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Objective: The number of clinical trials for Duchenne muscular dystrophy (DMD) has increased substantially lately, therefore appropriate clinical instruments are needed to measure disease progression and drug efficacy. Jumping mechanography is a medical diagnostic method for motion analysis, which allows to quantify physical parameters. In this study, we compared mechanography with timed function tests (TFTs)., Methods: 41 ambulatory DMD patients performed a total of 95 chair rising tests (CRT) and a total of 76 single two-legged jumps (S2LJ) on a mechanography ground reaction force platform. The results were correlated with a 6-minute walk test (6MWT) and the time required to run 10 meters, stand up from a supine position, and climb four stairs, all performed in the same setting., Results: Our measurements show a high correlation between mechanography and the TFTs: S2LJ/10-m run, r  = 0.62; CRT/10-m run, r  = 0.61; S2LJ/standing up from supine, r  = 0.48; CRT/standing up from supine, r  = 0.58; S2LJ/climb four stairs, r  = 0.55; CRT/climb four stairs, r  = 0.51. The correlation between mechanography and the 6MWT was only moderate with r  = 0.38 for S2LJ/6MWT and r  = 0.39 for CRT/6MWT., Interpretation: Jumping mechanography is a reliable additional method, which can be used for physical endpoint measurements in clinical trials. We confirmed our assumption, that the method provides additional information concerning performance at movement with higher power output. We suggest using the S2LJ as a first-choice tandem tool combined with the 6MWT. In patients with higher disability, the CRT is an alternative measuring method, because with the progression of the disease this is longer feasible., Competing Interests: Dr. Rawer is an employee of Novotec Medical GmbH, Pforzheim, Germany. Wolfgang Müller-Felber received a project-specific grant from PTC. All the other authors report no conflict of interest., (Thieme. All rights reserved.)

Objective: Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disorder. The number of studies investigating new therapeutic approaches is substantially increasing. This study aims to investigate the impact and diagnostic value of exercise-induced fatigue in DMD, which has been proposed as a suitable outcome parameter in other conditions like spinal muscular atrophy., Patients and Methods: A cohort of 55 DMD patients (49 of them treated with steroids and 9 with ataluren) underwent a total of 241 6MWT (mean 4.4 tests/patient) which were retrospectively analyzed. Exercise-induced fatigue was assessed by the ratio between the distance achieved in the sixth minute and the distance in the second minute of the 6MWT. In previous studies a quotient above 1 was defined as a sign of fatigue., Results: The average fatigue quotient in the whole cohort of patients was 1.0. In a further analysis no impact of age, steroid therapy, ataluren therapy, overall disability, and distance in the 6-minute walk test (6MWT) on fatigue in DMD patients could be shown., Conclusion: Our data show that fatigue does not play a relevant role in DMD. Analysis of fatigue is not a useful outcome parameter in DMD studies. For this reason we suggest the 2MWT, which is better accepted by the patients, as an alternative to the commonly 6MWT., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations., Methods: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms., Results: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene., Conclusions: PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature., Competing Interests: All authors state that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, affecting the skeletal and the peripheral nervous system with highly variable phenotypes. We report on a family with two affected individuals. The father clinically suffered from a classical scapuloperoneal syndrome, while the son presented with a severe neonatal onset with congenital respiratory distress, feeding problems and arthrogryposis multiplex. Multi-Gene Panel sequencing by next generation sequencing revealed the heterozygous mutation c.805C>T (p.R269C) in the TRPV4 gene. Long-term observation over two decades showed no relevant disease progression in the father and, after a dramatic neonatal period, a significant improvement in the son who became ambulant with orthoses at the age of 5 years, suggesting a reasonably good prognosis even in cases with severe neonatal onset. Long-term findings in muscle ultrasound correlated with the clinical course, showing stable or even slightly improved findings. Neurography revealed a late-onset sensory neuropathy in the father, which was so far not described in TRPV4 neuropathies., (Georg Thieme Verlag KG Stuttgart · New York.)

We report monozygotic twins, who presented with a clinical picture of Charcot-Marie-Tooth disease type 1 (CMT1) with bilateral foot drop, pes cavus, thoracic kyphosis, and scoliosis. Hereditary neuropathy with liability to pressure palsies (HNPP) showed up in one of them. Neurography showed demyelinating neuropathy, typical for CMT1, and transient conduction block in the ulnar nerve correlating with clinical ulnar palsy due to minor mechanical stress in only one of them. Genetic analysis revealed novel small de novo deletion c.407_418del12 in the PMP22 gene. Our patient shows the rarely reported combination of CMT1A and HNPP, caused by an in-frame deletion in the PMP22 gene. HNPP is in the majority of cases correlated with heterozygous deletion of the whole PMP22 gene or other mutations leading to functional haploinsufficiency. The cases give further evidence that pathogenesis of HNPP is not completely understood and can obviously result from existence of a defective protein, too. The intrafamiliar phenotypic variability, even in monozygotic twins, confirms the well-known fact that factors apart from genetics contribute to the clinical course., (Georg Thieme Verlag KG Stuttgart · New York.)

Diagnostic approach and treatment of idiopathic inflammatory myopathies have changed considerably during the past decades. In this review, new insights in the pathogenesis, the role of muscle biopsy, and magnetic resonance imaging in the diagnostic process in children with suspected myositis are discussed. Current treatment strategies and complication management is described in detail., (Georg Thieme Verlag KG Stuttgart · New York.)