Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging.

BACKGROUND AND PURPOSE: The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. METHODS: Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1-weighted and short-tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. RESULTS: The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro-caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. CONCLUSION: This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD-related disease spectrum.

Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.

OBJECTIVES: Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis. MATERIALS AND METHODS: Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients. INTERPRETATION: Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients.

The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.

The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis.

BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV. METHODS: We analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity (FVC), peak cough flow (PCF), maximum inspiratory and expiratory pressure (MIP and MEP) and sniff nasal inspiratory pressure (SNIP) in patients with ALS. Patients who had had at least one assessment of respiratory function and one visit at the HVS, were included. Our aim was to detect the test with the highest predictive value for the need for elective NIV in the following 3 months. We analysed time curves, currently used cut-off values for referral, and respiratory function test results between 'NIV indication' and 'no-NIV indication' patients. RESULTS: One hundred ten patients with ALS were included of whom 87 received an NIV indication; 11.5% had one assessment before receiving an NIV indication, 88.5% had two or more assessments. The NIV indication was based on complaints of hypoventilation and/or proven (nocturnal) hypercapnia. The five respiratory function tests showed a descending trend during disease progression, where SNIP showed the greatest decline within the latest 3 months before NIV indication (mean = -22%). PCF at the time of referral to the HVS significantly discriminated between the groups 'NIV-indication' and 'no NIV-indication yet' patients at the first HVS visit: 259 (±92) vs. 348 (±137) L/min, p = 0.019. PCF and SNIP showed the best predictive characteristics in terms of sensitivity. CONCLUSION: SNIP showed the greatest decline prior to NIV indication and PCF significantly differentiated 'NIV-indication' from 'no NIV-indication yet' patients with ALS. Currently used cut-off values might be adjusted and other respiratory function tests such as SNIP and PCF may become part of routine care in patients with ALS in order to avoid non-timely initiation of (non-invasive) ventilation.

The wrong end of the telescope: neuromuscular mimics of movement disorders (and vice versa).

The rapid advances in modern neurology have led to increased specialisation in clinical practice. Being an expert in a neurology subspecialty offers advantages for diagnosing and managing specific disorders. However, specialisation also risks tunnel vision: interpreting symptoms and signs within one's own framework of reference, while ignoring differential diagnostic options from other subspecialties. This is particularly relevant when the patient's presentation potentially belongs to different neurological subspecialties. We illustrate this challenge by highlighting a series of clinical features that partially overlap between two common subspecialties: movement disorders and neuromuscular disorders. An overlap in clinical presentation is not rare, and includes, for example, involuntary eyelid closure (which could be active eye closure due to blepharospasm, or ptosis due to weakness). Other overlapping features include abnormal postures, involuntary movements and gait changes. We describe two of these overlapping features in more detail and emphasise the possible consequences of 'looking through the wrong end of the telescope' in such patients, as this may lead to a wrong differential diagnosis, unnecessary investigations and a delayed treatment start.

RYR1-related myopathies: a wide spectrum of phenotypes throughout life.

BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

Facioscapulohumeral Disease as a myodevelopmental disease: Applying Ockham's razor to its various features.

 Facioscapulohumeral muscular dystrophy (FSHD) is an exclusively human neuromuscular disease. In the last decades the cause of FSHD was identified: the loss of epigenetic repression of the D4Z4 repeat on chromosome 4q35 resulting in inappropriate transcription of DUX4. This is a consequence of a reduction of the array below 11 units (FSHD1) or of a mutation in methylating enzymes (FSHD2). Both require the presence of a 4qA allele and a specific centromeric SSLP haplotype. Muscles become involved in a rostro-caudally order with an extremely variable progression rate. Mild disease and non-penetrance in families with affected individuals is common. Furthermore, 2% of the Caucasian population carries the pathological haplotype without clinical features of FSHD.In order to explain the various features of FSHD we applied Ockham's Razor to all possible scenarios and removed unnecessary complexities. We postulate that early in embryogenesis a few cells escape epigenetic silencing of the D4Z4 repeat. Their number is assumed to be roughly inversely related to the residual D4Z4 repeat size. By asymmetric cell division, they produce a rostro-caudal and medio-lateral decreasing gradient of weakly D4Z4-repressed mesenchymal stem cells. The gradient tapers towards an end as each cell-division allows renewed epigenetic silencing. Over time, this spatial gradient translates into a temporal gradient based on a decreasing number of weakly silenced stem cells. These cells contribute to a mildly abnormal myofibrillar structure of the fetal muscles. They also form a downward tapering gradient of epigenetically weakly repressed satellite cells. When activated by mechanical trauma, these satellite cells de-differentiate and express DUX4. When fused to myofibrils they contribute to muscle cell death in various ways. Over time and dependent on how far the gradient reaches the FSHD phenotype becomes progressively manifest. We thus hypothesize FSHD to be a myodevelopmental disease with a lifelong attempt to restore DUX4 repression.

Establishing the role of muscle ultrasound as an imaging biomarker in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary muscle disease, that causes weakness and wasting of skeletal muscles. In this cross-sectional cohort-study on FSHD patients, we assessed muscle ultrasound findings and their relation to clinical outcome measures, evaluating the role of ultrasound as biomarker in FSHD. We included 115 genetically confirmed FSHD patients (52% males, age-range 22-80 years). They were subjected to a standardized muscle ultrasound protocol of seven truncal and upper- and lower extremity muscles bilaterally. Muscle images were scored using the Heckmatt scale. Muscle echogenicity was quantified using z-scores. Compound echogenicity and Heckmatt scores were calculated. Nearly all patients (94%) had one or multiple muscles with an increased echogenicity z-score. The trapezius muscle was most severely affected, followed by the rectus femoris muscle. Both compound ultrasound scores strongly with multiple clinical outcome measures (ρ 0.68-0.79, p < 0.001). While most muscles showed a high level of agreement between the echogenicity z-score and Heckmatt score (>95%), the tibialis anterior and gastrocnemius muscle showed lower levels of agreement (82 and 92%). In conclusion, our study confirms the use of muscle ultrasound as clinical severity biomarker and provides a solid base for future longitudinal studies to establish ultrasound as a monitoring biomarker in FSHD.

Facing facial weakness: psychosocial outcomes of facial weakness and reduced facial function in facioscapulohumeral muscular dystrophy.

PURPOSE: To assess the psychosocial outcomes of facial weakness in facioscapulohumeral muscular dystrophy (FSHD). MATERIALS AND METHODS: A cross-sectional survey study. The severity of facial weakness was assessed by patients (self-reported degree of facial weakness) and by physicians (part I FSHD clinical score). Questionnaires on facial function, psychosocial well-being, functioning, pain, and fatigue were completed. Regression analyses were performed to explain variance in psychosocial outcomes by demographic and disease variables. RESULTS: One hundred and thirty-eight patients participated. They reported mild to moderate psychological distress, no to mild fear of negative evaluation, and moderate to good social functioning. However, patients with severe self-reported facial weakness scored lower in social functioning. Patients with more facial dysfunction experienced more fear of negative evaluation and lower social functioning. Furthermore, younger age, presence of pain, fatigue, walking difficulty, and current or previous psychological support were associated with lower psychosocial outcomes. Overall, patients report moderate to good psychosocial functioning in this study. The factors contributing to lower psychosocial functioning are diverse. CONCLUSIONS: A multidisciplinary, personalized approach, focusing on coping with physical, emotional, and social consequences of FSHD is supposed to be helpful. Further research is needed to assess the psychosocial outcomes of facial weakness in younger patients.Implications for rehabilitationResearch on the psychosocial consequences of facial weakness in facioscapulohumeral muscular dystrophy (FSHD) is limited.Patients with FSHD experience mild to moderate psychosocial distress, partly due to overall disease severity, such as reduced mobility, and partly due to facial weakness and reduced facial function.Self-reported degree of facial weakness and facial dysfunction were related to lower psychosocial outcomes (social functioning, fear of negative evaluation, and psychological distress).Physician-reported degree of facial weakness was not related to psychosocial outcomes, suggesting an absence of a strong correlation between observed facial weakness and experienced disease burden in this study.This calls for a multidisciplinary, personalized approach with a focus on coping with physical, emotional, and social consequences of FSHD.

Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation.

We here report on a 20-year-old female patient with EDS due to a homozygous CHST14 single nucleotide deletion resulting in D4ST-1 deficiency, accompanied by muscle hypoplasia and muscle weakness. Findings of muscle ultrasound, electromyography, and muscle biopsy pointed to a myopathy, similarly as in other EDS types. This myopathy probably contributes to the gross motor developmental delay in this type of EDS.

Sleep disturbances in chronic progressive external ophthalmoplegia.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. In addition to extraocular muscle weakness, various other organs can typically be affected, including laryngeal and limb muscles, cerebrum, cerebellum, and peripheral nerves. Given this multi-organ involvement, patients are likely to be prone to sleep disturbances. Here, we determined the nature, prevalence, and determinants of sleep disturbances in CPEO. METHODS: We used validated questionnaires for various sleep disorders and possible determinants such as mood and anxiety, and we performed ambulant polysomnography (PSG) in 20 patients with genetically confirmed CPEO. RESULTS: Three quarters of patients reported nocturnal sleep dysfunction. Thirty-five percent of patients fulfilled the criteria for restless legs syndrome, 30% excessive daytime sleepiness, and 70% significant periodic limb movements. PSG recordings revealed several indicators of a disrupted sleep architecture. Obstructive sleep disordered breathing was present in only one patient. However, four patients had an increased central sleep apnea index, all of whom had a polymerase gamma-1 mutation and a SANDO phenotype (sensoric atactic neuropathy, dysarthria, ophthalmoplegia). Physical examination and questionnaire outcomes were poor predictors of PSG results. CONCLUSION: Several specific sleep disturbances are part of the phenotype of CPEO. Given that the disease is otherwise incurable, symptomatic treatment of sleep disturbances may be an important tool to improve quality of life. Therefore, patients with CPEO should be actively screened for sleep disorders, with a low threshold to perform PSG.

Having an eye for myotonic dystrophy: A qualitative study on experiences and support needs in myotonic dystrophy type 1 patients with a diagnostic delay after early-onset cataract.

Myotonic dystrophy type 1 is a neuromuscular disorder affecting multiple organ systems and is characterized by a variety of clinical presentations. Anticipation leads to an earlier and more severe phenotype in subsequent generations. Early-onset cataract is a common initial manifestation of the late or adult-onset type of myotonic dystrophy 1. Due to its multicausal nature, early-onset cataract is often not recognized as a feature of this disease, leading to diagnostic delay resulting in consequences for successive generations, treatment and counseling. A qualitative study with semi-structured interviews was performed with purposive sampling of eight participants with myotonic dystrophy type 1 and early-onset cataract to investigate the physical and psychosocial consequences experienced due to diagnostic delay. Prior to the early-onset cataract, all participants experienced other multisystem symptoms that could have been explained by myotonic dystrophy. The diagnostic delay had severe hereditary consequences: a subsequent generation with more severely affected (grand)children was born resulting in large emotional burden for the patients. To conclude, early-onset cataract is a warning sign and ophthalmologists play a crucial role in the early detection of myotonic dystrophy type 1 by recognizing this symptom and preventing the birth of severely affected children leading to emotional and psychosocial consequences.

Mild muscular features in tenascin-X knockout mice, a model of Ehlers-danlos syndrome.

INTRODUCTION: Tenascin-X (TNX) is an extracellular matrix (ECM) glycoprotein, the absence of which in humans leads to a recessive form of Ehlers-Danlos syndrome (EDS), a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. A mouse model of TNX-deficient type EDS has been used to characterize the dermatological, orthopedic, and obstetrical features. The growing insight in the clinical overlap between myopathies and inherited connective tissue disorders asks for a study of the muscular characteristics of inherited connective tissue diseases. Therefore, this study aims to define the muscular phenotype of TNX knockout (KO) mice. MATERIALS AND METHODS: We performed a comprehensive study on the muscular phenotype of these TNX KO mice, consisting of standardized clinical assessment, muscle histology, and gene expression profiling of muscle tissue. Furthermore, peripheral nerve composition was studied by histology and electron microscopy. RESULTS: The main findings are the presence of mild muscle weakness, mild myopathic features on histology, and functional upregulation of genes encoding proteins involved in ECM degradation and synthesis. Additionally, sciatic nerve samples showed mildly reduced collagen fibril density of endoneurium. DISCUSSION: The muscular phenotype of TNX KO mice consists of mild muscle weakness with histological signs of myopathy and of increased turnover of the ECM in muscle. Furthermore, mildly reduced diameter of myelinated fibers and reduction of collagen fibril density of endoneurium may correspond with polyneuropathy in TNX-deficient EDS patients. This comprehensive assessment can serve as a starting point for further investigations on neuromuscular function in TNX KO mice.

Speech pathology interventions in patients with neuromuscular diseases: a systematic review.

PURPOSE: A systematic review was conducted to summarize and evaluate the literature on the effectiveness of speech pathology interventions in adults with neuromuscular diseases. METHOD: Databases searched included the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE, PsycINFO and PubMed. A total of 1,772 articles were independently screened on title and abstract by 2 reviewers. RESULTS: No randomized controlled trials or clinical controlled trials were found. Four other designs were included. Only one study on oculopharyngeal muscle dystrophy (OPMD) appeared to have sufficient methodological quality. There is evidence indicating that correction of head position in patients with OPMD improves swallowing efficiency (level III evidence). CONCLUSION: Despite 1,772 studies, there is only evidence of level III regarding the effectiveness of speech pathology interventions in patients with OPMD. Recommendations for future research are given.

Characterizing the face in facioscapulohumeral muscular dystrophy.

OBJECTIVE: To evaluate facial weakness in patients with FSHD to better define clinical signs, and pilot a facial weakness severity score. METHODS: 87 FSHD patients and 55 controls were video recorded while performing seven facial tasks. The videos were assessed by three independent examiners to compile an overview of signs of facial weakness. Next, videos were semi-quantitatively assessed using a newly developed 4-point facial weakness score (FWS). This score was evaluated and correlated to other FSHD disease characteristics. RESULTS: Patients had lower scores on the total FWS than controls (mean score 43 ± 28, range 4-118, vs 14 ± 9, range 0-35, p < 0.001) and on all seven individual facial tasks (all p < 0.001). 54% of patients had FWS scores outside the range of controls. Patients had more asymmetry between the left and right side of the face than controls. About 10% of the patients had very mild facial weakness. These were mostly males (89%) with longer D4Z4 repeat sizes of 7-9 units. More severe facial weakness correlated to more severe overall disease severity and shorter D4Z4 repeat size, but not to disease duration. Interobserver agreement for the FWS between three raters was low with a Fleiss Kappa of 0.437. CONCLUSION: This study provides an overview of the clinical spectrum of facial weakness and its relation to other disease characteristics. The 4-point scale we introduced to grade the severity of facial weakness enables correlation of facial weakness to disease characteristics, but is not suited as clinical outcome measure for longitudinal studies.

Isolated eyelid closure myotonia in two families with sodium channel myotonia.

Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype-phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194-202, 2005). We describe the first distinctive clinical genotype-phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype-phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.

Only fat infiltrated muscles in resting lower leg of FSHD patients show disturbed energy metabolism.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric dysfunctioning of individual muscles. Currently, it is unknown why specific muscles are affected before others and more particularly what pathophysiology is causing this differential progression. The aim of our study was to use a combination of (31)P magnetic resonance spectroscopic imaging (MRSI) and T1-weighted MRI to uncover metabolic differences in fat infiltrated and not fat infiltrated muscles in patients with FSHD. T1-weighted images and 3D (31)P MRSI were obtained from the calf muscles of nine patients with diagnosed FSHD and nine healthy age and sex matched volunteers. Muscles of patients were classified as fat infiltrated (PFM) and non fat-infiltrated (PNM) based on visual assessment of the MR images. Ratios of phosphocreatine (PCr), phosphodiesters (PDE) and inorganic phosphate (Pi) over ATP and tissue pH were compared between PFM and PNM and the same muscles in healthy volunteers. Of all patients, seven showed moderate to severe fatty infiltration in one or more muscles. In these muscles, decreases in PCr/ATP and increases in tissue pH were observed compared to the same muscles in healthy volunteers. Interestingly, these differences were absent in the PNM group. Our data show that differences in metabolite ratios and tissue pH in skeletal muscle between healthy volunteers and patients with FSHD appear to be specific for fat infiltrated muscles. Normal appearing muscles on T1 weighted images of patients showed normal phosphoryl metabolism, which suggests that in FSHD disease progression is truly muscle specific.

New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype.

Sandhoff disease is a lipid-storage disorder caused by a defect in ganglioside metabolism. It is caused by a lack of functional N-acetyl-beta-d-glucosaminidase A and B due to mutations in the HEXB gene. Typical, early-onset Sandhoff disease presents before 9 months of age with progressive psychomotor retardation and early death. A late-onset form of Sandhoff disease is rare, and its symptoms are heterogeneous. As drug trials that aim to intervene in the disease mechanism are emerging, the recognition and identification of Sandhoff disease patients-particularly those with atypical phenotypes-are becoming more important. The authors describe six new late-onset Sandhoff cases demonstrating cerebellar ataxia or lower motor neuron (LMN) involvement combined with, mostly subclinical, neuropathy. Two different mutations were found: IVS 12-26 G/A and c.1514G-->A. In patients with either progressive cerebellar ataxia or LMN disease in the setting of a possibly recessive disorder, Sandhoff disease should be suspected, even when the onset age is over 45 years.

Clinical features, lectin staining, and a novel GNE frameshift mutation in hereditary inclusion body myopathy.

We present a comprehensive report of two siblings with hereditary inclusion body myopathy (HIBM). The clinical features and histological characteristics of the muscle biopsies showed the typical pattern of predominantly distal vacuolar myopathy with quadriceps sparing. This was confirmed by muscle MRI. PNA lectin staining showed an increased signal at the sarcolemma in patient muscle sections compared to control muscle, indicating reduced sialylation of glycoconjugates. Mutation analysis revealed compound heterozygous mutations in the GNE gene, encoding the key enzyme in sialic acid synthesis UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase: a missense mutation (c.2086G > A; p.V696M) previously described in HIBM patients of Indian origin, and a novel frame shift mutation (c.1295delA; p.K432RfsX17) leading to a premature stopcodon. These findings confirmed the diagnosis of HIBM on the histological, molecular and biochemical level.