scale score was less than the cutoff score in 19 of 53 Chinese patients with NOTCH3 mutation, generating only a sensitivity of 64.1%. At the time of study, the total number of genetically confirmed CADASIL cases reached 158 from 97 unrelated mainland Chinese families, with 9/97 (9.3%) sporadic patients. The NOTCH3 gene mutation profile showed 43 mutations, with hotspots in exon 4, followed by exon 3. The considerable variability in onset age and CADASIL scale score in patients carrying the same NOTCH3 missense mutation suggested no obvious phenotype-genotype correlation. In conclusion, we report two novel mutations which expand the NOTCH3 mutational spectrum. Exons 4 and 3 are hotspots in mainland Chinese patients with NOTCH3 mutation. The low sensitivity of CADASIL scale in our patients group indicated that the CADASIL scale should be refined according to the clinical characteristics of Chinese CADASIL patients when used in Chinese populations.

MR evaluation of cerebral oxygen metabolism and blood flow in stroke-like episodes of MELAS.

Metabolic information is essential in the investigation of the pathophysiology of stroke-like episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Here, we used magnetic resonance imaging to evaluate the dynamic metabolic changes before and after a stroke-like episode in two patients with MELAS caused by the mitochondrial DNA mutation A3243G. We performed functional magnetic resonance imaging, including arterial spin labeling and oxygen extraction fraction imaging, and generated cerebral blood flow and oxygen extraction fraction maps. We recruited eight healthy volunteers to define the normal range of the oxygen extraction fraction. We detected a heterogeneous reduction in the oxygen extraction fraction in the brain in the interictal period as well as at the onset of a stroke-like attack. However, the oxygen extraction fraction in the stroke-like lesions normalized in the acute stage. The stroke-like lesions showed consistent hyperperfusion in the acute phase but hypoperfusion in the chronic phase. We have demonstrated the utility of using new magnetic resonance imaging techniques in the evaluation of the pathophysiology of stroke-like lesions. The increased utilization of oxygen in an acute lesion is a novel finding in our study, which might play a role in the oxidative stress.

Target and "Sandwich" Signs in Thigh Muscles have High Diagnostic Values for Collagen VI-related Myopathies.

Background: Collagen VI-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Muscle magnetic resonance imaging (MRI) has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. Methods: Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders (disease controls). T1-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuris scale. We assessed the sensitivity and specificity of the MRI features of collagen VI-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. Results: Eleven patients with collagen VI gene mutation-related myopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius (P = 0.033); therefore, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A “target” sign in rectus femoris (RF) was present in seven cases, and a “sandwich” sign in vastus lateralis (VL) was present in ten cases. The “target” and “sandwich” signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI-related myopathies, respectively. Fatty infiltration scores were 2.0–3.0 in seven patients with mutations in the triple-helical domain, and 1.0–1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. Conclusions: The “target” sign in RF and “sandwich” sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.

quantitative measurement of cerebral oxygen extraction fraction using MRI in patients with MELAS

Objective To quantify the cerebral OEF at different phases of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) by using MRI. Methods We recruited 32 patients with MELAS confirmed by gene analysis. Conventional MRI scanning, as well as functional MRI including arterial spin labeling and oxygen extraction fraction imaging, was undertaken to obtain the pathological and metabolic information of the brains at different stages of stroke-like episodes in patients. A total of 16 MRI examinations at the acute and subacute phase and 19 examinations at the interictal phase were performed. In addition, 24 healthy volunteers were recruited for control subjects. Six regions of interest were placed in the anterior, middle, and posterior parts of the bilateral hemispheres to measure the OEF of the brain or the lesions. Results OEF was reduced significantly in brains of patients at both the acute and subacute phase (0.266 ± 0.026) and at the interictal phase (0.295 ± 0.009), compared with normal controls (0.316 ± 0.025). In the brains at the acute and subacute phase of the episode, 13 ROIs were prescribed on the stroke-like lesions, which showed decreased OEF compared with the contralateral spared brain regions. Increased blood flow was revealed in the stroke-like lesions at the acute and subacute phase, which was confined to the lesions. Conclusion MRI can quantitatively show changes in OEF at different phases of stroke-like episodes. The utilization of oxygen in the brain seems to be reduced more severely after the onset of episodes in MELAS, especially for those brain tissues involved in the episodes.

The appearance of ADCs in the non-affected areas of the patients with MELAS

IntroductionThe exact mechanism of the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remain unclear. Diffusion-weighted imaging (DWI) is a magnetic resonance (MR) imaging technique for studying the pathophysiologic change of the MELAS. The purpose of the study is to see whether the apparent diffusion coefficient (ADC) of MELAS in the non-affected areas is different from the ADC of the normal subjects and to speculate the pathophysiological mechanisms of the MELAS.MethodsSixteen cases of MELAS were retrospectively analyzed. Thirty healthy subjects were chosen to constitute the control group. All of them were performed on the 3.0T whole-body MR scanner with axial view T2 fluid attenuated inversion recovery (flair), T2-weighted imaging, T1flair, and DWI. An ADC map was reconstructed in the workstation. Two to five regions of interest were put in the non-affected frontal lobe and basal ganglia. All data took statistical analysis.ResultsThere were significant differences between the ADC of the patients with MELAS and the controls in the non-affected areas, including the superior frontal gyrus, precentral gyrus, corpus striatum, thalamus, and white matter of the semi-oval centrum.ConclusionADCs in the non-affected areas of the patients with MELAS are higher than those of the normal subjects. Pathological changes take place in the non-affected areas of the patients with MELAS.

Phenotypic spectrum of mutations in IBA57, a candidate gene for cavitating leukoencephalopathy

IBA57 is involved in the biogenesis of mitochondrial [4Fe‐4S] proteins. Eighteen cases with IBA57 mutations have been reported to date. We described a novel phenotype in 11 children with cavitating leukoencephalopathy and summarized the phenotypic spectrum of IBA57 mutations. The median age of onset was 9 months, with an initial presentation of motor regression. Deterioration of neurological function reached its peak within 4 months. The median interval between onset and last follow‐up was 2.9 years (0.4‐10.0). All cases survived and remained stable. Severe motor handicap was observed in 50.0% of the patients, 52.9% to 71.4% had a delay in communication, problem solving or personal‐social skills, and 20.0% had mild symptomatic fluctuations. In the peak phase, magnetic resonance imaging (MRI) lesions were mainly observed in the periventricular/central white matter, and cavitating lesions and patchy high diffusion‐weighted imaging (DWI) signals were observed. The numbers and extent of restricted diffusional lesions were reduced, and atrophy was prominent in the recovery phase. Eight novel mutations in IBA57 were identified in our study. This study provided more information about the natural history and evolution of neuroimaging. Combined with previously reported patient studies, our findings suggest that defects in IBA57 can produce diverse phenotypes. IBA57 should be considered a candidate gene for cavitating leukoencephalopathy.

Heterogeneous characteristics of MRI changes of thigh muscles in patients with dysferlinopathy.

Introduction: The aim of this study was to evaluate the pattern of thigh muscle MRI changes in a large cohort of patients with dysferlinopathy. Methods: MRI of the thigh was performed in 60 patients. We correlated the scale of muscle involvement on MRI with the modified Gardner‐Medwin and Walton (GM‐W) scale and disease duration. We also analyzed the relationship between muscle changes and genetic mutations. Results: Fatty infiltration and edema were observed in 95.50% and 86.67% of patients, respectively. The hamstring muscles had the highest frequency and mean score of fatty infiltration, although a posterior‐dominant pattern was found in only 56%. Edema most commonly and severely affected the quadriceps and adductor magnus muscles. Fatty infiltration score correlated positively with disease duration and GM‐W scale. Conclusions: The pattern of fatty infiltration was heterogeneous in dysferlinopathy patients. Muscle edema was common. Fatty infiltration can be used to assess disease progression. Muscle Nerve 54: 1072–1079, 2016