Myotonic dystrophy type 1 - a multiorgan disorder. / Dystrofia myotonika type 1 ­ en multiorgansykdom.

Myotonic dystrophy type 1 is an autosomal dominant, inherited multiorgan disorder that can affect people of all ages. It is the most prevalent inherited muscular disease in adults. Late diagnosis points to limited knowledge among the medical community that symptoms other than typical muscular symptoms can dominate. The condition often worsens with each generation and some families are severely affected. Significantly delayed diagnosis means a risk of more serious development of the disorder and inadequate symptomatic treatment. We hope that this clinical review article may lead to more rapid diagnosis and better follow-up of this patient group.

A hospital based epidemiological study of genetically determined muscle disease in south western Norway.

We determined the prevalence of genetically determined neuromuscular diseases in adult Norwegian patients from Hordaland County. We identified patients using International Classification of Disease codes registered in our hospital database and reviewed patient notes to ensure diagnostic accuracy. To ensure maximal ascertainment, we screened both inpatient and outpatient contacts from two 5-year periods 01.01.2005 to 31.12.2009 and 01.01.2008 to 01.01.2013, and used the second data set to define prevalence. Myotonic dystrophy was the commonest adult muscle disorder with a minimum prevalence of 11.84/100,000 followed by facioscapulohumeral muscular dystrophy at 6.42/100,000. Genetically confirmed limb-girdle muscular dystrophies had a prevalence of 4.2/100,000 with CAPN3 mutations being the commonest followed by mutations in ANO5 and FKRP. Becker muscular dystrophy was rare (0.4/100,000). For the purposes of comparison, we also ascertained adults with spinal muscular atrophy (SMA) and found a prevalence of 4.42/100,000. The impact of neuromuscular disease is enormous both for the patient and for society. Progressive weakness and increasing dependency together with pulmonary and cardiac complications require specialised, multidisciplinary follow up. The provision of such care places substantial demands on health service resources. Thus, precise understanding of both type of neuromuscular disease and numbers of patients is essential in order to manage individuals appropriately and plan future health service needs.

A man in his seventies with spinal cord injury, fever and delirium. / En mann i 70-årene med ryggmargsskade, feber og delirium.

INTRODUCTION: Spinal cord injury includes damage to the motor, sensory and autonomic nervous system. CASE PRESENTATION: A man in his seventies was admitted to hospital after an acute traumatic incomplete cervical spinal cord injury. Over the following weeks, he experienced multiple febrile episodes with CRP elevated to 100 ­ >300 mg/L, but few other symptoms. Two weeks after admission, he was febrile with neuropathic pain, and oxygen saturation spontaneously decreased from 98 % to 87 %. Chest X-ray showed pneumonia, which was treated with antibiotics. Four weeks after the injury he again experienced fever and increased spasticity. Clinical examination revealed dull abdominal pain on palpation in the left upper quadrant. The same day, a PEG placement procedure had been performed. CT abdomen, chest X-ray and microbiological investigation revealed no clear infectious origin. The patient was treated with antibiotic coverage for presumed abdominal infection, with successful recovery. Two months after his injury, the patient became febrile and delirious. Clinical examination revealed mild pain on palpation in the upper right quadrant. CT abdomen revealed cholecystitis. DISCUSSION: Diagnosis of acute serious illness in a patient with spinal cord injury may be challenging due to scarce and atypical clinical presentation. Prevalence of gallstones is increased after spinal cord injury.

Mitochondrial DNA depletion in sporadic inclusion body myositis.

Sporadic inclusion body myositis (sIBM) is a late onset disorder of unkown aetiology. Mitochondrial changes such as cytochrome oxidase deficient fibres are a well recognised feature and mitochondrial DNA (mtDNA) deletions have also been reported, but not consistently. Since mtDNA deletions are not present in all cases, we investigated whether other types of mtDNA abnormality were responsible for the mitochondrial changes. We studied 9 patients with sIBM. To control for fibre loss or replacement with inflammatory cells, we compared sIBM patients with necrotising myopathy (n = 4) as well as with healthy controls. Qualitative anlysis for mtDNA deletions and quantitative measurement of mtDNA copy number showed that muscle from patients with sIBM contained on average 67% less mtDNA than healthy controls (P = 0.001). The level of mtDNA was also significantly depleted in sIBM when compared to necrotising myopathy. No significant difference in copy number was seen in patients with necrotising myopathy compared to controls. Deletions of mtDNA were present in 4 patients with sIBM, but not all. Our findings suggest that mtDNA depletion is a more consistent finding in sIBM, and one that may be implicated in the pathogenesis of the disease.

MT-ND5 mutation causing exercise intolerance displays intercellular heteroplasmy and rapid shifts between generations.

We studied the inheritance and cellular segregation of a maternally inherited, heteroplasmic MT-ND5 mutation, m.13271T>C, previously shown to cause only exercise intolerance despite being present in multiple tissues. The mutation was present at low levels in early passage, bulk muscle culture, but on subcloning, only homoplasmic clones were found. Studies of transmission showed that the mutation expanded from very low levels in the patient's mother to higher levels in the patient, particularly skeletal muscle, but was not found in the placenta and umbilical cord blood of her child. Our study suggests that the m.13271T>C is either already strictly segregated (intercellular heteroplasmy), or moves rapidly to this state in cultured cells. Transmission studies suggest that intercellular heteroplasmy may also be present in the patient's germline. Although rapid shifts in heteroplasmic mitochondrial DNA mutations reflect a bottleneck in the female germline, complete segregation will accentuate the effects of this and further complicate genetic counseling.

Antisense oligonucleotide corrects splice abnormality in hereditary myopathy with lactic acidosis.

Hereditary myopathy with lactic acidosis (HML) (OMIM #255125) presents in childhood with exercise intolerance and muscle pain on trivial exercise, lactic acidosis, dyspnoea, palpitations, and rhabdomyolysis which can be fatal. The disease is recessively inherited and caused by a deep intronic, single base transition in the iron-sulfur cluster scaffold, ISCU gene that causes retention of a pseudoexon and introduction of a premature termination codon. IscU protein deficiency causes secondary defects in several iron-sulfur dependant proteins, including enzymes involved in aerobic energy metabolism. We have shown in a previous study that the splice abnormality affects skeletal muscle more than other tissues, leading to the purely muscular phenotype. Antisense oligonucleotides (AOs) have been able to redirect mRNA splicing in a number of disease models, and show promise in clinical studies. We designed 2'O-methyl phosphorothioate AOs targeting either splice site of the detrimental HML pseudoexon. The acceptor site AO effectively redirected splicing towards the normal state in cultured muscle fibroblasts, whilst the donor site AO promoted pseudoexon inclusion in both patient and control cells. Our results show that AO therapy seems feasible in HML, but care must be taken to avoid adverse splicing effects.

[A man with progressive spastic paraparesis]. / En mann med progredierende spastisk paraparese.

BACKGROUND: Adrenomyeloneuropathy is an X-linked disease caused by defects in the ABCD1 gene, which encodes the ALD protein (a peroxisome membrane transport protein). Deficiency of the ALD protein impairs the breakdown of very long chain fatty acids (VLCFA) that subsequently accumulate. The disease can present with spastic paraplegia, adrenocortical failure, or a combination of both. Spastic paraplegia can be inherited as well as acquired and is seen relatively often in neurological practice. Precise diagnosis is important as it provides information on prognosis and treatment, and allows at-risk family members to be identified. MATERIAL AND METHODS: The case history of a man with adrenomyeloneuropathy is presented, and relevant literature concerning pathogenesis, clinical presentation and treatment of the disease was retrieved from Medline and reviewed. DISCUSSION: Adrenomyeloneuropathy is often accompanied by mild peripheral neuropathy or adrenal failure and usually presents in young men with spastic paraplegia. Female carriers may also manifest clinical symptoms. Screening for VLCFA is widely available and performed in blood samples. Specific diagnosis requires measurement of the VLCFAs; C26, C24 and C22, confirmation of absent ALD protein or the finding of a specific gene mutation. In addition to hormone replacement for adrenal failure, treatment is limited to standard spasmolytic agents and physical therapy. More specific treatments are currently being tested.

[A 90-year-old woman with acute hemiparesis]. / En 90 år gammel kvinne med akutt hemiparese.

A right-handed woman of 90, taking aspirin 160 mg daily, suffered acute neck pain radiating to the shoulders, with right side hemiparesis and numbness occurring minutes thereafter. On admission 2.5 hrs later, examination showed paresis and hyporeflexia of the right limbs accompanied by neck stiffness and vertebral tenderness in level C7. Acute stroke was the initial working diagnosis. Cerebral CT was normal. Symptoms progressed with left arm numbness and left ancle clonus, and eight hours after symptom onset there was bilateral plantar inversion, reduced skin prick sensibility below C4, bladder paresis and anal sphincter hypotonia. CT myelography revealed an intraspinal mass extending from C2 to C6. 14 hours after symptom onset, a spinal epidural haematoma was removed by spinal laminectomy. Recovery and functional outcome was good. Symptoms, work-up and treatment are discussed with reference to previous publications.