Adela Della Marina

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment.

Juvenile myasthenia gravis (JMG) is an autoimmune disorder of neuromuscular transmission caused by production of antibodies against components of the postsynaptic membrane of the neuromuscular junction. Ethnicity has influence on incidence, clinical presentation, and the course of the disease. The patients present with a wide range of symptoms-from isolated intermittent ocular symptoms to general muscle weakness with or without respiratory insufficiency. Compared with adults and adolescents, the clinical signs and course of disease in children exhibit differences and occasionally untypical symptoms. Therefore, JMG is often missed and the diagnosis delayed. Isolated ocular symptoms are frequent at onset, spontaneous remission or intermittent symptoms over the longer period of time can occur. Very young children may present with generalized muscle weakness already during the second year of life and in this patient group, specific antibodies can only be slightly increased or even negative. Existing therapeutic options include immunosuppressive therapy and thymectomy but potential long-term side effects on the growing organism and possible influence on immune response in very young children should be considered. Specific clinical symptoms, diagnostic procedures, and a therapeutic approach with consideration of this age groups specificities are discussed.

Congenital Myasthenic Syndromes: Current Diagnostic and Therapeutic Approaches

Congenital myasthenic syndromes (CMS) are rare genetically and clinically heterogeneous disorders characterized by an impaired neuromuscular transmission. Exact prevalence data are not available, approximately 2000 to 3000 patients worldwide have been diagnosed on a molecular level; mutations in 14 different genes are known to date leading to causal defects in presynaptic nerve terminal, synaptic cleft, and postsynaptic apparatus. At last, all known mutations are estimated to cause approximately 50% of all clinically diagnosed CMS. However, phenotypes may vary widely and symptoms can be unspecific, therefore CMS are often missed and their prevalence may be underestimated. But, the exact diagnosis is extremely important to start early appropriate therapy to prevent life-threatening events and to improve the clinical course. Most patients are eligible for drug therapy with esterase inhibitors, 3, 4-diaminopyridine, ephedrine, fluoxetine or quinidine, but the effect of these drugs differs depending on the underlying genetic defect. Moreover, very little is known about the best treatment and care in these patients over a longer period of time.This article provides an overview of specific clinical symptoms, diagnostic work-up, and care including possible pharmacotherapy in case of CMS.

Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

Background Autosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking. Methods In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6–21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 –MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined. Results Hyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946–0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found. Conclusion Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia.

Outcome after Robotic-Assisted Thymectomy in Children and Adolescents with Acetylcholine Receptor Antibody-Positive Juvenile Myasthenia Gravis

Abstract The aim of our study was to describe the long‐term outcomes after robotic‐assisted thymectomy in a cohort of acetylcholine receptor (AChR)‐antibody (Ab)‐positive, generalized juvenile myasthenia gravis (JMG). We retrospectively analyzed a cohort of 18 patients (15 females and 3 males) who underwent robotic‐assisted thymectomy. At the time of diagnosis, 12/18 patients were prepubertal; the mean age was 9.8 years at the onset of the disease. All patients received therapy with pyridostigmine; additional immunotherapy included: corticosteroid therapy in 18/18, azathioprine in 14/18 patients, mycophenolate mofetil in 4/18, and cyclosporine in 1/18 patients. Eight patients received intravenous immunoglobulin and four plasma exchange. The mean age of patients at thymectomy was 11.7 years (range: 4.2‐16 years). The mean duration of postoperative stay was 2.9 days. Thymectomy was followed by gradual clinical improvement (39% patients achieved clinical remission) and dose reduction in steroid therapy in all patients during the follow‐up period (mean: 27.4 months). In children and adolescents with AChR‐Ab‐positive JMG, thymectomy has a beneficial effect on the weaning off immunosuppressive therapy in patients with generalized symptoms and should be considered as a part of multimodal therapy. Robotic‐assisted thymectomy is a safe procedure with low morbidity and a comparable clinical outcome compared with the open sternal procedure.

Vorteil durch frühen Therapiebeginn bei proximaler spinaler Muskelatrophie

ZusammenfassungNeue Therapieansätze haben den Übergang vom theoretischen Konzept zu randomisierten, kontrollierten Studien und nun erstmals zu einer medikamentösen Behandlung der proximalen spinalen Muskelatrophie (SMA) bei Patienten vollzogen. Maßgebend für den Therapieerfolg sind der frühzeitige Einsatz der medikamentösen Behandlung und damit die Entdeckung der Erkrankung in einem frühen Stadium, sodass die Einführung eines flächendeckenden Neugeborenenscreenings für die SMA notwendig erscheint.

Correction: Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

[This corrects the article DOI: 10.1371/journal.pone.0173144.].

Reversible Infantile Respiratory Chain Deficiency

Abstract Here we provide detailed clinical and laboratory investigations of a case with a rare inherited mitochondrial disease, reversible infantile respiratory chain deficiency myopathy. The clinical symptoms were variable in affected siblings, and the differential diagnosis was changing through the clinical course of the disease. The recognition of cases with reversible mitochondrial disease is sometimes challenging, but it is of utmost importance because of the excellent prognosis of this disease. Understanding the recovery may provide further insights to major disease mechanisms and modifiers in mitochondrial disease.