Congenital muscular dystrophy (CMD) is defined as muscular dystrophy with neonatal or infantile onset. One of the most important facts about CMD is that the frequency of subtypes wide varies widely among different ethnic groups. For example, in Japan, Fukuyama CMD (FCMD), which is due to FKTN mutations, accounts for 50% of the cases while only few cases with FKTN mutations were documented in European countries. In contrast, merosin-negative CMD accounts for nearly half of the cases in European countries, and probably followed by MDC1C , both of which are very rare in Japan. Because of this peculiar nature of CMD occurrence, the classification of the CMD is different between Japan and European countries. In European countries, CMD is classically classified into merosin-negative CMD and merosin-positive CMD while in Japan it is grouped into FCMD and nonFCMD. Therefore, this situation serves as a caveat to other countries and regions and warrants the need to consider local statistical data about CMD for establishing the appropriate classification.

Both FCMD and MDC1C are caused by defective glycosylation on α-dystroglycan, thereby they are collectively called α-dystroglycanopathy. As laminin interacts with the sugar chains of α-dystroglycan, the binding between laminin and alpha-dystroglycan is loosened, resulting in the fragility of the sarcolemma.

Another important CMD is Ullrich disease. This disease is caused by mutations in any of the three genes that encode collagen VI. In terms of muscle histology, two forms are recognized: complete collagen VI deficiency and sarcolemma-specific collagen VI deficiency (SSCD). The former is caused by recessive mutations while the latter by dominant mutations in the triple helical domain. Majority of patients have SSCD form. Interestingly, in contrast to FCMD, MDC1C and merosin-negative CMD, the frequency of Ullrich disease seems to be similar among different ethnic groups. This is most likely because the major form of Ullrich CMD, SSCD, is caused by de novo mutation in the collagen VI genes rather than by common ancestral mutations.

In my talk, I will mainly cover α-dystroglycanopathy and Ullrich disease.

Mitochondrial diseases comprise a group of relatively rare (~1 in 5000 adults) but very serious genetic disorders. Caused by defects in mitochondria, the powerhouses of the cell, these diseases are characterized by a variety of symptoms, including muscle weakness, seizures, mental retardation, dementia, hearing loss, blindness, strokes, diabetes, and premature death. Some affect only skeletal muscle, but most are multi-systemic, often affecting the brain and muscle (encephalomyopathies). Although severity varies, by and large these are progressive and often crippling disorders.

Because of the range of symptoms and the frequent involvement of multiple body systems, mitochondrial diseases can be a great challenge to diagnose. Even when accurately diagnosed, they pose an even more formidable challenge to treat, as there are very few therapies. Nevertheless, it is important for clinicians to properly identify mitochondrial diseases as the correct diagnosis is important for predicting prognosis, providing accurate genetic counseling, and guiding treatments. 

In addition to their clinical complexity, mitochondrial diseases are genetically diverse due to their dual genomic origins, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). In contrast to nDNA, mtDNA is transmitted by mothers to all offspring. Thus, mitochondrial diseases can be inherited as maternally inherited disorders as well as autosomal dominant, autosomal recessive, or X-linked patterns. Another unique aspect of the mitochondrial genome is the fact that each cell contains hundreds of copies of mtDNA in contrast to the two copies of nDNA in each cell. Thus, patients with mtDNA mutations often harbor mixed populations of mutant and normal mitochondrial genomes in each cell – a concept know as heteroplasmy. The degree of heteroplasmy and distribution of mutant mtDNA in different cells (mitotic segregation) influences the clinical phenotype. Thus, a single mtDNA mutation can cause diverse clinical phenotypes depending upon the level of heteroplasmy and tissue distribution of the mtDNA mutation.

This lecture will review the major features of the most frequent mitochondrial diseases, discuss how to diagnose these complex disorders, and briefly describe the limited available therapies.

The objective of this work was to identify practice guidelines for the care of spinal muscular atrophy (SMA). SMA is a neurodegenerative disease that requires multi-disciplinary medical care. Recent progress in the understanding of molecular pathogenesis of SMA and improvement in medical technology have not been matched by similar development in the care for SMA patients. Variations in medical practice coupled with differences in family resources and values have resulted in variable clinical outcomes that are likely to compromise valid measure of treatment effects during clinical trial studies. The International Standard of Care Committee (SCC) for SMA was formed in 2005 with a goal to establish practice guidelines for clinical care of SMA patients. The 12 core committee members worked with over 60 SMA experts in the field; through conference calls, e-mail communications, Delphi survey, and two in-person meetings to achieve consensus on 5 care areas: Diagnostic/New Interventions, Pulmonary, Gastrointestinal/Nutrition, Orthopedics/Rehabilitation, and Palliative Care. Consensus was achieved in several topics regarding common medical problems in SMA, the diagnostic strategies, recommendations for assessment and monitoring, and for therapeutic interventions in each care area. A consensus statement was drafted to address the 5 care areas according to three functional levels of the patients: non-sitter, sitter, and walker. The SCC also identified several medical practices where there is no consensus and warrant further investigation. SMA is in urgent need of a practice guideline to help with the multi-disciplinary care of these patients. The SCC has achieved a consensus for the care of SMA patients. It is the intention of the Committee that this document be used as consensus guidelines and not a practice standard in the care for SMA patients. 

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord which leads to muscular paralysis and muscular atrophy and the leading genetic cause of infant mortality. SMA is classified into type I, II, III according to the age of onset and progression of the disease. The causative gene, survival motor neuron (SMN), has two copies SMN1 and SMN2, with 99% identical sequence. A critical nucleotide difference at position 6 in exon 7 of SMN2, C to T, causes alternative splicing in pre-mRNA and consequently results in a considerable amount of truncated mRNA with the lack of exon 7, while SMN1 expresses exclusively full-length transcript. All SMA patients are effectively null for SMN1 but retain at least one copy of SMN2, indicating SMA is generated by a fall in the level of full-length SMN protein and the level expressed by the retained SMN2 might control the severity. Accordingly, sodium butyrate was firstly to show effectively to increase the amount of full-length SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene and ameliorating SMA symptoms in SMA-like mice in 2001.

Since then, some drugs, compounds or small molecules including sodium butyrate, trichostatin A, suberoylanilide hydroxamic acid (SAHA) , benzamide M344, phenylbutyrate, hydroxyurea, valproic acid, aclarubicin, 5-(N-ethyl-N-isopropyl)-amiloride (Na+/H+ exchanger inhibitor), polyphenol botanical compounds, geneticin and 2,4-diaminoquinazoline derivatives have been used in SMA-like mice, SMA patients' fibroblasts, lymphoid cell lines or SMA patients, with some showing effective results either in terms of elevation of SMN2 expression in cell lines or improving muscle strength, lung function, and increasing SMN2 gene expression in SMA patients. We will overview the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials including valproic acid, phenylbutyrate, hydroxyurea, riluzole, gabapentin, albuterol and somatotropin in SMA.