Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan.

BACKGROUND: Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group. We hypothesized that there would be age-related differences in the clinical characteristics. METHODS: A retrospective analysis of MH data collected in our database during 1960 to 2020 was performed to identify pediatric subjects (≤18 years) with a Clinical Grading Scale of ≥35, indicating "very likely" or "almost certain" MH. We compared clinical characteristics among the 0 to 24 month, 2 to 12 year, and 13 to 18 year (youngest, middle, and oldest, respectively) age groups. RESULTS: Data were available for 187 patients: 15 in the youngest age group, 123 in the middle-aged group, and 49 in the oldest age group. Of these, 55 patients (29.4%) had undergone muscle biopsy and muscle contracture test. The mortality rates during the study period were 13.3%, 13.8%, 20.4%, and 15.5% in the youngest, middle, and oldest cohorts and overall, respectively. In contrast, the overall mortality rate from 2000 to 2020 was 8.8%. The most frequent initial symptoms of MH were elevated temperature (46.7%) and generalized muscular rigidity (26.7%) in the youngest cohort, masseter spasm (35.0%) and generalized muscular rigidity (19.5%) in the middle cohort, and elevated end-tidal carbon dioxide (26.5%) and tachycardia (22.4%) in the oldest cohort. Physical examination revealed that elevated temperature, sinus tachycardia, and respiratory acidosis occurred frequently in all groups. The middle cohort had high frequencies of masseter spasm (58.4%; P = .02) and dark urine (75.5%; P = .01) compared to those in the oldest groups, and had a higher peak creatine kinase level compared to those in the 3 groups. Skeletal muscle symptoms tended to be more common in patients administered succinylcholine (generalized muscular rigidity, P = .053; masseter spasm, P < .0001; dark urine, P < .0001). In particular, masseter spasm and dark urine were more common in the middle cohort when succinylcholine was administered (masseter spasm: versus youngest cohort, P = .06, versus oldest cohort, P = .027; dark urine: versus youngest cohort, P = .0072, versus oldest cohort, P = .0015). CONCLUSIONS: The clinical characteristics of pediatric patients with MH vary according to age group. The difference in initial symptoms of MH depending on age group is noteworthy information for the early diagnosis of MH.

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia.

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease.

Is Parkinson's disease an unique clinical entity? Rigid or tremor dominant PD: Two faces of the same coin.

Parkinson's disease is one of the most described neurodegenerative pathologies; though it is one of the most complex pathologies, is not fully understood, correctly identified, with its different types of presentation, its clinical course and the neural networks involved. We report on a series consisting of 432 de novo PD diagnosed patients, and 457 control cases. We identify a possible independent relationship between two clinical PD presentation, akinetic-rigid and tremor-dominant, and cognitive and behavioral changes. A 24-months follow-up allows to identify new information still not fully explored.

Shear wave velocity is sensitive to changes in muscle stiffness that occur independently from changes in force.

Clinical assessments for many musculoskeletal disorders involve evaluation of muscle stiffness, although it is not yet possible to obtain quantitative estimates from individual muscles. Ultrasound elastography can be used to estimate the material properties of unstressed, homogeneous, and isotropic materials by tracking the speed of shear wave propagation; these waves propagate faster in stiffer materials. Although elastography has been applied to skeletal muscle, there is little evidence that shear wave velocity (SWV) can directly estimate muscle stiffness since this tissue violates many of the assumptions required for there to be a direct relationship between SWV and stiffness. The objective of this study was to evaluate the relationship between SWV and direct measurements of muscle force and stiffness in contracting muscle. Data were collected from six isoflurane-anesthetized cats. We measured the short-range stiffness in the soleus via direct mechanical testing in situ and SWV via ultrasound imaging. Measurements were taken during supramaximal activation at optimum muscle length, with muscle temperature varying between 26°C and 38°C. An increase in temperature causes a decrease in muscle stiffness at a given force, thus decoupling the tension-stiffness relationship normally present in muscle. We found that increasing muscle temperature decreased active stiffness from 4.0 ± 0.3 MPa to 3.3 ± 0.3 MPa and SWV from 16.9 ± 1.5 m/s to 15.9 ± 1.6 m/s while force remained unchanged (mean ± SD). These results demonstrate that SWV is sensitive to changes in muscle stiffness during active contractions. Future work is needed to determine how this relationship is influenced by changes in muscle structure and tension.NEW & NOTEWORTHY Shear wave ultrasound elastography is a noninvasive tool for characterizing the material properties of muscle. This study is the first to compare direct measurements of stiffness with ultrasound measurements of shear wave velocity (SWV) in a contracting muscle. We found that SWV is sensitive to changes in muscle stiffness, even when controlling for muscle tension, another factor that influences SWV. These results are an important step toward developing noninvasive tools for characterizing muscle structure and function.

Patterns of grey matter loss associated with motor subscores in early Parkinson's disease.

Classical motor symptoms of Parkinson's disease (PD) such as tremor, rigidity, bradykinesia, and axial symptoms are graded in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. It is yet to be ascertained whether parkinsonian motor symptoms are associated with different anatomical patterns of neurodegeneration as reflected by brain grey matter (GM) alteration. This study aimed to investigate associations between motor subscores and brain GM at voxel level. High resolution structural MRI T1 scans from the Parkinson's Progression Markers Initiative (PPMI) repository were employed to estimate brain GM intensity of PD subjects. Correlations between GM intensity and total MDS-UPDRS III and its four subscores were computed. The total MDS-UPDRS III score was significantly negatively correlated bilaterally with putamen and caudate GM density. Lower anterior striatal GM intensity was significantly associated with higher rigidity subscores, whereas left-sided anterior striatal and precentral cortical GM reduction were correlated with severity of axial symptoms. No significant morphometric associations were demonstrated for tremor subscores. In conclusion, we provide evidence for neuroanatomical patterns underpinning motor symptoms in early PD.

Degeneration of the corticofugal tract from the secondary motor area in a Parkinson's disease patient with limb-kinetic apraxia: A case report.

RATIONALE: In this case report, we describe a Parkinson's disease (PD) patient with limb-kinetic apraxia (LKA) in whom degeneration of the corticofugal tract (CFT) from the supplementary motor area (SMA) was observed in diffusion tensor tractography (DTT). PATIENT CONCERNS: A 63-year-old woman presented with a loss of dexterity in both upper extremities, which indicated LKA, and typical PD-related symptoms, including a gait disturbance with a short step, resting tremor in both upper extremities, and rigidity, and these symptoms had been present for 2 years. The F-florinated-N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-lodophenyl) nortropane positron emission tomography scanning findings were consistent with PD. Based on the clinical symptoms and imaging findings, we diagnosed the patient with PD. In a coin-rotation test that was used to evaluate the severity of the LKA, the patient's results significantly decreased compared to the results of the normal controls. DIAGNOSES: The DTT showed that the CFTs from the SMAs in both hemispheres were partially torn and thinned. The fractional anisotropy values and CFT volumes in both SMAs were >2 standard deviations lower than those of the normal controls. INTERVENTIONS: The patient was treated with an initial dose of 150/37.5 mg/day of levodopa/benserazide, and the dose was gradually increased to 400/100 mg/day. OUTCOMES: After treatment, although the bradykinesia, rigidity, and resting tremor of the patient significantly decreased, the dexterity of the patient's hands did not improve. LESSONS: These observations indicated degeneration of the CFTs from the SMAs in both hemispheres in the patient. This degeneration might have, at least in part, contributed to the patient's LKA. The results of this study suggest that CFT degeneration could be one of the pathological mechanisms underlying LKA in patients with PD.

Tension-referenced measures of gastrocnemius slack length and stiffness in Parkinson's disease.

BACKGROUND: It is not known how passive muscle length and stiffness contribute to rigidity in Parkinson's disease. The objective of this study was to compare passive gastrocnemius muscle-tendon slack length and stiffness at known tension in Parkinson's disease subjects with ankle rigidity and in able-bodied people. METHODS: Passive ankle torque-angle curves were obtained from 15 Parkinson's disease subjects with rigidity and 15 control subjects. Torque-angle data were used to derive passive gastrocnemius length-tension data and calculate slack length and stiffness of the gastrocnemius muscle. Between-group comparisons were made with linear models. RESULTS: Gastrocnemius muscle-tendon slack lengths (adjusted between-group difference, 0.01 m; 95% CI, -0.02 to 0.04 m; P = 0.37) and stiffness (adjusted between-group difference, 15.7 m-1 ; 95% CI, -8.5 to 39.9 m-1 ; P = 0.19) were not significantly different between groups. CONCLUSIONS: Parkinson's disease subjects with ankle rigidity did not have significantly shorter or stiffer gastrocnemius muscles compared with control subjects. © 2016 International Parkinson and Movement Disorder Society.

Acupuncture for Erectile Dysfunction: A Systematic Review.

BACKGROUND: Acupuncture is increasingly used to treat patients with erectile dysfunction (ED), and our systematic review aimed to evaluate the current evidence for the efficacy and safety of acupuncture in treating ED. METHODS: An electronic search was conducted in eight databases to identify randomized controlled trials (RCTs) of acupuncture for treating erectile dysfunction that were published in English and Chinese. The Cochrane Risk of Bias tool was used to assess the risk of bias. RESULTS: Three RCTs with a total of 183 participants met the inclusion criteria. One trial showed the beneficial effects of acupuncture compared with sham acupuncture while the others did not. One trial suggested that acupuncture combined with psychological therapy was superior to psychological therapy alone. However, the overall methodological and reporting quality of the studies was low. The safety of acupuncture for ED was unclear because there were too few reports on this topic. CONCLUSION: The available evidence supporting that acupuncture alone improves ED was insufficient and the available studies failed to show the specific therapeutic effect of acupuncture. Future well-designed and rigorous RCTs with a large sample size are required. This trial is registered with CRD42014013575.

Neural and nonneural contributions to wrist rigidity in Parkinson's disease: an explorative study using the NeuroFlexor.

OBJECTIVE: The NeuroFlexor is a novel method incorporating a biomechanical model for the measurement of neural and nonneural contributions to resistance induced by passive stretch. In this study, we used the NeuroFlexor method to explore components of passive movement resistance in the wrist and finger muscles in subjects with Parkinson's disease (PD). METHODS: A cross-sectional comparison was performed in twenty-five subjects with PD with clinically identified rigidity and 14 controls. Neural (NC), elastic (EC), and viscous (VC) components of the resistance to passive extension of the wrist were calculated using the NeuroFlexor. Measurements were repeated during a contralateral activation maneuver. RESULTS: PD subjects showed greater total resistance (P < 0.001) and NC (P = 0.002) compared to controls. EC and VC did not differ significantly between groups. Contralateral activation maneuver resulted in increased NC in the PD group but this increase was due to increased resting tension. Total resistance and NC correlated with clinical ratings of rigidity and with bradykinesia. CONCLUSIONS: The findings suggest that stretch induced reflex activity, but not nonneural resistance, is the major contributor to rigidity in wrist muscles in PD. The NeuroFlexor is a potentially valuable clinical and research tool for quantification of rigidity.

Antimicrobial surveillance in idiopathic parkinsonism: indication-specific improvement in hypokinesia following Helicobacter pylori eradication and non-specific effect of antimicrobials for other indications in worsening rigidity.

BACKGROUND: Following Helicobacter pylori eradication in a placebo-controlled trial, the hypokinesia of idiopathic parkinsonism improved but flexor rigidity worsened. METHODS: We surveyed the effect of all antimicrobial prescriptions in 66 patients with idiopathic parkinsonism over a median of 1.9 (interquartile range 0.4, 3.5) years. Initial Helicobacter screening was followed (where positive) by gastric biopsy. Serial lactulose hydrogen breath tests (364 tests) for small intestinal bacterial overgrowth monitored the need to encourage fluid intake and bulk/osmotic laxatives. We measured hypokinesia (401 assessments of mean stride length at free walking speed in 58 patients) and upper limb flexor rigidity (396 assessments in 49). RESULTS: Following successful H. pylori eradication (12 cases) but not failed (2), stride increased in entire group (including those receiving levodopa), core group (those receiving only longer-t½ antiparkinsonian medication or untreated) and untreated (p = .001 each case). The effect was greater with less antiparkinsonian medication (19 (95% CI, 14, 25) cm/year in untreated). Flexor rigidity was unchanged. Following antimicrobials for other indications (75 courses), hypokinesia was unchanged. However, flexor rigidity increased cumulatively. It increased in core group only after a first course (by (10 (0, 20)%/year, p = .05)), but then in entire, core and untreated after a second course (18 (6, 31), 33 (19, 48) and 29 (12, 48)%/year respectively; p = .002, .001 and .001) and further still after a third (17 (2, 34), 23 (8, 41) and 38 (15, 65)%/year; p = .02, .003 and .001). Initially, 40/66 were lactulose hydrogen breath test positive. Odds for positivity fell with time (by 59 (46, 75)%/year, p = .001) and tended to be lower with Helicobacter positivity (28 (8, 104)%, p = .06), but were unrelated to other antimicrobial interventions. CONCLUSIONS: Improved hypokinesia following antimicrobials appeared unique to Helicobacter eradication. Rigidity increased following successive antimicrobial exposures for other indications, despite diminishing lactulose hydrogen breath test positivity.

The clinical features of pathologically confirmed vascular parkinsonism.

OBJECTIVE: To evaluate in detail the clinical features in a large series of pathologically confirmed cases of vascular Parkinsonism (VP). BACKGROUND: In the absence of widely accepted diagnostic criteria for VP pathological confirmation of diagnosis is necessary to ensure diagnostic reliability, and has only been reported in a few small series. DESIGN/METHODS: The archival records of the Queen Square Brain Bank (QSBB) have been used to identify cases of Parkinsonism where cerebrovascular disease was the only pathological finding. Clinical notes were scrutinised and milestones of disease progression were compared with other atypical Parkinsonian syndromes from previous QSBB studies. RESULTS: Twenty-eight cases were included. Mean age of onset and disease duration were 70.6 (SD± 6.42) and 10.5 (SD± 66.1) years respectively. Bradykinesia was present in all cases, rigidity in 96%, falls in 76%, pyramidal signs in 54%, urinary incontinence in 50% and dementia in 39%.Visual hallucinations in 0%. Two-thirds had an insidious onset and a relentless rather than stepwise progression of disability. When compared with other Parkinsonian syndromes, VP had an older age of onset. CONCLUSIONS: In comparison with other Parkinsonian syndromes the patients were older and had an extremely low frequency of visual hallucinations compared with Parkinson's disease.

Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies.

BACKGROUND: The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus. METHODS: The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months. RESULTS: Serum antibodies to both NMDA receptors (NMDAR) and glycine receptors (GlyR) were detected postmortem, and examination of the brain confirmed an autoimmune encephalomyelitis, with particular involvement of hippocampal pyramidal and cerebellar Purkinje cells and relative sparing of the neocortex. No evidence for an underlying systemic neoplasm was found. CONCLUSION: This case displayed not only the clinical features of PERM, previously associated with GlyR antibodies, but also some of the features associated with NMDAR antibodies. This unusual combination of antibodies may be responsible for the particularly progressive course and sudden death.

Cerebral cortical areas in which thickness correlates with severity of motor deficits of Parkinson's disease.

The pathology of Parkinson's disease (PD) is not confined to the nigrostriatal dopaminergic pathway, but also involves widespread cerebral cortical areas. Such non-nigrostriatal lesions may contribute to disabling dopa-resistant parkinsonian motor deficits. We performed cortical thickness analysis to identify cerebral cortical brain areas in which thickness correlates with the severity of parkinsonian motor deficits. We performed T1-weighted brain magnetic resonance imaging studies in 142 PD patients. Motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS) were measured, and subscores were calculated for bradykinesia, rigidity, tremor, and axial motor deficits. Using FreeSurfer software, we studied cortical areas in which thickness correlates with disease duration or the severity of parkinsonian motor deficits. The cortical thickness of the parieto-temporal association cortex, including the inferior parietal and posterior parietal cortices, showed a negative correlation with disease duration, total UPDRS motor score, and UPDRS subscores for bradykinesia and axial motor deficits. We found no cortical areas in which thickness correlated with subscores for tremor and rigidity. In addition to nigrostriatal dopaminergic deficit, progressive thinning of the parieto-temporal sensory association cortices related to disease duration seems to be related in part to the exacerbation of bradykinesia and the axial motor symptoms of PD.

Akinetic-rigid syndrome due to extrapontine and pontine myelinolysis following appropriate correction of hyponatraemia.

Extrapontine myelinolysis in association with the more common central pontine variety is increasingly reported. Although typically associated with rapid correction of hyponatraemia, myelinolysis is also seen when sodium correction occurs at recommended rates. We present a 60-year-old man who developed hyponatraemia and hypokalaemia due to repeated vomiting. An acute symmetric akinetic-rigid syndrome followed correction of hyponatraemia, performed in line with current guidelines. There were no clinical features of pontine involvement even though a typical lesion was seen on MRI. Bilateral putaminal and caudate lesions were seen. He recovered well with only symptomatic treatment. Myelinolysis can present with features of extrapontine involvement with the pontine lesions remaining asymptomatic. Current guidelines for the correction of hyponatraemia do not prevent development of myelinolysis in all instances. In contrast to the generally expected poor outcome in this condition, patients do make a good recovery with symptomatic treatment and good nursing care.

FRET characterisation for cross-bridge dynamics in single-skinned rigor muscle fibres.

In this work we demonstrate for the first time the use of Förster resonance energy transfer (FRET) as an assay to monitor the dynamics of cross-bridge conformational changes directly in single muscle fibres. The advantage of FRET imaging is its ability to measure distances in the nanometre range, relevant for structural changes in actomyosin cross-bridges. To reach this goal we have used several FRET couples to investigate different locations in the actomyosin complex. We exchanged the native essential light chain of myosin with a recombinant essential light chain labelled with various thiol-reactive chromophores. The second fluorophore of the FRET couple was introduced by three approaches: labelling actin, labelling SH1 cysteine and binding an adenosine triphosphate (ATP) analogue. We characterise FRET in rigor cross-bridges: in this condition muscle fibres are well described by a single FRET population model which allows us to evaluate the true FRET efficiency for a single couple and the consequent donor-acceptor distance. The results obtained are in good agreement with the distances expected from crystallographic data. The FRET characterisation presented herein is essential before moving onto dynamic measurements, as the FRET efficiency differences to be detected in an active muscle fibre are on the order of 10-15% of the FRET efficiencies evaluated here. This means that, to obtain reliable results to monitor the dynamics of cross-bridge conformational changes, we had to fully characterise the system in a steady-state condition, demonstrating firstly the possibility to detect FRET and secondly the viability of the present approach to distinguish small FRET variations.

Mitochondrial transfer RNA(Phe) mutation associated with a progressive neurodegenerative disorder characterized by psychiatric disturbance, dementia, and akinesia-rigidity.

BACKGROUND: Mitochondrial diseases are characterized by wide phenotypic and genetic variability, but presentations in adults with akinetic rigidity and hyperkinetic movement disorders are rare. OBJECTIVES: To describe clinically a subject with progressive neurodegeneration characterized by psychosis, dementia, and akinesia-rigidity, and to associate this phenotype with a novel mitochondrial transfer RNA(Phe) (tRNA(Phe)) (MTTF) mutation. DESIGN, SETTING, AND PATIENT: Case description and detailed laboratory investigations of a 57-year-old woman at a university teaching hospital and a specialist mitochondrial diagnostic laboratory. RESULTS: Histopathological findings indicated that an underlying mitochondrial abnormality was responsible for the subject's progressive neurological disorder, with mitochondrial genome sequencing revealing a novel m.586G>A MTTF mutation. CONCLUSIONS: The clinical phenotypes associated with mitochondrial disorders may include akinesia-rigidity and psychosis. Our findings further broaden the spectrum of neurological disease associated with mitochondrial tRNA(Phe) mutations.

Magnetic resonance imaging findings of shoulders in Parkinson's disease.

The aim of this study is to evaluate shoulder disturbances in Parkinson's disease (PD) patients using magnetic resonance imaging (MRI) which is the best tool in the demonstration of complex shoulder pathologies; and to determine probable relations between shoulder pathologies and PD clinical features. Twenty-eight PD patients with a total of 56 shoulders were used as the study group while 13 age-matched cases with 26 shoulders were used as the control group (CG) in the study. Both patients with PD and the CG underwent shoulder MRI. The Hoehn and Yahr (H&Y) disability scale and Unified Parkinson's Disease Rated Scale (UPDRS) were used to determine the severity of the disease. Our results showed that patients with full-thickness supraspinatus (SSP) tear have statistically significant higher UPDRS (P = 0.012), tremor (P = 0.023), rigidity (P = 0.023), and total (P = 0.002) scores. Mild group patients (P = 0.045) showed significantly higher frequency resting tremor and subcoracoid effusion than those of severe group patients (P = 0.002). Subcoracoid effusion was observed in patients with significantly higher UPDRS (P = 0.045) and rigidity (P = 0.022) scores. When the resting tremor and subcoracoid effusion groups were compared according to the severity of the resting tremor but not according to the H&Y, higher frequency of full-thickness tear in SSP tendon was detected in the group of resting tremor (P = 0.053). Longer duration of disease was also observed in patients with full-thickness SSP tear (P = 0.029) and acromioclavicular joint changes (P = 0.018). Higher UPDRS, tremor, rigidity and total scores and longer PD duration appear as the predisposing factors for the development of shoulder disturbances in PD in this study.

Neurotoxic manifestations of an overdose intrathecal injection of gadopentetate dimeglumine.

The intravenous administration of gadopentetate dimeglumine (GD) is relatively safe and rarely causes systemic toxicity in the course of routine imaging studies. However, the general safety of intrathecal GD has not been established. We report a very rare case of an overdose intrathecal GD injection presenting with neurotoxic manifestations, including a decreased level of consciousness, global aphasia, rigidity, and visual disturbance.

Acquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity in a 46,XY male with a de novo MECP2 gene mutation.

We report a case of acquired microcephaly in a male infant. Testing for mutations in the MECP2 gene identified a de novo hemizygous c.378-3C>G mutation at a highly conserved 3' splice site, consistent with Rett syndrome. Other distinctive features included periodic hypertonicity, decreased mitochondrial complex III activity, and abnormal magnetic resonance imaging (MRI) T2 signal in the pons. Rett syndrome was originally described in females with a clinical phenotype of deceleration of head growth, abnormal hand movements, and developmental regression. The clinical diagnosis can now be supported by genetic testing for MECP2 mutations, and the phenotype of disorder has expanded. Cases of Rett syndrome in males are rare and a total of 17 such cases have been reported. This case extends the clinical phenotype of Rett syndrome in males and associates this mutation with mitochondrial dysfunction.

Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype?

Myotilinopathies are a group of muscle disorders caused by mutations in the MYOT gene. It was first described in two families suffering from limb girdle muscle dystrophy type 1 (LGMD 1A), and later identified in a subset of dominant or sporadic patients suffering from myofibrillar myopathy, as well as in a family with spheroid body myopathy. Disease phenotypes associated with MYOT mutations are clinically heterogeneous and include pure LGMD forms as well as late-onset distal myopathies. We report here on a 53-year-old male suffering from a unique clinical profile characterized by generalized symmetrical increase in muscle bulk leading to a Herculean appearance. Muscle weakness and stiffness in the lower extremities were the patient's main complaints. Muscle MRI showed extensive fatty infiltration in the thigh and leg muscles and a muscle biopsy showed a myofibrillar myopathy with prominent protein aggregates. Gene sequencing revealed a Ser55Phe missense mutation in the myotilin gene. The mutation was identified in his older brother, who presented a mild hypertrophic appearance and had a myopathic pattern in EMG, despite not presenting any of the complaints of the proband and having normal muscle strength. This finding, and his deceased father and paternal aunt's similar gait disorders, suggest that this is in fact a new autosomal dominant kindred. The present observations further expand the spectrum of clinical manifestations associated with mutations in the myotilin gene.