Abstract Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked end-plate potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.
A 16-year-old girl presented because her mother had noticed her speech had changed over the preceding 3 months. She had also been clumsy since the age of 10 years. Her family history was unremarkable. On examination, there was dysarthria with a full range of eye movements but the saccades were broken up. Tone and power were normal but there were occasional choreiform movements. She was areflexic with flexor plantar responses. She had symmetrical limb ataxia and a broad based gait. Sensory testing was normal. There were no telangiectasias.
What is your differential diagnosis and which investigations would you recommend at the first consultation?
### Comment
The clinical picture is predominantly of cerebellar ataxia with mild chorea and possible sensory involvement (areflexia in the presence of normal tone and power). The main differential can be broken down into genetic and acquired causes. A symmetrical ataxia progressing over several years is not typical of acquired causes but nonetheless the initial emphasis should be on diagnosing a reversible condition; the commoner acquired causes which may present with an isolated ataxia are listed in table 1.
View this table:
Table 1
Commoner causes of acquired cerebellar ataxia
Initial blood tests were normal: full blood count, urea and electrolytes, bone profile, liver function, angiotensin converting enzyme, lupus anticoagulant, α-fetoprotein, vitamins A and E, antitissue transglutaminase and anti-Purkinje cell antibodies, and white cell lysosomal enzymes. Antinuclear antibodies were present at 1:100 but anti-dsDNA and extractable nuclear antigens were normal. MR brain, chest x-ray and ECG were all normal. Further investigations included a normal CSF (glucose, protein and cytology, no oligoclonal bands) but nerve conduction studies revealed absent sensory action potentials with normal motor action potentials and motor conduction velocities.
What differentiates an acquired from an inherited ataxia?
### Comment
The young age of onset and the suggestion that the problem has been progressing slowly …
Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by venous malformations predominantly affecting the skin and gastrointestinal tract, commonly the small bowel. Small bowel gastrointestinal bleeding is often the presenting complaint and is difficult to diagnose and treat. Push enteroscopy, capsule endoscopy, and intraoperative enteroscopy are techniques described for the localization and management of small bowel bleeding. We present the case of a 68-year-old male with BRBNS who presented with symptomatic anemia and melena. Initial endoscopic evaluations identified intraluminal vascular blebs, which were injected; however, bleeding continued, prompting intraoperative enteroscopy. During the procedure, multiple small bowel vascular malformations consistent with BRBNS were identified. Cyanoacrylate glue was used endoscopically to treat active bleeding sites. The patient developed a rare postoperative complication of small bowel ischemia and obstruction secondary to cyanoacrylate glue, necessitating surgical resection. Small bowel bleeding in BRBNS poses diagnostic and therapeutic challenges. Intraoperative enteroscopy together with cyanoacrylate glue offers a valuable approach to localization and intervention. While cyanoacrylate glue is generally considered safe, rare complications, including ischemic events, have been reported. This case highlights the utility of intraoperative enteroscopy and endoscopic cyanoacrylate glue in managing small bowel bleeding associated with BRBNS. While effective, clinicians must be vigilant regarding potential complications, including ischemic events, associated with endoscopic hemostatic agents.
Diabetic lumbosacral radiculoplexus neuropathy is a monophasic syndrome of diffuse pain and weakness that typically affects the lower limbs asymmetrically and is often associated with significant weight loss. Recovery can be prolonged and unpredictable. It is a clinical diagnosis and investigations are performed mainly to exclude other causes. Although it is most likely caused by a microvasculitis, there is no evidence to support using intravenous immunoglobulin or any long-term immunosuppression. Pulsed methylprednisolone may help pain if given within 2-3 months of symptom onset.
There seems little doubt that this unfortunate young person has unusually severe diabetic gastroparesis, a condition thought to be due to vagal denervation of the stomach. It is important, however, to identify and correct factors that may be aggravating the gastroparesis to cause such a difficult problem that required admission to hospital for one whole year.
Swings in blood sugar concentrations, in particular hyperglycaemia, and fluctuation in serum potassium concentrations, may slow gastric emptying. Also dietary fat is known to impair gastric motility. Certain drugs may worsen the situation. With severe gastric …
Background: Antibodies against glutamic acid decarboxylase (GAD) are associated with Stiff Person Syndrome (SPS). Case report: A 50-year-old woman presented with symptoms progressed over 9 years, resulting in a cerebellar ataxia and right upper limb tremor. Investigations revealed elevated serum and CSF anti-GAD antibody titres (98.6 and 53.4 μ/ml, respectively). Treatment included intravenous immunoglobulin and immunomodulation (infliximab and rituximab), improving her stiffness, but with no impact on the ataxia-related symptoms. Subsequent high-dose steroids led to diabetic ketoacidosis and unmasking of an insulin-dependent diabetes mellitus. Discussion: This case illustrates several key features: (1) the combined clinical picture of SPS and cerebellar ataxia is a rare phenotype associated with anti-GAD antibodies; (2) the cerebellar ataxia described was progressive and poorly responsive to immunomodulatory therapy; and (3) the potential for development of further autoimmune sequelae in response to immunosuppression, namely, the development of insulin-dependent diabetes in response to treatment with high-dose oral steroids.
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