FKRP generelated congenital muscular dystrophycongenital muscular dystrophy 1C

The FKRP gene is a homolog of the fukutin gene encoding for fukutin-related protein. It has been localized in the Golgi apparatus and is involved in the glycosylation processing of a-dystroglycan. It is ubiquitously expressed. Mutations in the fukutin-related protein gene (FKRP) located on chromosome 19q13 give rise to a spectrum of phenotypes, including a form of congenital muscular dystrophy (MDC1C), WWS phenotype and a relatively mild form of limb-girdle muscular dystrophy (LGMD2I). FKRP is...

Isolated mitochondrial myopathy in infants

Isolated mitochondrial myopathy in infants has mainly been associated with COX deficiency (DiMauro et al., 1980 1983 Oldfors et al., 1989). A fatal (DiMauro et al., 1980) and a benign reversible form (DiMauro et al., 1983) have been described. Both infantile myopathies begin soon after birth and are associated with severe generalized weakness, breathing and feeding difficulties and lactic acidosis. In the reversible form the children improve spontaneously after 5 months of age, and the lactic...

Clinical phenotypes

The clinical presentations of mitochondrial diseases are highly variable and the symptoms are often initially vague and non-specific. This clinical heterogeneity reflects in part the complex genetics underlying these disorders. In addition organs with high energy demands are more susceptible to defects in the OXPHOS system. Striated muscle and the nervous system are especially vulnerable. Patients with mitochondrial disease may present their first signs and symptoms at any age, and...

Defects of other nuclear encoded proteins with effects on the respiratory chain

Friedreich ataxia and hereditary spastic paraplegia (HSP) may be considered as mitochondrial diseases with secondary effects on the OXPHOS system. In Friedreich ataxia, which is due to a trinucleotide expansion in the frataxin gene, complex I-III and aconitase deficiency have been demonstrated (Rotig et al., 1997a). The patho-genesis has been proposed to involve oxidative damage to iron-sulfur clusters, resulting from hampered superoxide dismutase signaling (Chantrel-Groussard et al., 2001). In...

Pearson syndrome

In 1979 four children were described with a syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction with onset in infancy (Pearson et al., 1979). There was a variable degree of neutropenia and thrombocytopenia, and of exocrine pancreatic dysfunction. All infants Fig. 6.5. Magnetic resonance scan of the brain showing hyperintense signals in the dorsal parts of putamen in a 18-month-old girl with Leigh syndrome, cytochrome c oxidase...

Congenital myopathies

SEWRY2' 3, AND PHILLIPA LAMONT4 1Centre for Medical Research, University of Western Australia, West Australian Institute for Medical Research, Nedlands, Western Australia, Australia 2Centre for Inherited Neuromuscular Disorders, Department of Histopathology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK 3Dubowitz Neuromuscular Centre, Department of Paediatrics and Neonatal Medicine, Imperial College Faculty of Medicine,...

Magnetic resonance imaging in the congenital myopathies

Neonatal Rectus Abdominal Muscles

The clinical presentation of the congenital myopathies is often similar and somewhat non-specific, making them difficult to distinguish from each other. The tradi tional first investigation, once a clinician decides that an infant's phenotype is compatible with a congenital myopathy, has been to proceed to muscle biopsy. However, researchers have turned to MRI to investigate whether there are identifiable patterns of muscle involvement that would allow differentiation between the various...

Primary mtDNA mutations associated with Oxphos diseases

Only 13 of some 87 proteins, which build up the OXPHOS system, are encoded by mtDNA (Fig. 6.2), and it has been estimated that mtDNA mutations are responsible for approximately 20 of the OXPHOS diseases. However, the majority of mitochondrial disorders, in which the etiology has been established, are due to primary mtDNA defects. Since mtDNA is maternally inherited, mutations will only be transmitted from mother to child, although there are rare exceptions to this rule (Schwartz and Vissing,...

Leber hereditary optic neuropathy LHON

Leber hereditary optic neuropathy (LHON) is the most frequent mtDNA disease with a prevalence of 1 in 50 000 in Finland (Huoponen, 2001) and approximately 1 in 25 000 in north-east England (Man et al., 2003). It is characterized by acute or subacute visual loss with an age at onset between 15 and 35 years, but the range is from young children to individuals older than 60 and there is a marked male predominance (Newman et al., 1991 Johns et al., 1992a Harding et al., 1995b Nikoskelainen et al.,...

Genetics of MH

The ryanodine receptor, encoded by the RYR1 gene, a calcium-release channel located on the SR, appears to be crucial to the pathogenesis of MH. The first clues to its involvement originated from the discovery of the Hal locus in pigs from the investigation of PSS.The Hal locus was mapped to pig chromosome 6p11-q21 (Harbitz et al., 1990) which shows conservation with human chromosome 19q13.1 where the RYR1 gene is located. RYR1 was mapped and cloned in 1990 (MacKenzie et al., 1990 McCarthy et...

References

Afifi AK, Smith JW, Zellweger H (1965). Congenital nonprogressive myopathy. Central core disease and nemaline myopathy in one family. Neurology 15 371-381. Agrawal PB, Strickland CD, Midgett C, et al. (2004). Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 56 86-96. Anderson SL, Ekstein J, Donnelly MC, et al. (2004). Nema-line myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 115 185-190. Arts...

Familial hyperkalemic periodic paralysis hyperPP

In the early 1950s the Swedish pediatric neurologist Gamstorp recognized a new form of periodic paralysis associated with an elevated serum potassium. In her thesis in 1956 she coined the term adynamia episodica hereditaria (Gamstorp, 1956) but later it was referred to as hyperkalemic periodic paralysis. Familial hyperPP is due to mutations in SCN4A encoding the a-subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. The clinical presentation of hyperPP includes attacks of limb...

Xlinked myotubular myopathy 1271 Clinical aspects

The terms myotubular myopathy (MTM) and centronuc-lear myopathy were originally applied to all congenital myopathy patients in whom the muscle biopsy was characterized by central nuclei. With advances in molecular genetics and identification of gene defects the term myotubular myopathy is generally applied to the X-linked cases with a mutation in the gene encoding myotubularin, whilst centronuclear myopathy is used for the heterogenous autosomal conditions with central nuclei (Pierson et al.,...

Autosomaldominantrecessive PEO with multiple mtDNA deletions

Autosomal-dominant -recessive progressive external ophthalmoplegia (ad ar PEO) usually refers to an adult-onset condition with PEO plus various additional clinical manifestations and multiple mtDNA deletions in muscle (Suomalainen and Kaukonen, 2001 Van Goethem et al., 2003b). A special entity, which usually is included in this group of disorders, is the mitochondrial neurogas-trointestinal encephalomyopathy (MNGIE) syndrome (Hirano et al., 1994 Nishino et al., 2001 Hirano et al., 2004). In ad...

Medication options

Potassium chloride can be used in the treatment of an acute attack in hypoPP. Oral preparations are preferable as there is a higher risk of rebound hyperkalemia with intravenous administration. Regular use may reduce the frequency of attacks. Agents that reduce urinary potassium loss such as spironolactone (100 mg day) or triamterene (150 mg day) can also improve symptoms in hypoPP. Patients with hyperPP may benefit from treatment to prevent hyperkalemia including thiazide diuretics (McArdle,...

Point mutations of tRNA and rRNA genes

Although nearly 80 of the coding part of the mitochon-drial genome is allocated to protein-coding genes and approximately 10 to tRNA genes, the majority of the pathogenic point mutations so far described affect tRNA genes (approximately 100 point mutations). Most cases are maternally inherited but de-novo mutations occur. Pathogenic mutations have been identified in most of the 22 tRNA genes, but some tRNA genes are more frequently affected than others. Among these are the tRNALeu(UUR), tRNAIle...

Emg

The electrophysiological correlate of myotonia, regardless of the type of channel affected, is involuntary repetitive firing of muscle fiber action potentials. The impressive electrical activity following a voluntary contraction is too painful to monitor. Instead, the EMG needle is usually inserted into the resting muscle. Needle insertion itself elicits myotonic bursts. In patients with Thomsen and Becker myotonia, the myotonic bursts can be observed in all routinely examined skeletal muscles....

Secondary periodic paralysis

A number of secondary causes of periodic paralysis should to be considered when evaluating a patient with periodic paralysis. Both hypo- and hyperkalemia of any origin can result in muscle weakness or paralysis. Usually the patient remains weak until the underlying cause of potassium alteration is identified and treated. Occasionally patients with a secondary cause may present with intermittent attacks of weakness and this may make the distinction with sporadic genetic periodic paralysis more...

Nervous system and ocular manifestations

Muscle Glycogen Biopsy

The central nervous system (CNS), peripheral nervous system (PNS) and skeletal muscle are affected in the majority of mitochondrial disorders. The signs and symptoms from the nervous system may include mental retardation, autistic features, mental depression, apnea attacks, myoclonic seizures, epilepsy, ataxia, migrainelike headache, stroke-like episodes, sensorineural hearing loss, reduced vision and blindness, hemianopsia, peripheral neuropathy, muscle weakness and fatigue, muscle hypotonia...

Emery Dreifuss muscular dystrophy 2241 Xlinked recessive form

In 1961 and later in 1966 an unusual variant of the well-known X-linked muscular dystrophies (Duchenne and Becker-type) was described with conspicuous atrophy of the upper arms, contractures at the elbows, absence of calf hypertrophy and intellectual impairment, and distinctive cardiac features (Dreifuss and Hogan, 1961 Emery and Dreifuss, 1966). It is likely that the first descriptions of the disease date back to the beginning of the 20th century (http www.affari.com smanet edmd. htm). The...

Autosomal dominant form

Autosomal dominant (and recessive) Emery-Dreifuss muscular dystrophy (AD-EDMD orEDMD2) is less frequent than X-EDMD and is caused by mutations in the LMNA gene on chromosome 1q11-q23 (Bonne et al., 1999 Di Barletta et al., 2000). Mutations in the LMNA gene encoding lamins A and C by alternative splicing cause primary laminopathies including various types of lipodystrophies, muscular dystrophies (EDMD2 and LGMD1B) and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies,...

Muscle biopsy IVCT

This is an open surgical procedure in which several strips of muscle bundles are carefully dissected from the surface of the vastus medialis muscle via a 5 cm incision under either a femoral nerve block or occasionally a MH-safe general anesthetic. Each muscle sample weighs around 100 mg, measuring 2-3 cm in length and less than 0.5 cm in width and is kept in carboge-nated Krebs solution at room temperature for storage and transport to the laboratory. A muscle sample is placed in a tissue bath...

Genetic testing

DNA testing is now a major diagnostic tool in familial periodic paralysis. However, even with extensive DNA sequencing of the ion channel genes known to be involved in periodic paralysis, mutations are not detected in one-third of patients with either hyper- or hypokalemic periodic paralysis (Miller et al., 2004). Both CACNA1S and SCN4A are large genes containing 44 and 24 exons respectively. The genetic testing generally available in DNA diagnostic-service laboratories often only encompasses...

Congenital muscular dystrophy type MDC1A

Congenital Muscular Dystrophy

Primary deficiency of laminin a2 merosin accounts for approximately 30-40 of all patients with CMD in European countries and only 6 in Japan Pegoraro et al., 1996 Allamand and Guicheny, 2002 Muntoni and Voit, 2004 . This variant was initially identified by Fernando Tome and associates 1994 and called the classical, occidental-type CMD, or merosin-deficient CMD indicating the deficiency of the trimer formed by the combined expression of laminin a2, laminin p1 and laminin g1. Subsequent studies...

Andersen Tawil syndrome ATS

Andersen Tawil Syndrome

Andersen-Tawil syndrome first fully described by Andersen et al. 1971 is characterized by a triad of periodic paralysis, ventricular arrhythmia and distinctive physical features. Many patients do not have all of these features and there can be marked intrafamilial variation and evidence of incomplete penetrance Plaster et al., 2001 . It is the rarest form of periodic paralysis and no reliable data exist on prevalence. Mutations in KCNJ2 encoding the inward-rectifying potassium channel Kir2.1...

Management of patients with congenital myopathies with particular emphasis on respiratory support

Vastus Lateralis Atrophie

The degree of respiratory involvement in the congenital myopathies depends on the precise diagnosis. This has been outlined in the individual sections. Respiratory failure can occur at any age in a patient with a congenital myopathy, including adulthood. It can happen slowly, but more alarmingly, can be sudden and catastrophic. The latter often, but not always, happens in the setting of an intercurrent respiratory tract infection. The likelihood of respiratory compromise cannot be judged from...

Molecular pathogenesis

How exactly nemaline bodies form is not known, but we do know that mutations in five thin filament proteins lead to their formation. Analysis of those mutations is beginning to provide insight into the molecular pathogenesis. The slow a-tropomyosin mutation causing dominant childhood onset distal myopathy has been studied in a number of systems and a mouse model has been generated Corbett et al., 2001 . The mutation has been shown to 1. alter the regulation of force production Michele et al.,...

Nemaline myopathy 1211 Clinical aspects

Douglas Reye

It is usually considered that the first description of nemaline myopathy was in 1963 Conen et al., 1963 , Shy et al., 1963 . However, in 1958 Dr Douglas Reye in Sydney, Australia, described a patient with rod Fig. 1.1. Somatic mosaicism for a ryanodine receptor RYR1 mutation. Lane 1 normal control lane 2 proband A4940T mutation lane 3 mother of proband lane 4 normal control. Note the faint aberrant band in the mother's sample arrow . M size standard B blank. Courtesy of Mark Davis. Fig. 1.1....

MELAS syndrome

Brain Mitochondrial Mutation A3243g

Pavlakis et al. 1984 described two of their own patients and reviewed nine other patients from the literature with normal early development, short stature, seizures and alternating hemiparesis, hemianopia or cortical blindness. They concluded that patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes MELAS syndrome represented a distinct clinical entity that should be differentiated from Kearns-Sayre and MERRF syndromes. The first mutation associated with...

Paramyotonia congenita

Paramyotonia Congenita Pregnancy

Paramyotonia congenita PC is inherited as an autosomal dominant MIM 168300 . Signs are present at birth and often remain unchanged throughout life. The cardinal symptom is cold-induced muscle stiffness that increases with continued activity paradoxical myoto-nia . On repeated strong contractions of the orbicularis oculi, the opening of the eyelids is increasingly impeded finally the eyes cannot be opened to more than a slit. As a rule, muscles are bilaterally and symmetrically affected. Many...

Treatment of nemaline myopathy

A single published report exists of a father and son with nemaline myopathy whose muscle strength improved with daily L-tyrosine Kalita, 1989 . Unpublished reports suggest that there may be an improvement in overall muscle strength and endurance. In particular it is said to reduce drooling. In a multicentre cohort of 143 patients, mortality was invariably due to respiratory insufficiency Ryan et al., 2001 . Thus the management of respiratory insufficiency is very important in nemaline myopathy....

Potassiumaggravated myotonia PAM O paramyotonia congenita PC C

Membrane topology model of the voltage-gated sodium channel. A. The skeletal muscle a-subunit functions as an ion-conducting channel and consists of four highly homologous domains repeats I-IV containing six transmembrane segments each S1-S6 . The S6 transmembrane segments and the S5-S6 loops form the ion-selective pore, and the S4 segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected by intracellular loops one of them,...

General examination and laboratory investigations

General examination of patients between attacks is often normal. Muscle strength testing may reveal evidence of persistent proximal weakness. Patients with hyperPP may show signs of action and percussion myo-tonia. Lid lag often proves to be the most sensitive indicator of myotonia but it can also be seen in healthy volunteers. Patients with periodic paralysis and myoto-nia may also exhibit a degree of muscle hypertrophy McArdle, 1962 Layzer et al., 1967 . Attention should be paid to detect any...

Sodiumchannel periodic paralysis

Clinically the sodium channelopathies of skeletal muscle can be divided into three main allelic disorders hyperkalemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia. Patients with sodium channel hyperPP may also complain of symptoms suggestive of paramyotonia congenita or potassium-aggravated myotonia as these conditions frequently overlap Sasaki et al., 1999 . The pioneering work on muscle specimens from myotonic goat by Bryant and colleagues Bryant, 1962 Lipicky...

Tel Hashomer camptodactyly syndrome THCS

Tel Hashomer camptodactyly syndrome THCS is a rare disorder comprising camptodactyly, hypotonia and muscle hypoplasia, skeletal dysplasia, inguinal hernia and mitral valve prolapse and abnormal dermatoglyphics. Melegh et al. 2005 described a mentally retarded Hungarian boy who was diagnosed with THCS at age 4 months. Features compatible with skeletal muscle and or connective tissue involvement include high-arched palate, hypoplastic and hypotonic muscles, scapulae ala-tae, thoracic scoliosis,...

Neurophysiological examination

Routine nerve conduction studies between attacks are normal. EMG may show myopathic changes, particularly in those patients who have developed fixed weakness. In patients with hyperPP evidence of sarcolemmal hyperexcitability in the form of myotonic discharges, increased insertional activity and spontaneous fibrillation and positive sharp waves may be found. Myotonic discharges can be present even in the absence of clinical symptoms or signs of para myotonia but the degree of abnormality tends...

Familial hypokalemic periodic paralysis hypoPP

Most of the early original publications on periodic paralysis were probably describing hypoPP, as this is the commonest form of periodic paralysis. Talbott published an extensive review of the literature on periodic paralysis in 1941 Talbott, 1941 . This paper summarized many of the characteristic features of periodic paralysis including age of onset, male predilection, development of fixed weakness and provoking factors. Talbott cites Musgrave's interesting observation from 1727 of a...

Congenital myopathies for which genes have not yet been identified

There are a large number of congenital myopathies in the literature for which the genes have not yet been identified Table 1.2 Engel et al., 1970 Brooke and Neville, 1972 Engel et al., 1972 Lake and Wilson, 1975 Fardeau et al., 1976 Ringel et al., 1978 Carpenter et al., 1979 Fidzianska et al., 1981 Goebel et al., 1981 Mrak et al., 1993 Mrak et al., 1996 Marbini et al., 1998 Bourque et al., 1999 Goebel and Anderson, 1999 Ikezoe et al., 2000 Selcen et al., 2001 Gommans et al., 2003 . All of these...