David Dick

Titin mutation segregates with hereditary myopathy with early respiratory failure

In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Progressive external ophthalmoplegia (PEO) is a canonical feature of mitochondrial disease, but in many patients its genetic basis is unknown. Using exome sequencing, Pfeffer et al. identify mutations in SPG7 as an important cause of PEO associated with spasticity and ataxia, and uncover evidence of disordered mtDNA maintenance in patients.

Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy.

Mitochondrial abnormalities in oculopharyngeal muscular dystrophy.

This report describes a 56-yr-old man with a dominantly inherited disorder affecting four generations and characterized by bilateral ptosis and dysphagia. Muscle biopsy showed only minor light microscopic abnormalities but electron microscopy revealed fibres containing paracrystalline mitochondrial inclusions. Southern analysis of mitochondrial DNA obtained from muscle did not reveal mitochondrial gene deletions. An extensive search eventually identified the characteristic intranuclear filaments of oculopharyngeal muscular dystrophy (OPMD). Abnormal mitochondria are non-specific epiphenomena in OPMD but a potential source of confusion with a late-onset mitochondrial cytopathy. This case further emphasizes the necessity for a diligent search for the diagnostic intranuclear filaments when oculopharyngeal muscular dystrophy is suspected clinically.

AMACR mutations cause late-onset autosomal recessive cerebellar ataxia

Progressive cerebellar disorders presenting in late middle age often have a structural, toxic, inflammatory, or endocrine basis. Having excluded these causes, many patients are given a clinical diagnosis of multiple systems atrophy type C, or idiopathic late-onset cerebellar ataxia, and not investigated further. Here we describe a sporadic cerebellar syndrome leading to the diagnosis of a rare metabolic disorder with important implications for treatment. ### Case report. A 58-year-old man presented with an 8-year history of gait unsteadiness, slurred speech, a few tonic/clonic seizures, and a decline in short-term memory. There was no relevant family history or consanguinity. On examination, he had a cerebellar dysarthria with appendicular and gait ataxia. Deep tendon reflexes were preserved, and plantar responses flexor. His Mini-Mental State Examination test score was 19/23 at 51 years of age, and 21/30 at age 58, with an Addenbrooke cognitive assessment of 61/100. Routine hematology, thyroid function, vitamin E, B12, and copper studies were normal. CSF examination revealed normal protein content, cell count, and no oligoclonal bands. Urinary amino and organic acids, hexosaminidase, and acylcarnitines were normal. Echocardiography was normal. An EEG showed a mild generalized …

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with sudden sensorineural hearing loss

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an autosomal dominant angiopathy characterized by recurrent cerebrovascular events, migraine and dementia. We describe a case of sensorineural hearing loss as the presenting feature of this condition. We have found no previous reports in the world literature of CADASIL presenting with a sudden sensorineural hearing loss. The significance of questioning a patient with regard to family history is exemplified in this case.

Management of sialorrhoea in motor neuron disease: a survey of current UK practice

Abstract Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians’ attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety-three patients were described. Forty-two percent of patients reviewed in clinicians’ last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians’ preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance.

A multicentre evaluation of oropharyngeal secretion management practices in amyotrophic lateral sclerosis

Abstract Failure to clear oral secretions can be debilitating for patients with amyotrophic lateral sclerosis (ALS), but the treatment of this symptom is poorly defined and there is no consensus on best practice. The objective of this study was to identify the treatments that are commonly prescribed, and to describe how experienced clinicians manage a patient with treatment resistant symptoms. Twenty-three clinicians were approached, of which 19 from 16 centres across the UK provided case report forms for a total of 119 ALS patients identified as having problematic oral secretions. The use of five anticholinergics, salivary gland botulinum toxin injections, conservative management approaches and carbocisteine were reported. Of the 72 patients who were evaluated following the initiation of a first anticholinergic, 61% had symptomatic improvement. Only 19% of patients achieved symptomatic improvement with the use of an alternative anticholinergic when an initial anticholinergic achieved no symptomatic improvement. Problems with thick and thin secretions often coexisted, with 37% of patients receiving treatment for both types of problem. In conclusion, a variety of treatment options are employed by expert clinicians for problematic oral secretions in ALS patients. The variation in management highlights the need for further prospective research in this area.

Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.

Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS‐specific measures of spasticity. The aim of this study was to develop and use a self‐report outcome measure for spasticity in ALS.

EXOME SEQUENCING IN THREE FAMILIES WITH CYTOPLASMIC BODY MYOPATHY WITH EARLY RESPIRATORY FAILURE

Introduction Cytoplasmic body myopathy with early respiratory failure (CBM) is a rare muscular dystrophy with the clinical presentation of early respiratory failure with distal and/or proximal muscle weakness. The genetic defect has been identified in two families, having the R279W mutation in the sarcomeric protein TTN, although cases without this mutation have already been reported. Methods Three pedigrees with CBM were included in this study. Clinical characteristics and diagnostic investigations were summarised. Western blot of C-terminal TTN protein was performed. Genome-wide 1000 microsatellite analysis was performed in one of the families to identify a linkage region and shared haplotype. Exome sequencing was performed on three patients. Results Onset was usually in middle-age, and tibialis anterior muscle was earliest and most severely affected. Pulmonary function tests indicated low FEV1 and FVC, worsening when supine. EMG demonstrated necrotising myopathic process. MRI invariably revealed signal abnormalities of semitendinosus muscle. Blot of C-terminal TTN protein was normal. A 20 cM linkage region on chromosome 2 was identified. Exome sequencing detected the disease mutation and identified other candidates excluded with segregation analysis. Conclusions We report the disease gene, and describe in detail the phenotype and diagnostic investigations from these three pedigrees. Genetic testing for these CBM genes should be performed in patients with myopathy and early respiratory failure if muscle pathology reveals cytoplasmic bodies or is nonspecific.