Holmes-Adie syndrome associated with high altitude pulmonary edema and low chemo-responsiveness to hypoxia.

A 63-year-old patient with Holmes-Adie syndrome presented an altered peripheral chemoreflex and suffered from high altitude pulmonary edema, suggesting an alteration of sensitive afferent fibers from the peripheral chemoreceptors. Chemo-responsiveness to hypoxia should be explored before any exposure to moderate altitude in Holmes-Adie patients.

Flexion contractures possibly reflect the existence of hypocortisolism: two case reports.

The diagnosis of adrenal insufficiency is discussed in case of low blood pressure and digestive symptoms. Rare inaugural abdomino-crural muscle contracture can be a misleading symptom. Here we report two new cases. A 50-year-old woman presenting a leaning forward walking attitude and negligence for the past 2 months was referred to the neurologic unit. Abdomino-crural contracture, clinical hypogonadism, and hyponatremia directed towards a panhypopituitarism, which was confirmed by subsequent investigations. Pituitary MRI found an empty sella turcica. The outcome was dramatic after hormone replacement therapy, with drawing up of the trunk and re-establishment of walking after a few days. The second case is a 58-year-old man, hospitalized with altered general condition, with a weight loss of 22 kg, and anorexia in the aftermath of a comminuted fracture of the right lower limb, complicated by pseudoarthrosis. There was amyotrophy on the extremities with intense cruralgia. The patient had an antalgic attitude in the flexion affecting his rehabilitation. During 1 year, the symptoms were mimicking psychiatric disorders, malabsorption, or cancer before the final diagnosis of central hypocorticism with normal MRI was established. The evolution was remarkable after a few days of therapy with hydrocortisone, where the myalgia disappeared, the patient quickly gained weight, and the disappearance of the retractions allowed rehabilitation. These two observations emphasize the delayed diagnosis of adrenal insufficiency in the case of abdomino-crural-related symptoms and the presence of misleading neurological symptoms. The mechanisms of this syndrome remain unknown.

Severe dilated cardiomyopathy and quadriceps myopathy due to lamin A/C gene mutation: a phenotypic study.

UNLABELLED: This study reports a family affected by a new phenotype associated with dilated cardiomyopathy and quadriceps myopathy. METHODS: 29 family members underwent a physical and neurological examination, including an electromyogram and biopsy of muscle abnormalities. A cardiac examination was performed in all subjects. RESULTS: The family pedigree (n=72) demonstrated that transmission was autosomal dominant. Eleven subjects had cardiac involvement, only four had quadriceps muscle involvement. Cardiac impairment preceded neurological involvement. The mean age for neurological involvement was 44+/-0.8 years (range 43-45) and cardiac involvement was 37+/-7.9 years (range: 24-45). Cardiac involvement consisted of: hypokinetic dilated cardiomyopathy (64%); atrial fibrillation (100%); ventricular arrhythmias (64%); impaired conduction with bundle branch or complete atrio ventricular block (73%). Four patients required pacemakers and anti arrhythmic therapies. Four patients died: two of refractory heart failure and two of sudden death; two patients were resuscitated following cardiac arrest. Three patients required a prophylactic implantable cardiac defibrillator (ICD). Muscle morphological abnormalities were characterized by a variable number of fibers with rimmed vacuoles. The quadriceps deteriorated progressively without impairment of other muscles. Genotypic study showed a lamin A/C gene mutation. CONCLUSIONS: This family was affected by a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or arrhythmias and quadriceps myopathy. Cardiac abnormalities preceded neuromuscular disorders and defined the prognosis of this disease.

Neurofibromatosis 1-associated neuropathies: a reappraisal.

Neurofibromatosis 1 (NF1) is a common disease which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. The neurofibroma is the hallmark lesion of NF1 and develops from peripheral nerves. However, to date, the description of peripheral neuropathies of NF1 has not been investigated. To examine this question, we have evaluated 688 NF1 patients for the presentation, prognosis and associated morbidity of peripheral neuropathies in two hospital-based series. We collected 18 patients (four women and 14 men) with diffuse peripheral neuropathy (2.3%). Eight patients had a paucisymptomatic or an asymptomatic neuropathy detected only on electrophysiological study, two had minor sensory manifestations, five had moderate motor and sensory manifestations and three had severe motor and sensory manifestations. Superimposed radicular changes were observed in seven cases. Two patients had a subacute and 16 a chronic polyneuropathy. Fourteen patients had a demyelinating neuropathy with either severe axonal changes (three), moderate or minor axonal changes (four) or no axonal changes (seven). Four patients had axonal neuropathies. There was a strong association between the presence of a peripheral neuropathy and large root diffuse neurofibromas (P < 0.03) and subcutaneous neurofibromas (P < 0.0001). Severe morbidity and mortality of patients with NF1 and peripheral neuropathies was 50%, much higher than what is observed in the general population of patients with NF1, and 100% in patients with the most severe symptoms and electrophysiological changes (demyelination with severe axonal features). Four patients out of 18 (22%) developed a malignant peripheral nerve sheath tumour (MPNST), a much higher proportion than in the whole population of NF1. Two patients died. Peripheral neuropathy constitutes a potentially severe complication in patients with NF1 associated with a frequent morbidity related to spinal complications and MPNSTs. Association of proximal large neurofibromas, peripheral neuropathies and subcutaneous neurofibromas may constitute a phenotype of NF1 with a severe prognosis.

Functional consequences of an LMNA mutation associated with a new cardiac and non-cardiac phenotype.

Heritable dilated cardiomyopathy is a genetically highly heterogeneous disease. To date 17 different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy with or without additional clinical manifestations. Among the 10 mutated genes associated with dilated cardiomyopathy, the lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy. For the first time, we report here a French family affected with a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias, and a specific quadriceps muscle myopathy. In all previously reported cases with both cardiac and neuromuscular involvement, neuromuscular disorders preceded cardiac abnormalities. The screening of the coding sequence of the LMNA gene on all family members was performed and we identified a missense mutation (R377H) in the lamin A/C gene that cosegregated with the disease in the family. Cell transfection experiments showed that the R377H mutation leads to mislocalization of both lamin and emerin. These results were obtained in both muscular (C2C12) and non-muscular cells (COS-7). This new phenotype points out the wide spectrum of neuromuscular and cardiac manifestations associated with lamin A/C mutations, with the functional consequence of this mutation seemingly associated with a disorganization of the lamina.