Dystrophinopathies and Limb-Girdle Muscular Dystrophies
Muscular dystrophies are a heterogeneous group of inherited diseases. The natural history of these disorders along with their management have changed mainly due to a better understanding of their pathophysiology, the evolution of standards of care, and new treatment options. Dystrophinopathies include both Duchenne's and Becker's muscular dystrophies, but in reality they are a spectrum of muscle diseases caused by mutations in the gene that encodes the protein dystrophin. Duchenne's muscular dystrophy is the most common form of inherited muscle disease of childhood. The current standards of care considerably prolong independent ambulation and survival. Several therapeutic options either aiming at substituting/correcting the primary protein defect or limiting the progression of the dystrophic process are currently being explored in clinical trials.Limb-girdle muscular dystrophies (LGMDs) are rare and heterogeneous conditions, characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Originally classified into dominant and recessive, > 30 genetic forms of LGMDs are currently recognized. Further understanding of the pathogenic mechanisms of LGMD will help identifying novel therapeutic approaches that can be tested in clinical trials.
Vitamin B6–Responsive Epilepsy due to a Novel KCNQ2 Mutation
Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.
Inherited and Acquired Muscle Weakness: A Moving Target for Diagnostic Muscle Biopsy
Inherited and acquired muscular weakness is caused by multiple conditions. While the inherited ones are mostly caused by mutations in genes coding for myopathic or neurogenic diseases, the acquired ones occur due to inflammatory, endocrine, or toxic etiologies. Precise diagnosis of a specific disease may be challenging and may require a multidisciplinary approach. What is the current place for a diagnostic biopsy of skeletal muscle? Diagnostic muscle biopsy lost in this context its first-tier place in the primary diagnostic workup for some diseases, but it is still mandatory for others. We here summarize conditions in which we believe a diagnostic sample is most relevant and mention those in which a biopsy may be secondary or can even be left out. We would like to stress that muscle biopsy nowadays has a new important place in description and definition of new diseases, for example, discovered by modern genetic approaches.
Novel STAC3 Mutations in the First Non-Amerindian Patient with Native American Myopathy
Native American myopathy (NAM) is an autosomal recessive congenital myopathy, up till now exclusively described in Lumbee Indians who harbor one single homozygous mutation (c.1046G>C, pW284S) in the STAC3 gene, encoding a protein important for proper excitation–contraction coupling in muscle. Here, we report the first non-Amerindian patient of Turkish ancestry, being compound heterozygous for the mutations c.862A>T (p.K288*) and c.432+4A>T (aberrant splicing with skipping of exon 4). Symptoms in NAM include congenital muscle weakness and contractures, progressive scoliosis, early ventilatory failure, a peculiar facial gestalt with mild ptosis and downturned corners of the mouth, short stature, and marked susceptibility to malignant hyperthermia. This case shows that NAM should also be considered in non-Indian patients with congenital myopathy, and suggests that STAC3 mutations should be taken into account as a potential cause of malignant hyperthermia.
Congenital Glioblastoma Multiforme: An Unusual and Challenging Tumor
Congenital glioblastoma multiforme is a rare tumor of the central nervous system with unique features. The existing evidence on its pathogenesis, genetic and molecular profile, special characteristics, treatment, and prognosis is reviewed. An increased number of antenatal diagnoses and prolonged survival for those individuals who can tolerate combined surgical resection and chemotherapy has been noted. The overall prognosis, however, remains poor. A better understanding of this unusual entity is important. Further research is needed to discern tumor's pathogenesis and natural history. This will likely lead to the development and implementation of treatment strategies that may decrease mortality and morbidity in these patients.
Autosomal Recessive Primary Microcephaly (MCPH): An Update
Autosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.