Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation.

BACKGROUND: Myopalladin (MYPN) is a component of the sarcomere that tethers nebulin in skeletal muscle and nebulette in cardiac muscle to alpha-actinin at the Z lines. Autosomal dominant MYPN mutations cause hypertrophic, dilated, or restrictive cardiomyopathy. Autosomal recessive MYPN mutations have been reported in only six families showing a mildly progressive nemaline or cap myopathy with cardiomyopathy in some patients. CASE PRESENTATION: A consanguineous family with congenital to adult-onset muscle weakness and hanging big toe was reported. Muscle biopsy showed minimal changes with internal nuclei, type 1 fiber predominance, and ultrastructural defects of Z line. Muscle CT imaging showed marked hypodensity of the sartorius bilaterally and MRI scattered abnormal high-intensity areas in the internal tongue muscle and in the posterior cervical muscles. Cardiac involvement was demonstrated by magnetic resonance imaging and late gadolinium enhancement. Whole exome sequencing analysis identified a homozygous loss of function single nucleotide deletion in the exon 11 of the MYPN gene in two siblings. Full-length MYPN protein was undetectable on immunoblotting, and on immunofluorescence, its localization at the Z line was missed. CONCLUSIONS: This report extends the phenotypic spectrum of recessive MYPN-related myopathies showing: (1) the two patients had hanging big toe and the oldest one developed spine and hand contractures, none of these signs observed in the previously reported patients, (2) specific ultrastructural changes consisting in Z line fragmentation, but (3) no nemaline or caps on muscle pathology.

Novel SPEG Mutations in Congenital Myopathy without Centralized Nuclei.

Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy. This study expands the phenotypic spectrum of SPEG-related myopathy and prompts to consider SPEG for congenital myopathies without specific histological features.

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.

Thomsen disease with ptosis and abnormal MR findings.

Myotonia congenita is a non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction caused by a mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1). We encountered a case of Thomsen disease with ptosis. A short tau inversion recovery MR imaging demonstrated high-intensity lesions in the levator palpebrae superioris muscles. Molecular genetic testing revealed a heterozygosity for the c.1439C>A (p.P480H) mutation in the CLCN1 gene. The expression level of ClC-1 was significantly reduced on the sarcolemma of the biceps brachii muscle from the patient, compared with that from healthy volunteer. Functional analysis of the p.P480H mutation is required for further elucidating the pathogenesis of Thomsen disease.

Left ventricular diastolic function in congenital myotonic dystrophy.

OBJECTIVE: Examination of left ventricular function and conduction abnormalities in myotonic dystrophy. DESIGN: Twelve patients (median age, 13.7 years) with myotonic dystrophy had detailed electrocardiography and echocardiography performed. Echocardiographic parameters were compared with body surface area (BSA) matched median normal values. RESULTS: Fractional shortening was slightly reduced (by 28-29%) in three patients and three patients had mild mitral valve prolapse. Diastolic function was abnormal; isovolumic relaxation time (IVRT) and duration of early filling were prolonged compared with control values (median IVRT, 74 v 61 ms). Peak E velocity was increased (median, 0.82 v 0.78 m/s) but atrial phase filling was normal. Heart rate was reduced (median, 68 v 81 beats/min). Conduction abnormalities were common but showed no clear relations with diastolic abnormalities. CONCLUSIONS: Young patients with myotonic dystrophy have myocardial diastolic dysfunction as well as abnormal electrophysiology. The prognostic implications of such abnormalities require further study.

Cerebral abnormalities in congenital myotonic dystrophy.

The brain structure of 14 infants born with congenital myotonic dystrophy at 2 hospitals was evaluated by cranial ultrasonography, and the findings were correlated with clinical and neuropathologic data. Ventricular dilation was diagnosed in 11 infants (78%). Seven infants died during the neonatal period; all had ventricular dilation which remained essentially static. In the ultrasound scans of the 5 infants with ventricular dilation. Of the 7 survivors, 4 had ventricular dilation born at 1 hospital, 4 had widening of the interhemispheric fissure. Macrocephaly, a previously unrecognized finding in congenital myotonic dystrophy, was present in 10 infants (71%), 8 of whom presented with ventricular dilation. None had clinical evidence of increased intracranial pressure. There was no ventricular obstruction in the 4 brains examined pathologically. Histologic examination revealed minor expression of neuronal migrational disturbances in each patient. Macrocephaly together with the ultrasonographic and neuropathologic findings in our patients suggest that these abnormalities may originate in an external hydrocephalus.

CT of primary muscle diseases.

Seventy-five patients with a variety of muscular dystrophies were studied using computed tomography (CT). At least 11 slices were taken in each patient, from the forearm to the lower leg. Sufficient information was obtained to provide some CT characteristics of several dystrophies, including Duchenne muscular dystrophy, facioscapulohumeral syndrome, limb-girdle muscle myopathies, and myopathic dystrophies. CT promises to be of increasing value in these areas in the future.