M. von der Hagen

REFINEMENT OF THE CLINICAL PHENOTYPE IN MUSK-RELATED CONGENITAL MYASTHENIC SYNDROMES

Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders caused by genetic defects that affect transmission at the neuromuscular junction.1 To date, 10 genes are known to cause CMS if mutated.2 Mutations in the muscle specific kinase ( MUSK ) gene have been published in a single family worldwide.3 Two siblings of this family were reported carrying heteroallelic MUSK mutations. ### Case reports. We report on CMS caused by a novel homozygous missense mutation in MUSK in 5 affected sibs (patients 1–5) from a consanguineous Sudanese family. The father and the maternal grandmother are first-degree cousins. The patients were followed up for 5 years (ages at the end of follow-up: 9–19.5 years). All studies were carried out with informed consent of the patients’ parents and approved by the institutional ethics review board. All affected individuals demonstrated ptosis at age 1–3 years and fatigability, when walking for a long distance, more pronounced in the evening. At the first examination they had exercise-induced weakness of the deltoid muscle. Four of them had partial ophthalmoparesis (except patient 3). Patients 2 and 3 showed modified Gowers sign and waddling gait or pronounced lordosis, respectively. Treatment with pyridostigmine (30–60 mg/day) led to slight benefit. Increased doses were reported to result in the “feeling of muscle stiffness” and the medication was discontinued. Five years later (table), there was some progression, i.e., ophthalmoparesis in all, involving additional directions of gaze in patients 2 and 5 and mild facial weakness. Patient …

Frequency of GCH1 deletions in Dopa-responsive dystonia.

We performed a systematic study on the frequency of point mutations and deletions of the gene GCH1 in dopa-responsive dystonia (DRD). A total of 136 dystonia patients were studied. Fifty of these had a sustained response to oral l-Dopa therapy (group 1: definite diagnosis of DRD), whereas the response to l-Dopa was incomplete or not tested in 86 patients (group 2: possible diagnosis of DRD). We found a GCH1 point mutation in 27 patients of group 1 (54%) and in four patients of group 2 (5%). Of these, nine single and one double mutation have not been described before. GCH1 deletions were detected in four patients of group 1 (8%) and in one patient of group 2 (1%). Among GCH1 point-mutation-negative patients with a definite diagnosis of DRD (group 1), the frequency of GCH1 deletions was 17% (4/23). We conclude that GCH1 deletion analysis should be incorporated into the routine molecular diagnosis of all patients with DRD with a sustained response to l-Dopa.

Facing the genetic heterogeneity in neuromuscular disorders: Linkage analysis as an economic diagnostic approach towards the molecular diagnosis

The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.

Diagnostic algorithms in Charcot–Marie–Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients

We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot–Marie–Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly <38 m/s in median or ulnar nerves in PMP22 duplication, >40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost‐efficient mutation detection and for the interpretation of large‐scale genetic data made available by next generation sequencing strategies.

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c.70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c.70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000.

Novel RYR1 missense mutation causes core rod myopathy.

M. von der Hagen, W. Kress, G. Hahn, K. S. Brocke, P. Mitzscherling, A. Huebner, C. Müller-Reible, G. Stoltenburg-Didinger and A. M. Kaindl Department of Pediatric Neurology, Technical University, Dresden, Germany; Institute of Human Genetics, JuliusMaximilian University, Würzburg; Department of Radiology, Technical University, Dresden; Children s Hospital, Technical University, Dresden; Departments of Neuropathology; Pediatric Neurology, Charité, Berlin, Germany and Inserm U676-Paris 7, Paris, France

Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine

Episodic ataxia type 2 (EA2, MIM#108500) is the most common form of EA and an autosomal-dominant inherited disorder characterized by paroxysmal episodes of ataxia. The disease causative gene CACNA1A encodes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel. We report on a family with a novel mutation in the CACNA1A gene. The clinical symptoms within the family varied from the typical clinical presentation of EA2 with dysarthria, gait ataxia and oculomotor symptoms to migraine and dystonia. A novel nonsense mutation of the CACNA1A gene was identified in all affected family members and is most likely the disease causing molecular defect. The pharmacological treatment with acetazolamide (AAA) was successful in three family members so far. Treatment with AAA led to a reduction of migraine attacks and an improvement of the dystonia. This relationship confirmed the hypothesis that this novel mutation results in a heterogeneous phenotype and confutes the coincidence with common migraine. Dystonia is potentially included as a further part of the phenotype spectrum of CACNA1A gene mutations.

Psycho-organic symptoms as early manifestation of adult onset POMT1-related limb girdle muscular dystrophy

We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced α-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits.

Macrocephaly, obesity, mental (intellectual) disability, and ocular abnormalities: alternative definition and further delineation of MOMO syndrome.

MOMO syndrome, previously defined as Macrosomia, Obesity, Macrocephaly, and Ocular abnormalities (OMIM 157980) is a rare intellectual disability syndrome of unknown cause. We describe two further patients with MOMO syndrome. Reported data of patients with MOMO syndrome and our own findings indicate that overgrowth does not appear to be a specific feature. We propose to form the acronym “MOMO” from Macrocephaly, Obesity, Mental (intellectual) disability, and Ocular abnormalities, excluding macrosomia from the syndrome name. The combination of obesity, macrocephaly, and colobomas is unique, therefore these features can be used as major diagnostic criteria of MOMO syndrome.

Primary Microcephaly, Muscle Hypotonia, and Global Developmental Delay: A Case of an Exceptional Clinical Manifestation of Maternally Inherited Mitochondrial T8993T>G Mutation in MT-ATP6 Gene

Objective: The m.8993T>G mutation in the gene MT-ATP6 (MIM:516060) which encodes subunit six of complex V (adenosine triphosphate synthase) of the mitochondrial respiratory chain is one of the more common disease associated mutations in mitochondrial DNA (mtDNA). The mutation is heteroplasmic, occurring together with wild-type mtDNA in affected individuals, and is associated with two different clinical phenotypes: NARP (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome), with the latter usually associated with a high mutation load. Case Report: Here, we report the case of a 2-year-old girl with postnatal primary microcephaly and muscle hypotonia. The infant is the only child of healthy, nonconsanguineous parents. At the age of 6 months, severe development delay appeared. At the age of 20 months, extensive clinical diagnostics revealed elevated serum lactate, brain atrophy in magnetic resonance imaging, and interictal epileptiform discharges. Polymerase chain reaction-restriction fragment length polymorphism analysis detected a high load of the m.8993T>G mutation in blood, confirmed by sequencing. Conclusion: Primary microcephaly is a rare manifestation of mtDNA mutations, and has not yet been described in patients with the m.8993T>G mutation. Genotype--phenotype correlations related to the m.8993T>G mutation seem to be variable, and is not always associated with typical features of MILS or NARP.