Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Effects of teriparatide on bone mineral density and quality of life in Duchenne muscular dystrophy related osteoporosis: a case report.

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle disease characterized by secondary osteoporosis and increased fractures. We describe the case of a 20-year-old boy with DMD suffering from back pain due to multiple vertebral fractures who was treated with teriparatide. Improvement of bone density, pain, and quality of life was achieved. DMD is an X-linked recessive muscle disease with secondary osteoporosis and related frequently occurring fractures. To date, only bisphosphonates have been used to treat osteoporosis in DMD. Black bear parathyroid hormone has been previously reported to enhance bone mass in the dystrophin-deficient mouse. This study reports the positive effect of osteoanabolic treatment with once-daily recombinant human parathyroid hormone 1-34 (rhPTH 1-34, teriparatide) in a 20-year-old DMD boy suffering from multiple vertebral fractures causing back pain. Bone formation and resorption markers (osteocalcin and C-telopeptide of type I collagen, respectively), as expected, increased within 6 months and intensity of back pain early decreased, with no pain reported after 6 months at visual analog scale. Over a 18-month period of treatment with teriparatide, bone mineral density and quality of life, assessed by the 36-item short-form questionnaire, considerably improved and no side effects were reported. Further studies on large cohorts are warranted to test the efficacy of this promising treatment for DMD related osteoporosis.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Extracorporeal shockwaves as regenerative therapy in orthopedic traumatology: a narrative review from basic research to clinical practice.

Extracorporeal Shock Wave Therapy (ESWT), after its first medical application in the urological field for lithotripsy, nowadays represents a valid therapeutical tool also for many musculoskeletal diseases, as well as for regenerative medicine applications. This is possible thanks to its mechanisms of action, which in the non-urological field are not related to mechanical disruption (as for renal stones), but rather to the capacity, by mechanotransduction, to induce neoangiogenesis, osteogenesis and to improve local tissue trophism, regeneration and remodeling, through stem cell stimulation. On the basis of these biological assumptions, it becomes clear that ESWT can represent a valid therapeutic tool also for all those pathological conditions that derive from musculoskeletal trauma, and are characterized by tissue loss and/or delayed healing and regeneration (mainly bone and skin, but not only). As a safe, repeatable and non–invasive therapy, in many cases it can represent a first–line therapeutic option, as an alternative to surgery (for example, in bone and skin healing disorders), or in combination with some other treatment options. It is hoped that with its use in daily practice also the muscle–skeletal field will grow, not only for standard indications, but also in post–traumatic sequelae, in order to improve recovery and shorten healing time, with undoubted advantages for the patients and lower health service expenses.

Restless legs syndrome and multiple sclerosis: a population based case-control study in Catania, Sicily.

BACKGROUND AND PURPOSE: A population-based case-control study in the city of Catania, Sicily, was carried out to determine restless legs syndrome (RLS) prevalence and its association with multiple sclerosis (MS). METHODS: Patients were randomly selected from a cohort of MS patients resident in the study area and a group of age and sex matched controls was enrolled from the general population. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria. RESULTS: In total, 152 MS patients and 431 controls were included in the study. A significantly higher prevalence of RLS amongst MS patients (14.5%) compared with controls (6.0%) was detected, corresponding to an almost threefold increased risk (odds ratio 2.7, 95% confidence interval 1.4-5.0) of developing RLS. Spinal cord lesions in MS patients were associated with a higher risk of RLS (odds ratio 3.7, 95% confidence interval 1.1-13.5). CONCLUSION: RLS was strongly associated with MS, with a significantly higher risk in patients presenting spinal cord lesions.

Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide.

BACKGROUND: Cyclophosphamide (Cyc) can induce ovarian failure and can have teratogenic effect. Few case reports of successful pregnancies after Cyc treatment in women with autoimmune diseases and malignancies have been described. To date, there are no data about Cyc effect on pregnancy outcomes in MS patients. AIM OF THE STUDY: To describe pregnancy outcomes in multiple sclerosis (MS) patients treated with Cyc before conception. METHODS: We reviewed retrospectively the medical records of all MS patients who received Cyc from 1st of January 1997 to 31st of March 2012, referring to the MS centre of the University of Catania. All pregnancies, occurred during the follow-up period after Cyc treatment, were recorded according to a computerized and standardized protocol (iMED). RESULTS: We found a total of 105 MS women of childbearing age; eleven patients experienced a pregnancy (10.4%); 10 of them had a successful delivery; and one experienced a voluntary abortion. Five women had a preterm delivery. One child was small for gestational age. CONCLUSIONS: Although the favourable pregnancy outcomes, Cyc should be avoided in young women planning a pregnancy. However, Cyc might be considered as a possible alternative to licensed therapies in few selected cases of very aggressive MS, including women of childbearing age.

ANT1 is reduced in sporadic inclusion body myositis.

To investigate ANT1 and NF-κB expression in inclusion body myositis (IBM) muscle and to verify their possible roles in the pathogenesis of the disease, we collected muscle samples from five patients with IBM, polimyositis (PM) and controls. p65 form of NF-κB was analyzed using immunocytochemistry, Western blot and EMSA. Western blot of ANT1 was performed and confirmed by gene expression study. Mann-Whitney test was used for groups comparisons. NF-κB (p65) was found over-expressed both with western blot and EMSA, either in IBM or PM patients versus controls (p < 0.01). Expression of ANT1 were lower in IBM samples versus both PM and controls (p < 0.01). ANT1 reduction and NF-κB over-expression in IBM muscle could explain the lack of apoptosis in such disease. Normal ANT1 expression in PM could be related to the scarcity of mitochondrial abnormalities in the disease, but it could also suggest that these two conditions diverge in activating different anti-apoptotic pathways.

A very late onset AChR and MuSK double positive myasthenia gravis: a case description and literature review.

AChR and MuSK double positive myasthenia gravis has been rarely reported. Generally, it occurs in children and adults after thymectomy or immunotherapy. Furthermore, in a few patients with bulbar or respiratory involvement, MuSK antibodies might be detected after clinical deterioration. We report a man with a very late onset myasthenia gravis (86-year-old) and the coexistence of both antibodies at the time of the diagnosis. Despite the presence of MuSK antibodies, he manifested no bulbar symptoms and had a favorable clinical outcome. However, side effects related to low dose pyridostigmine were evident. Hence, double positivity can also occur in elderly and in more benign forms of myasthenia gravis. Other cases of AChR and MuSK double positive myasthenia gravis could allow a better definition of this condition.

Benign Enhancing Foramen Magnum Lesions.

Benign enhancing foramen magnum lesions have been previously described as T2-hyperintense small, enhancing lesions located posterior to the intradural vertebral artery. We present the first case with pathologic correlation. These lesions are fibrotic nodules adhering to the spinal accessory nerve. While they can enlarge with time on subsequent examinations, on the basis of the imaging characteristics and location, they do not necessitate surgical resection.

Frequency and severity of headache is worsened by Interferon-ß therapy in patients with multiple sclerosis.

BACKGROUND: The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon-beta (IFNß) could induce or worsen HA. OBJECTIVE: To evaluate the impact of IFNß treatment on HA and the relationship between HA and the various commercial preparations of IFNß in mildly disabled patients with MS. METHODS: A specific questionnaire was administered to 357 relapsing-remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNß administration. RESULTS: One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNß-1a (Avonex(®)), 84 with subcutaneous injections of IFNß-1b (Betaferon(®)) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNß-1a (Rebif(®)) 22 mcg or IFNß-1a (Rebif(®)) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre-existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNß therapy; this was more frequently reported by patients treated with Avonex(®) and Rebif(®) 44. Ninety-five patients experienced new HA. CONCLUSION: IFNß treatment could worsen HA in patients with pre-existing HA or cause the appearance of new HA. Among different IFNß preparations, Rebif(®) 44 and Avonex(®) seemed to be more cephalalgic than the other drugs.

Prognostic role of sentinel node biopsy in patients with thick melanoma: a meta-analysis.

OBJECTIVES: Sentinel lymph node (SLN) biopsy is a prognostic tool for patients with intermediate-thickness melanomas. However, controversies exist regarding its role in patients with thick melanomas (tumour thickness greater than 4.0 mm). We performed a meta-analysis to assess the prognostic role of SLN in thick melanoma in terms of disease-free survival (DFS) and overall survival (OS). METHODS: An electronic search in MEDLINE and EMBASE databases using the terms 'melanoma' and 'sentinel lymph node' was performed. Studies were considered if they reported data on thick melanoma and SLN biopsy results (positive and negative) and outcomes (DFS or OS). A proportion meta-analysis was used to calculate weighted means and an incidence rate ratio meta-analysis was used to compare outcomes according to SLN biopsy results. RESULTS: Nine studies were included. The weighted mean thickness of melanoma was 4.4 mm, 42% of patients had ulcerated melanoma. SLN was positive in 36% of the patients. Overall, DFS was 71% in patients with a negative SLN and 39% in patients with a positive SLN after a median follow-up of 33 months (IRR 1.83, 95% CI = 1.56-2.14). OS was 71% in patients with a negative SLN and 49% in patients with a positive SLN (IRR 1.44, 95% CI = 1.25-1.65). CONCLUSIONS: The results of this analysis showed that thick melanoma patients with a positive SLN had a significantly worse survival compared with SLN negative patients, thus supporting the routine adoption of SLN biopsy as a prognostic tool also for this subgroup of patients.

Rates of Epidural Blood Patch following Lumbar Puncture Comparing Atraumatic versus Bevel-Tip Needles Stratified for Body Mass Index.

BACKGROUND AND PURPOSE: Postdural puncture headache, a known complication of lumbar puncture, typically resolves with conservative management. Symptoms persist in a minority of patients, necessitating an epidural blood patch. One method of decreasing rates of postdural puncture headache is using atraumatic, pencil-point needles rather than bevel-tip needles. To the best of our knowledge, this is the first study comparing epidural blood patch rates between pencil- and bevel-tip needles with a subgroup analysis based on body mass index. MATERIALS AND METHODS: This single-institution retrospective study identified 4435 patients with a recorded body mass index who underwent a lumbar puncture with a 22-ga pencil-tip Whitacre needle, a 20-ga bevel-tip Quincke needle, or a 22-ga Quincke needle. The groups were stratified by body mass index. We compared epidural blood patch rates between 22-ga pencil-tip Whitacre needles versus 22-ga Quincke needles and 22-ga Quincke needles versus 20-ga bevel-tip Quincke needles using the Fischer exact test and χ2 test. RESULTS: Postdural puncture headache necessitating an epidural blood patch was statistically more likely using a 22-ga Quincke needle in all patients (P < .001) and overweight (P = .03) and obese (P < .001) populations compared with using a 22-ga pencil-tip Whitacre needle. In the normal body mass index population, there was no statistically significant difference in epidural blood patch rates when using a 22-ga pencil-tip Whitacre needle compared with a 22-ga Quincke needle (P = .12). There was no significant difference in epidural blood patch rates when comparing a 22-ga Quincke needle versus a 20-ga bevel-tip Quincke needle in healthy (P = .70), overweight (P = .69), or obese populations (P = .44). CONCLUSIONS: Using a 22-ga pencil-tip Whitacre needle resulted in lower epidural blood patch rates compared with a 22-ga Quincke needle in all patients. Subgroup analysis demonstrated a statistically significant difference in epidural blood patch rates in overweight and obese populations, but not in patients with a normal body mass index.

Activation of NF-kappaB pathway in Duchenne muscular dystrophy: relation to age.

Muscle degeneration in Duchenne muscular dystrophy (DMD) is exacerbated by increased oxidative stress and the endogenous inflammatory response, with a key role played by nuclear factor kappa-B (NF-kappaB) and other related factors such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. However the time course of expression of these molecules and the relation with the amount of necrosis and regeneration have never been investigated. The expression of NF-kappaB, the cytokines TNF-alpha and IL-6 and the antioxidant enzyme glutathione peroxidase (GPx) was studied in muscle samples from 14 patients with DMD aged between 2 and 9 years. Moreover a quantitative morphological evaluation was performed to evaluate necrotic and regenerative areas. The highest percentage of necrosis was revealed within 4 years of age, with a significant negative correlation with age (p < 0.003), which paralleled to a significant decrement of regenerating area (p < 0.0004). We reported the novel observation that the number of NF-kappaB positive fibers and the NF-kappaB DNA-binding activity, revealed by EMSA, are high at two years of life and significantly decline with age (p < 0.0005 and p < 0.0001). The expression of TNF-alpha, IL-6 and GPx was upregulated in DMD muscles compared to controls and significantly increased with age on real-time PCR analysis (p < 0.0002; p < 0.0005; p < 0.03 respectively) and ELISA (p < 0.002; p < 0.02; p < 0.0001 respectively). Since anti-inflammatory and anti-oxidant drugs are nowadays being translated to clinical studies in DMD, the reported insights on these therapeutic targets appear relevant. Further studies on the interactions among these pathways in different DMD phases and on the response of these cascades to treatments currently under investigation are needed to better elucidate their relevance as therapeutic targets.

The use of OCT in good visual acuity MOGAD and AQP4-NMOSD patients; with and without optic neuritis.

Myelin oligodendrocyte-antibody-associated disease (MOGAD) often presents with severe optic neuritis (ON) but tends to recover better than in aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD). We measured OCT and VEP in MOGAD and AQP4-NMOSD eyes with good visual function, with or without previous ON episodes. Surprisingly, OCT and/or VEPs were abnormal in 84% MOGAD-ON versus 38% AQP4-NMOSD-ON eyes (p = 0.009) with good vision, compared with 18% and 17% respectively of eyes with no previous ON. A sub-group with macular OCT performed as part of a research study confirmed both retinal and macular defects in visually-recovered MOGAD eyes. These findings have implications for investigation and management of MOGAD patients.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young as a Partially Calcified Intra-Axial Mass in an Adult.

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.

Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up.

BACKGROUND AND PURPOSE: Although developmental venous anomalies have been frequently studied in adults and occasionally in children, data regarding these entities are scarce in neonates. We aimed to characterize clinical and neuroimaging features of neonatal developmental venous anomalies and to evaluate any association between MR imaging abnormalities in their drainage territory and corresponding angioarchitectural features. MATERIALS AND METHODS: We reviewed parenchymal abnormalities and angioarchitectural features of 41 neonates with developmental venous anomalies (20 males; mean corrected age, 39.9 weeks) selected through a radiology report text search from 2135 neonates who underwent brain MR imaging between 2008 and 2019. Fetal and longitudinal MR images were also reviewed. Neurologic outcomes were collected. Statistics were performed using χ2, Fisher exact, Mann-Whitney U, or t tests corrected for multiple comparisons. RESULTS: Developmental venous anomalies were detected in 1.9% of neonatal scans. These were complicated by parenchymal/ventricular abnormalities in 15/41 cases (36.6%), improving at last follow-up in 8/10 (80%), with normal neurologic outcome in 9/14 (64.2%). Multiple collectors (P = .008) and larger collector caliber (P < .001) were significantly more frequent in complicated developmental venous anomalies. At a patient level, multiplicity (P = .002) was significantly associated with the presence of ≥1 complicated developmental venous anomaly. Retrospective fetal detection was possible in 3/11 subjects (27.2%). CONCLUSIONS: One-third of neonatal developmental venous anomalies may be complicated by parenchymal abnormalities, especially with multiple and larger collectors. Neuroimaging and neurologic outcomes were favorable in most cases, suggesting a benign, self-limited nature of these vascular anomalies. A congenital origin could be confirmed in one-quarter of cases with available fetal MR imaging.

The p85 regulatory subunit of PI3K mediates TSH-cAMP-PKA growth and survival signals.

Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85alpha(PI3K) phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells (FRTL-5). The aspartic version of the p85alpha(PI3K) (p85D) inhibited apoptosis following TSH withdrawal. The p85alpha(PI3K) wild type not the p85A bound PKA regulatory subunit RIIbeta in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85alpha(PI3K) to RIIbeta was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wild-type p85alpha(PI3K) but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factor-stimulated PI3K activity. We suggest that (1) TSH-cAMP-induced PKA phosphorylates p85alpha(PI3K) at serine 83, (2) phosphorylated p85alpha(PI3K) binds RIIbeta-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH-cAMP growth signals.

POMT1 and POMT2 mutations in CMD patients: a multicentric Italian study.

Mutations in POMT1 and POMT2 genes were originally identified in Walker-Warburg syndrome (WWS) and subsequently reported in patients with milder phenotypes characterised by mental retardation with or without brain abnormalities and without ocular malformations. As part of a multicentric Italian study we screened the POMT1 and POMT2 genes in 61 congenital muscular dystrophy (CMD) patients with alpha-dystroglycan reduction on muscle biopsy and/or clinical and radiological findings suggestive of the known forms of CMD with alpha-dystroglycan deficiency. The aim of the study was to establish how frequently mutations in POMT1 and POMT2 occur in CMD patients in the Italian population and to evaluate the spectrum of associated phenotypes. Thirteen patients showed mutations in POMT1 and five harboured mutations in POMT2, accounting for a total of 20 different mutations, eight of which were novel (two in POMT1 and six in POMT2). Normal brain MRI associated with mental retardation and microcephaly was the most frequent finding in patients with mutations in POMT1 (six out of 13), but was also found in a patient with POMT2 mutations. Predominant cerebellar hypoplasia was also frequent both in patients with POMT1 (three out of 13) and POMT2 (three out of 5) mutations. A MEB phenotype with frontal cortical dysplasia and pons abnormalities was found in two patients with POMT1 and in one with POMT2 mutations, while a WWS phenotype was only found in a case with mutations in POMT1. Mutations causing frameshifts and stop codons were responsible for the more severe phenotypes. Our results provide further evidence that, as previously reported for FKRP, the array of mutations in POMT1 and POMT2 is ample and the spectrum of associated phenotypes is wider than initially thought.