Muscle phosphorylase b kinase deficiency revisited

Muscle phosphorylase b kinase (PHK) deficiency (glycogenosis type VIII) is a rare disorder caused by mutations in the PHKA1 gene encoding the α_M subunit of PHK. Only 5 patients with molecular defects in the X-linked PHKA1 gene have been described until now, and they all presented with exercise intolerance. Here, we report a patient with a new mutation in the PHKA1 gene who presented with PHK deficiency, cognitive impairment, but no overt myopathy. This report supports the concept that PHK deficiency is a mild metabolic myopathy and suggests that PHK mutations may interfere with normal brain function.     

Novel TNNT1 mutation and mild nemaline myopathy phenotype in an Italian patient

Mutations in the TNNT1 gene cause an infantile, lethal form of myopathy named “Amish” Nemaline Myopathy. Adult patients are very rarely described. We report a 49-year-old patient who presented a slowly progressive phenotype characterized by myalgia, exercise intolerance and dyspnea since infancy. In adult life she lapsed into a coma as a result of acute respiratory failure, with the need of tracheostomy, subsequently removed once her respiratory condition improved. Afterwards, non-invasive ventilation was started. Short stature, contractures, a small size posterior cranial fossa and osteonecrosis were additional clinical findings. Muscle MRI showed minor hypotrophy and degenerative changes of the muscles of the posterior thigh compartment and involvement of the paraspinal, medial gastrocnemius and soleus muscles with sparing of the gracilis muscle. Muscle biopsy revealed multiminicores and nemaline rods. Genetic analysis identified a new pathogenetic biallelic deletion c.786delG p.(Lys263Serfs*36) in exon 13 of TNNT1 gene. This case confirms that recessive mutations in TNNT1 gene can manifest mainly with respiratory failure in adult life.     

Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies

In this retrospective cross-sectional study clinical and muscle imaging data of patients with Miyoshi distal myopathy phenotype (MMD1 and MMD3) and limb girdle muscular dystrophy 2L (LGMD2L) were described. MMD1 and MMD3 are genetically heterogenous diseases based on DYSF and ANO5 gene defects. MMD3 and LGMD2L are clinically different diseases caused by an ANO5 gene defect. All groups showed predominant fatty degeneration of the gluteus minimus muscle and of the posterior segments of the thigh and calf muscles with sparing of the gracilis muscle. Muscle atrophy, hypertrophy and asymmetric muscle involvement on muscle imaging did not differ between groups. The pattern of fatty degeneration of muscles and of muscle weakness shows only minor differences between MMD1 (n = 6) and MMD3 (n = 8) patients with more frequently fatty degeneration of the rectus femoris, anterior tibial, and extensor digitorum muscles and more frequently muscle weakness in the anterior tibial, peroneal and calf muscle in MMD1. In the ANO5 related phenotypes the lateral head of the gastrocnemius muscle was less frequently involved in LGMD2L (n = 13) and no differences in the incidence of muscle weakness was found. Therefore, MMD3 and LGMD2L should be considered as part of one spectrum of ANO5 related muscle disease.     

Exercise induced muscle blood flow is decreased in Charcot–Marie–Tooth disease type 1 polyneuropathy: a power Doppler analysis

Background and purpose

Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post-exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot–Marie–Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles.

Methods

This was a cross-sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post-exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography.

Results

Polyneuropathy patients showed reduced post-exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126).

Conclusion

Post-exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy.     

The first Italian patient with oculopharyngodistal myopathy: case report and considerations on differential diagnosis

Oculopharyngodistal myopathy is a clinicopathologically distinct muscular disease. The underlying genetic defect has not been identified. We report here a 43-year old woman with asymmetric bilateral ptosis, dysphonia, swallowing difficulties, and weakness of the distal leg muscles. Serum creatine kinase was moderately increased. Electromyography revealed myopathic changes and myotonic discharges. Both cardiologic and pneumologic evaluation did not reveal abnormalities. Muscle computed tomography images showed adipose tissue replacement of abdominis rectus, lateral vastus, adductor magnus, and both the posterior and anterior compartment muscles below the knee, with prevalent involvement of medial gastrocnemius muscle. Muscle biopsy uncovered changes in fiber size and the presence of atrophic fibers with rimmed vacuoles of varying diameter, and core-like structures in type I fibers. Diagnosis was performed according to clinical and histopathologic findings, which were fully consistent with the other reported patients, and on the genetic exclusion of similar conditions such as oculopharyngeal muscular dystrophy, myotonic dystrophy type 1 and multi-minicore disease associated to RYR1 mutations. Differential diagnosis with mitochondrial myopathies, facioscapulohumeral muscular dystrophy and distal myopathies was also considered. This is the first Italian case of oculopharyngodistal myopathy, further suggesting the worldwide distribution of this rare neuromuscular disorder.     

Novel dysferlin mutations and characteristic muscle atrophy in late-onset Miyoshi myopathy

Miyoshi myopathy is characterized by weakness of the calf muscles during early adulthood. We report a case of late-onset Miyoshi myopathy presenting at 48 years of age, with novel mutations in the dysferlin gene. Muscle computed tomography clearly revealed severe atrophy in the soleus and medial gastrocnemius muscles. Even older patients with atrophy in the posterior compartment of the distal lower extremities and a relatively high serum creatine kinase level should be examined for the dysferlin gene.     

Vacuolar myopathies in adults with myalgias: Value of paraspinal muscle investigation

We evaluated 4 women with chronic fatigue and myalgias. Two had proximal weakness. All had elevated serum creatine kinase levels, but none was diagnosed with myopathy until electrodiagnostic studies revealed myotonic or complex repetitive discharges predominantly in paraspinal muscles. Histopathology of paraspinal muscles revealed vacuolar myopathies with glycogen storage; biochemical assays revealed phosphorylase deficiency in 1. Since vacuolar myopathies may affect paraspinal muscles more than limb muscles, electromyographic and histopathologic studies of paraspinal muscles may be required for diagnosis. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1321–1323, 1997     

An unusual case of recurrent episodes of muscle weakness: Co-occurrence of Andersen-Tawil syndrome and glycogen storage disease type IXd

A 25-year-old male patient presented with periodic paralysis that increased in severity and frequency with age, accompanied with muscle pain and significantly elevated creatine kinase (CK) levels. Initial clinical and genetic examination confirmed Andersen-Tawil syndrome. Although his father carried the same genetic mutation (p.G300A), he experienced minor and infrequent attacks of paralysis. A change in the patient's symptoms, such as accompanying pain, contracture, and significant CK elevation, lead to a reconsideration of the diagnosis. A muscle biopsy of the biceps brachii in the patient revealed glycogen storage, but no tubular aggregates. Analysis of the phosphorylase kinase regulatory subunit alpha 1 (PHKA1) gene revealed a pathogenic mutation (p.C1082X), indicating glycogen storage disease type Ⅸd. The case demonstrates that co-occurrence of glycogen storage disease type Ⅸd may prolong attacks of muscle weakness, and cause serious muscle pain in patients with Andersen-Tawil syndrome.     

Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin

Desminopathy is a genetically heterogeneous disorder with autosomal dominant pattern of inheritance in most affected families; the age of disease onset is on average 30 years. We studied a patient with a history of recurrent episodes of syncope from infancy who later developed second-degree AV block and restrictive cardiomyopathy; she subsequently suffered several episodes of ventricular tachyarrhythmia requiring implantation of bicameral defibrillator. Neurological examination revealed rapidly progressive bilateral facial weakness, winging of the scapulae, symmetric weakness and atrophy of the trunk muscles, shoulder girdle and distal muscles of both upper and lower extremities. Muscle biopsy demonstrated signs of myofibrillar myopathy with prominent subsarcolemmal desmin-reactive aggregates. Molecular analysis identified a homozygous deletion in DES resulting in a predicted in-frame obliteration of seven amino acids (p.R173_E179del) in the 1B domain of desmin. We describe the youngest known desminopathy patient with severe cardiomyopathy and aggressive course leading to the devastation of cardiac, skeletal and smooth musculature at an early age.     

远端型肌病71例的临床及肌肉病理分析

目的　探讨远端型肌病的临床表现及肌肉病理特点。方法　对71例远端型肌病患者进行回顾性分析。结果　71例患者中,Nonaka型26例,呈散发或常染色体隐性遗传,多以胫前肌无力为首发症状,肌肉坏死较轻,镶边空泡(rimmedvacuole,RV)多见,可见管状细丝包涵体;Miyoshi型38例,呈散发或常染色体隐性遗传,多以腓肠肌力弱为首发症状,肌肉变性坏死严重,RV少见;TMD型2例,均为散发病例,病变主要局限于胫前肌,病情进展较慢,有肌肉变性坏死,可见RV;Welander型4例,呈散发或常染色体显性遗传,以手指、腕部无力为首发症状,可波及下肢远端,轻度肌肉变性坏死,偶可见RV;OPDM型1例,呈常染色体显性遗传,表现为下肢远端肌无力伴眼外肌、面部肌肉、咽肌无力,肌肉坏死不显著,可见RV。结论　在中国Miyoshi型、Nonaka型、TMD型、Welander型及OPDM型远端型肌病均可见到,各型临床表现及病理改变与国外报道基本一致。     

Childhood-onset autosomal-dominant limb-girdle muscular dystrophy with cardiac conduction block

We report childhood-onset autosomal-dominant limb-girdle muscular dystrophy (LGMD) in a Chinese family with complete atrioventricular conduction block in the adult members. Six patients, including 5 men and 1 woman with an age of onset from 3 to 7 years, were affected. The grandfather had exercise intolerance since childhood and complete heart block with pace-maker placement at age 52. Three siblings had proximal muscle weakness and/or wasting since age 5 and heart block in their 40s. Two grandsons at the ages 7 and 3 showed exercise intolerance, and proximal muscle weakness and wasting. Sinus bradycardia was present in the elder grandson. Muscle enzymes were elevated in 3, particularly in childhood. Muscle biopsies from the proband showed myopathic changes with fatty degeneration, whorled fibers, and rimmed vacuoles. In adult patients, muscle magnetic resonance imaging scans disclosed atrophic changes and fatty degeneration in the gluteal, quadriceps, adductors, hamstrings, gastrocnemius, and soleus muscles, while in child probands the early atrophic changes were seen in the gluteal and hamstrings muscles. We conclude that this distinct family is characterized by childhood-onset autosomal-dominant LGMD with heart block and that prevention of sudden death in these patients is important. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 286–292, 1997.     

Tubular aggregate myopathy with features of Stormorken disease due to a new STIM1 mutation

STIM1 is a reticular Ca²⁺ sensor composed of a luminal and a cytosolic domain. Missense mutations in the luminal domain have been associated with tubular aggregate myopathy (TAM), while cytosolic mutations can cause Stormorken syndrome, a multisystemic disease associating TAM with asplenia, thrombocytopenia, miosis, ichthyosis, short stature and dyslexia. Here we present the case of a 41-year-old female complaining of exercise intolerance. Clinical examination showed short stature, scoliosis, proximal muscle weakness with lower limb predominance, and ophthalmoplegia. Laboratory tests revealed hypocalcemia, mild anemia and elevated creatine kinase (CK) levels. Whole-body muscle magnetic resonance imaging (MRI) revealed asplenia. Muscle biopsy was consistent with TAM. STIM1 gene analysis disclosed the novel c.252T>A, p.D84E missense mutation which was shown to induce constitutive STIM1 clustering in a functional study. This study reports a novel STIM1 mutation located in the Ca²⁺-binding EF domain causing TAM with features of Stormorken syndrome.     

A novel missense HNRNPA1 variant in the PY-NLS domain in a patient with late-onset distal myopathy

Pathogenic HNRNPA1 variants underlying myopathy have been reported only in the prion-like domain of the heterogenous nuclear ribonucleoproteins A1, while two variants in the nuclear localization (PY-NLS) domain were described in ALS. Here we report a 61-year-old man who presented with 1-year history of bilateral foot drop without Paget disease or dementia. Examination revealed severe asymmetric distal weakness, predominantly affecting tibialis anterior and toe extensors. Creatine kinase was 1,013 U/L (normal <308). Alkaline phosphatase was normal. EMG demonstrated small polyphasic motor unit potentials and fibrillation potentials. Muscle biopsy showed numerous fibers containing rimmed vacuoles and occasional fibers harboring congophilic inclusions, or p62/TDP-43/hnRNPA1-immunoreacted aggregates. Next generation sequencing identified a novel heterozygous (c.959A>T, p. Asn320Ile) variant in HNRNPA1, affecting a highly conserved amino acid in PY-NLS domain. Muscle MRI showed abnormalities, consistent with HNRNPA1-myopathy. This patient expands the phenotypic spectrum of hnRNPA1-opathy due to a PY-NLS domain variant to include isolated distal myopathy.     

全身性癫癎伴高热惊厥附加症致病基因的连锁定位研究

目的　定位全身性癫癎伴高热惊厥附加症的致病基因。方法　采用全基因组扫描的连锁分析方法对全身性癫癎伴高热惊厥附加症4个家系进行研究。结果　在染色体5q34多点连锁分析显示最大LOD值为3. 815。染色体单体型分析将连锁范围缩小至D5S820至D5S1476之间4. 0厘摩(cM)的区域。结论　全身性癫癎伴高热惊厥附加症致病基因定位在染色体5q34。     

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy

We report a family with adult-onset myofibrillar myopathy with BAG3 mutation who presented peroneal weakness and axonal polyneuropathy, mimicking axonal Charcot-Marie-Tooth disease. The male proband noticed difficulty in tiptoeing at age 34. At age 42, the examination showed muscle weakness and atrophy in distal lower extremities with diminished patellar and Achilles tendon reflexes. Thermal and vibration sensations were also impaired in both feet. The serum CK level was 659 U/L. On muscle imaging, predominant semitendinosus muscle atrophy coexisted with atrophies in the quadriceps, gastrocnemius and lumbar paraspinal muscles. The muscle biopsy showed myofibrillar myopathy with fiber type grouping. His 68-year-old mother also had suffered from distal leg weakness and sensory impairment since her forties. A heterozygous mutation in BAG3 (P470S) was identified in both patients. Clinical features of myofibrillar myopathy with axonal polyneuropathy were consistent with BAG3-related myopathy. Our patients showed remarkably mild presentations without cardiomyopathy, unlike the majorities of previously reported cases.     

Asymptomatic hyperCKemia in a case of Danon disease due to a missense mutation in Lamp-2 gene

Primary lysosome-associated membrane protein-2 (LAMP-2) deficiency is an X-linked disease, characterized by the clinical triad of cardiomyopathy, vacuolar myopathy and mental retardation, previously known as Danon disease. Mutations of lamp-2 gene have been reported so far in about 20 patients, one of whom was Italian. We describe a new Italian case with persistent hyperCKemia, exercise intolerance and hypertrophic cardiomyopathy but with no muscle weakness or mental impairment. Muscle biopsy revealed a vacuolar myopathy with mild glycogen storage, and immunohistochemical studies detected LAMP-2 deficiency. A new nucleotide substitution (T961C) on exon 8 of lamp-2 gene was identified as responsible for the protein deficiency. This is the first missense mutation so far described. LAMP-2 deficiency should be considered as a cause of recurrent hyperCKemia and hypertrophic cardiomyopathy.     

A novel mutation in the PDZ‐like motif of ZASP causes distal ZASP‐related myofibrillar myopathy

Mutations in the LDB3 gene have been identified in patients with Z‐disc‐associated, alternatively spliced, PDZ motif‐containing protein (ZASP)‐related myofibrillar myopathy (ZASP‐MFM) characterized by late‐onset distal myopathy with signs of cardiomyopathy and neuropathy. We describe an autosomal dominant inherited pedigree with ZASP‐MFM that is in line with the typical phenotype of distal myopathy without cardiomyopathy and neuropathy, while mild asymmetrical muscle atrophy can be observed in some affected members. Muscle MRI revealed considerable fatty degeneration involved in the posterior compartment of thigh and lower leg, but relatively preserved in rectus femoris, sartorius, gracilis, adductor longus and biceps femoris breve muscles in the later stage. In addition, fatty infiltration of medial gastrocnemius muscle can be initiated as early as in the third decade in asymptomatic individuals. Myopathological features showed sarcoplasmic accumulation of multiple protein deposits and electron dense filamentous bundle aggregates. A novel heterozygous missense mutation (p.N155H) in a highly conserved PDZ‐like motif of ZASP was identified. The results indicate that typical ZASP‐MFM presenting with late‐onset distal myopathy is commonly associated with mutations in PDZ‐like motif of ZASP. The development of fatty degeneration is consistent with the typical pattern of ZASP‐MFM, and the initial fatty infiltration might be started from medial gastrocnemius muscle. Our study expands the clinical and mutational spectrum of ZASP‐MFM.     

Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget’s disease of bone and frontotemporal dementia

We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget’s disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget’s disease or cognitive impairment.     

Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1

Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far.We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5 years of age. Muscle biopsy at 5 weeks of age was uninformative. Repeat biopsy at 4.5 years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met47Val mutation.In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness.