Mark R. Davis

Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores

Abstract—Central core disease (CCD) is a congenital myopathy due to dominant mutations in the skeletal muscle ryanodine receptor gene (RYR1). The authors report three patients from two consanguineous families with symptoms of a congenital myopathy, cores on muscle biopsy, and confirmed linkage to the RYR1 locus. Molecular genetic studies in one family identified a V4849I homozygous missense mutation in the RYR1 gene. This report suggests a congenital myopathy associated with recessive RYR1 mutations.

A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy

Background Central core disease (CCD) and nemaline rod myopathy are generally considered two genetically and histologically distinct disorders. CCD is defined by the presence of well-demarcated round cores within most myofibers. Nemaline rod myopathy is distinguished by the presence of characteristic nemaline bodies within myofibers. The simultaneous occurrence of both cores and rods in the same muscle biopsy has been described, but no gene mutations have been reported yet for this condition. Objective To describe a family containing 16 affected individuals in six generations with an autosomal dominant congenital myopathy that shows clinical and histologic features of both CCD and nemaline myopathy, and to determine the genetic etiology and protein composition of the cores/rods in this family. Methods and Results The results of linkage analyses excluded involvement of the two autosomal dominant nemaline myopathy loci on chromosome 1, but were consistent with a localization of the disease gene at the CCD locus on chromosome 19q13.1 (ryanodine receptor). SSCP analysis and DNA sequencing identified a novel Thr4637Ala mutation in the transmembrane region of the ryanodine receptor protein. Immunofluorescence studies of patient muscle biopsies showed the central cores to stain for ryanodine receptor. Conclusions These data suggest that the occurrence of nemaline bodies can be a secondary feature of CCD, and that genetic studies on previously reported core/rod families should be targeted to the ryanodine receptor locus. The results of the immunofluorescence studies suggest that the cores contain excess abnormal ryanodine receptor protein.

Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.

Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mutations in the X‐linked MECP2 gene. However, there is a high degree of variability in the clinical phenotypes produced by mutations in MECP2, even amongst classical RTT patients. In a large‐scale screening project, this variability has been examined by looking at the effects of mutation type, functional domain affected and X‐inactivation. Mutations have been identified in 60% of RTT patients in this study (25% of whom were atypical), including 23 novel mutations and polymorphisms. More mutations were found in classical patients (63%) compared to atypical patients (44%). All of the pathogenic mutations were de novo in patients for whom parent DNA was available for screening. A composite phenotype score was developed, based on the recommendations for reporting clinical features in RTT of an international collaborative group. This score proved useful for summarising phenotypic severity, but did not correlate with mutation type, domain affected or X‐inactivation, probably due to complex interactions between all three. Other correlations suggested that truncating mutations and mutations affecting the methyl‐CpG‐binding domain tend to lead to a more severe phenotype. Skewed X‐inactivation was found in a large proportion (43%) of our patients, particularly in those with truncating mutations and mutations affecting the MBD. It is therefore likely that X‐inactivation does modulate the phenotype in RTT.

Refining the phenotype of common mutations in Rett syndrome

Rett syndrome (RTT; MIM No 312750) is a neurodevelopmental disorder mainly affecting girls, with an incidence of 1:10 000 female births.1 The clinical features of the syndrome were first described in a series of publications2–5 during the decade after it was first reported in English language journals.6 At that time, in the absence of a biological marker, criteria to assist with the diagnosis were developed by an international working group.7 These criteria relate to the typical characteristics which are: normal prenatal and perinatal period and apparently normal development for the first six months of life; deceleration in head growth; loss of hand and communication skills between six and 30 months; apparent severe psychomotor retardation; acquisition of stereotypical hand movements; and evidence of gait or truncal apraxia between one and four years. These necessary criteria were supplemented by a set of supportive but not mandatory criteria, which help to delineate the phenotype further. These include breathing dysfunction, EEG abnormalities, seizures, spasticity, peripheral vasomotor disturbance, scoliosis, growth retardation, and hypotrophic small feet. In 1999 the association between Rett syndrome and mutations in the methyl-CpG binding protein 2 (MECP2; MIM No 300005) located on Xq28 was first identified.8 In the last decade there had already been much commentary about the expanding clinical spectrum of Rett syndrome and the occurrence of atypical forms.9 This culminated in 2001 in a meeting to revise the existing diagnostic criteria.10 It is now clear that, although this condition must be considered a severe neurodevelopmental disorder, there is still considerable variation in both functioning and associated morbidity, even in those cases with confirmed MECP2 mutations. We have been able to demonstrate this variability11 using a tool to measure functional ability12 and three clinical scales. The first was developed by …

Early progressive encephalopathy in boys and MECP2 mutations

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?

Rett syndrome is an X linked dominant neurodevelopmental disorder with an incidence of 1:10 000 females in Australia.1 It is characterised by apparently normal development between 6 and 18 months, followed by a period of regression with loss of purposeful hand use, deceleration of head growth, and onset of repetitive, stereotypic hand movements.2 Affected people also manifest gait ataxia and apraxia, autistic features, epileptic seizures, respiratory dysfunction, autonomic dysfunction, and decreased somatic growth.2,3 In recent years it has become apparent that the phenotypic range of this disorder is much wider than previously thought. Some patients may have a milder phenotype and retain the ability to walk or speak and others have an earlier onset and more severe features. People who have some but not all of the necessary criteria have been categorised as atypical4 or as one of six variant forms.5 Rett syndrome has now been shown to be associated with mutations in the methyl-CpG-binding protein 2 (MeCP2).6 For many genetic disorders, the next stage in research after the identification of the gene involves describing the relation between genotype and phenotype, and the phenotypic diversity produced by different mutations in the same gene. Some research has found that people with missense MECP2 mutations may have a milder phenotype than those with truncating mutations.7,8 Weaving et al 9 found that age at onset of hand stereotypies was later and speech and height (but not head growth) were slightly more normal in those with missense mutations whereas Nielsen et al 10 found no difference in severity between these mutation types. In the study of Amir et al 11 breathing abnormalities were found to be more common with truncating mutations and scoliosis more common with missense mutations. Hoffbuhr et al 12 concluded that patients …

Central core disease : clinical, pathological, and genetic features

Central core disease (CCD) is a dominantly inherited congenital myopathy allelic to malignant hyperthermia (MH) caused by mutations in the RYR1 gene on chromosome 19q13.1. Eleven individuals with RYR1 mutations are described. Four index cases showed features consistent with a congenital myopathy (hypotonia, delayed motor milestones, and skeletal abnormalities including congenital hip dislocation and scoliosis). All four cases and subsequently seven other family members were found to possess novel mutations in the RYR1 gene. The degree of disability varied from one clinically normal individual, to another who had never achieved independent ambulation (the only patient with a de novo mutation). Four cases showed a mild reduction in vital capacity, repeated nocturnal polysomnography showed hypoxaemia in one case. A variety of muscle biopsy features were found; central cores were absent in the youngest case, and the biopsy specimens from two others were more suggestive of mini-core myopathy. In all cases missense mutations in exons 101, 102, and 103 of the RYR1 gene on were found. Future laboratory diagnosis of suspected cases and family members will be less invasive and more accurate with DNA analysis. Clinicians, especially paediatricians and orthopaedic surgeons, should be aware of this disorder because of the potential risk of MH.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy

See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Dominant gain-of-function mutations in SCN4A , which encodes the α-subunit of the voltage-gated sodium channel, are a common cause of myotonia and periodic paralysis. Zaharieva et al. now report recessive loss-of-function SCN4A mutations in 11 patents with congenital myopathy. The mutations cause fully non-functional channels or result in reduced channel activity.

A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies

MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated.

Expanding the phenotype of GMPPB mutations

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis.