Long-term clinical and MRI follow-up in two POMT2-related limb girdle muscular dystrophy (LGMDR14) patients

IntroductionPOMT2-related limb girdle muscular dystrophy (LGMDR14) is a rare muscular dystrophy caused by mutations in the POMT2 gene. Thus far only 26 LGMDR14 subjects have been reported and no longitudinal natural history data are available.Case reportWe describe two LGMDR14 patients followed for 20 years since infancy. Both patients presented a childhood-onset, slowly progressive pelvic girdle muscular weakness leading to loss of ambulation in the second decade in one patient, and cognitive impairment without detectable brain structural abnormalities. Glutei, paraspinal, and adductor muscles were the primarily involved muscles at MRI.DiscussionThis report provides natural history data on LGMDR14 subjects, with a focus on longitudinal muscle MRI. We also reviewed the LGMDR14 literature data, providing information on the LGMDR14 disease progression. Considering the high prevalence of cognitive impairment in LGMDR14 patients, a reliable application of functional outcome measures can be challenging, therefore a muscle MRI follow-up to assess disease evolution is recommended.     

Correlative MR imaging and P-MR spectroscopy study in sarcoglycan deficient limb girdle muscular dystrophy

We combined magnetic resonance (MR) imaging and phosphorus magnetic resonance spectroscopy (³¹P-MRS) to study skeletal muscle in seven patients with limb girdle muscular dystrophy (LGMD) with a variable deficiency of the -, β-, and γ-sarcoglycan but normal dystrophin expression on muscle biopsy. T1- and T2-weighted spin-echo axial leg images showed the highest degree of fat replacement in soleus, tibialis anterior and peroneal muscles while gastrocnemius and tibialis posterior were less affected. In LGMD patients as a group, calf muscle phosphorylated compound content did not differ from controls, but the cytosolic pH was increased (P=0.02). The degree of calf muscle fat replacement correlated inversely with cytosolic pH (r=0.74) and directly with PCr/ATP (r=0.74). Muscle oxidative metabolism was normal in LGMD patients. Our findings show that primary deficits of sarcoglycan complex lead to specific morphological and metabolic patterns of skeletal muscle involvement.     

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker–Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker–Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.     

Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy

Within a group of 76 sporadic/autosomal recessive limb girdle muscular dystrophy (LGMD) patients we tried to identify those with LGMD type 2C-E. Muscle biopsy specimens of 40 index patients, who had 22 affected sibs, were analyzed immuno-histochemically for the presence of three subunits: α-, β-, and γ,-sarcoglycans. Abnormal sarcoglycan expression was established in eight patients, with six affected sibs. In one patient γ-sarcoglycan was absent, and both α- and β-sarcoglycans were reduced. In the remaining seven patients γ-sarcoglycan was (slightly) reduced, and α- and β-sarcoglycans were absent or reduced. By DNA sequencing mutations were detected in one of the three sarcoglycan genes in all eight cases. Three patients had mutations in the α-, three in the β-, and two in the γ-sarcoglycan gene. The patients with sarcoglycanopathy comprised the more severely affected cases (P=0.04). In conclusion, sarcoglycanopathy was identified in 23% (14/62) of the autosomal recessive LGMD patients. Received: 11 November 1999, Received in revised form: 27 January 2000, Accepted: 29 February 2000     

ANO5 mutations in the Dutch limb girdle muscular dystrophy population

A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening.     

Milder phenotype of congenital muscular dystrophy in a novel POMT1 mutation

Introduction: Congenital muscular dystrophies (CMD) with hypoglycosylated α‐dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity.Methods: We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. Results: Histochemical analysis of the index case's muscle showed deficiency of glycosylated α‐dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. Conclusions: Our patient's milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation. Muscle Nerve 45: 752–755, 2012     

一个肢带型肌营养不良家系的临床和分子遗传学分析

目的 研究1个肢带型肌营养不良(limb girdle muscular dystrophy,LGMD)家系的临床表现,并应用基因突变分析、基因组扫描技术和连锁分析对该家系进行分子遗传学分析.方法 对1个来自浙江的连续4代发病的LGMD家系进行家系调查和体格检查,先证者行电生理检查及肌肉病理活体组织检查分析;26名家系成员在知情同意的情况下抽取基因组DNA进行基因突变分析、基因组扫描和连锁分析.结果 家系分析证明该家系符合常染色体显性遗传,家系中存在遗传早现现象,主要表现为四肢近端肌无力,无构音障碍、肌强直;电生理检查和肌肉活体组织检查符合肌肉病变特点;基因突变分析未发现LGMD1A、1B、1C和面肩肱型肌营养不良(FSHD)基因的致病突变;基因组扫描和连锁分析显示该家系致病基因与已报道的LGMD1D和LGMD1F的染色体区间连锁关系不成立.结论 LGMD家系患者的临床表现具有高度异质性,该家系的致病基因不在已报道的位点内,推测可能存在新的致病位点或是一种新的LGMD遗传类型.     

Multisystem disorder and limb girdle muscular dystrophy caused by LMNA p.R28W mutation

Primary laminopathies caused by mutations in the LMNA gene typically display an extremely pleiotropic clinical presentation including cardiac, muscular and metabolic phenotypes. Additionally, many atypical laminopathies have been described combining features of two or more of the distinctive disorders or syndromes associated with LMNA mutations. We report on a 46-year-old female patient with a heterozygous p.R28W LMNA mutation, who presented with a novel clinical phenotype comprising severe limb-girdle muscular dystrophy, pronounced partial lipodystrophy, cardiac conduction defect, polycystic ovary disease and a metabolic syndrome with insulin-resistant diabetes mellitus and hypertriglyceridemia. On examination, her 23-year old daughter solely showed early signs of a LGMD phenotype.     

A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy

Defects in glycosylations of α-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of α-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff–Parkinson–White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal <150 IU/L). A homozygous, novel c.917A>G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far.     

Plasma phosphoglycerate mutase as a marker of muscular dystrophy

An elevation of phosphoglycerate mutase (PMG) has been detected in the blood plasma of the genetically dystrophic chicken and in Duchenne muscular dystrophy (DMD) patients. In the dystrophic chicken, plasma PGM in the pectoral muscle was simultaneously depressed to less than one-half that of the normal chicken. In a group of 9 DMD patients, plasma PGM activity was found to be significantly raised above the normal range. A survey of a small group of plasma specimens from human fetuses at risk for muscular dystrophy also suggested that PGM merits investigation as a potential adjunct to other diagnostic indices.     

重视Duchenne型肌营养不良症的康复治疗

康复治疗对改善Duchenne型肌营养不良症患者生活质量、延缓病情进展至关重要,一些国家业已制定了康复治疗指南,我国尚缺乏这方面的指导性研究和意见。为了提高临床医师对该病症康复治疗的认识,现对其病情分期、临床特征,以及康复治疗的一般原则、常用方法和注意事项进行概述,为临床康复治疗提供一些参考。     

Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies)

Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin 2 chain (merosin) and dysferlin-deficiency.     

Limb girdle muscular dystrophy: Description of a phenotype

The phenotype is reported of 20 patients with autosomal recessive or sporadic, pelvifemoral limb girdle muscular dystrophy (LGMD). Selective wasting of muscles was observed at the moderately advanced stage of illness. The pattern of weakness was uniform. Attention to clinical detail allowed the identification of a phenotype different from a hypothetical scheme of LGMD based on previous literature, and other causes of limb girdle weakness. These patients may represent yet another nosologic entity within the autosomal recessive dystrophies; molecular genetic studies are awaited. A limited magnetic resonance imaging (MRI) study of muscle was of little consequence. Although additional detail was obtained, no pathognomonic distribution of the dystrophic process was observed; interindividual variation existed even among closely matched siblings. The severity of MRI signal change did not consistently correlate with the degree of weakness in an individual. When a diagnosis is uncertain, however, the added detail may be useful. © 1994 John Wiley & Sons, Inc.     

Spin-lock magnetic resonance imaging of muscle in patients with autosomal recessive limb girdle muscular dystrophy.

Spin-lock imaging is a new magnetic resonance imaging (MRI) technique used to reflect the microstructural integrity of muscle. The purpose of this study was to characterize spin-lock contrast (SLC) of calf muscles in limb girdle muscular dystrophy (LGMD). The calf muscles of 5 patients with LGMD and 10 healthy volunteers were imaged with an off-resonance magnetic resonance (MR) spin-lock suppression pulse. Spin-lock suppression ratios were calculated for anterior tibialis, posterior tibialis, soleus, and gastrocnemius muscles. Clinical assessments of muscle strength were compared to the spin-lock suppression ratios in the LGMD group. Strong SLC was observed in healthy muscles, with mean (+/- SD) suppression ratios ranging from 51.2% (+/- 3.6%) to 56.3% (+/- 1.3%). In diseased muscle, spin-lock signal suppression was reduced by 8%-70%, demonstrating an inverse correlation between symptom duration and suppression ratios. Spin-lock contrast in the patients with LGMD, as a reflection of tissue integrity, was best preserved in posterior tibialis, anterior tibialis, soleus, and gastrocnemius muscles in descending order. Clinical assessments did a poorer job of differentiating than SLC did and were in poor agreement with spin-lock suppression ratios. Spin-lock MRI can quantify microstructural changes in LGMD and appears to provide information not obtainable from clinical evaluations. This suggests that this noninvasive technique may be useful in evaluating the extent, progression, and response to therapy of LGMD.     

Calcium homeostasis and ultrastructural studies in a patient with limb girdle muscular dystrophy type 2C

There is increasing evidence that gamma-sarcoglycan is absent and other sarcoglycans are reduced in patients with the limb-girdle muscular dystrophy type 2C (LGMD2C) form of severe childhood autosomal recessive muscular dystrophy. In the present investigation, we combined microspectrofluorimetry and electron microscopy techniques to investigate the physiological function and the ultrastructure of control and LGMD2C myotubes. Results obtained from Ca2+ measurements showed that the resting level of the cytosolic free calcium ([Ca2+ ]i ) in control myotubes was 73+/-3.4 nmol/l (mean+/-se, n=35) and in LGMD2C myotubes was 69+/-4 nmol/l (n=44). Carbachol (CCh, 10 micromol/l ) induced a 335+/-10 nmol/l (n=8) rise in [Ca2+ ]i in control myotubes and 531.9+/-32 nmol/l (n=23) in LGMD2C myotubes. Similarly, elevations of [Ca2+ ]i by 35 mmol/l K+ were 324+/-32 nmol/l (n=8) in control myotubes and 442.8+/-24 nmol/l (n=22) in LGMD2C myotubes. Caffeine (10 mmol/l) activated similar [Ca2+]i peaks in control and LGMD2C myotubes but induced a biphasic response in LGMD2C in four out of 12 myotubes and only a monophasic response in control myotubes. The ultrastructural results showed that the plasma membrane was abnormally indented and convoluted in both the LGMD2C biopsy and the LGMD2C cultured myotubes. It is suggested that the reduction in components of the dystrophin-glycoprotein complex results in the instability and an increase in the surface area of the plasma membrane, which may result in a higher population of Ca2+ channels in the LGMD2C myotubes.     

Freeze fracture studies of muscle plasma membrane in human muscular dystrophy

Summary Freeze fracture analysis of intramembranous particle density in skeletal muscle plasma membrane from 7 patients with Duchenne muscular dystrophy (DMD), 5 patients with facioscapulohumeral muscular dystrophy (FSH) and 5 patients with myotonic dystrophy (MyD) were carried out. Marked deplction of intramembranous particles including orthogonal arrays were significantly decreased in FSH. No abnormalities were noted in MyD.This work was supported by a Research Center Grant from the Muscular Dystrophy Association of America and by grants NS-08075, NS-14471 and 5 M01 RR00040 from the U.S. Public Health Service