Barbara Ryniewicz

“Cap disease” New congenital myopathy

In a 7-year-old boy with delayed motor development, a congenital non progressive myopathy was diagnosed. Histochemical and ultrastructural examination of a muscle specimen revealed unusual pathologic findings. In 70% of muscle fibers, peripherally located zones lacking in ATPase activity and consisting of abnormally arranged myofibrils were observed. The characteristic position of the peripherally located myofibrils and their abnormal sarcomere pattern seem to point to an error in the fusion as well as in the synthesis of muscle protein.

Follow-up study of myasthenic children after thymectomy

SummaryThe results of thymectomy of 28 myasthenic children observed from 1 to 9 years after operation are discussed. Improvement was obtained in 19 cases (67.8%), with full remission in 12 cases (42.8%). Six children died. No correlation was found between the results of thymectomy and the duration of the disease, sex or histological findings in the thymus. No increase of incidence or severity of infections were observed in thymectomized children. Caution is recommended regarding vaccination of myasthenic children.ZusammenfassungEs wird über das Ergebnis der Thymektomie bei 28 myasthenischen Kindern berichtet, aufgrund einer katamnestischen Studie nach 1–9 Jahren nach dem Eingriff. In 19 Fällen (67,8%) wurde eine Besserung, bei 12 dieser 19 Kinder (42,8%) eine Heilung bewirkt. 6 Kinder verstarben. Es bestand keine Korrelation zwischen den Ergebnissen der Thymektomie einerseits und der Dauer der Erkrankung, dem Geschlecht oder der Histologie des exstirpierten Thymus andererseits. Es wurde keine Zunahme der Häufigkeit oder des Schweregrades von Infektionen bei thymektomierten Kindern beobachtet. Es wird hingegen Vorsicht bei der Impfung myasthenischer Kinder empfohlen.

A novel MPZ gene mutation in congenital neuropathy with hypomyelination

Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.

Clinical, electrophysiological, and molecular findings in early onset hereditary neuropathy with liability to pressure palsy

Introduction: The first episode of hereditary neuropathy with liability to pressure palsy (HNPP) in childhood is rare. Methods: We analyzed retrospectively the data of 7 patients with a deletion in PMP22 and onset of symptoms before age 18 years. Direct sequencing of the LITAF (lipopolysaccharide‐induced tumor necrosis factor) gene was performed in patients and family members. Results: Clinical presentations varied from mononeuropathies to brachial plexopathy, with recurrent episodes in 4 patients. Electrophysiological abnormalities characteristic for HNNP were found in most subjects. Analysis of the LITAF gene revealed an Ile92Val polymorphism in 6 of 7 (86%) probands and 5 of 7 (83%) family members, over 4 times greater frequency than in the general population. Conclusions: Clinical suspicion of HNPP even when nerve conduction study results do not fulfill HNPP criteria should indicate genetic testing. In our patients, early‐onset HNPP was associated frequently with isoleucine92valine LITAF polymorphism. Muscle Nerve 50: 914–918, 2014

L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.

Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot–Marie–Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype–genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected “regional” S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.

Lambert–Eaton myasthenic syndrome in childhood

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. LEMS can be associated with a variety of neoplasms. Patients present with proximal muscle weakness and fatigability, often combined with areflexia. Only 5% of reported cases are children. We report a case of 11-year old boy with non-neoplastic Lambert-Eaton myasthenic syndrome. Repetitive nerve stimulation test showed 83% increment after maximal voluntary contraction, presence of antibodies against voltage-gated calcium channels confirmed the diagnosis. The boy responded well to immunosuppressive treatment with prednisone and azathioprine and remains cancer-free for 4 years.

Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy – A preliminary study

Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (Pu2009<u20090.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (Pu2009<u20090.05). Increased SMUP amplitude values correlated with decreased HFMS scores (Pu2009<u20090.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed.

Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients

The aim of our study was to identify point mutations in a group of 606 patients diagnosed for spinal muscular atrophy with excluded biallelic loss of the SMN1 gene. Point missense mutations or small deletions in the SMN1 gene were ultimately identified in 18 patients. Six patients were found to have small deletions, the c.429_435del mutation in 3 cases, the c.431delC mutation in 2 and c.722delC in one. Those mutations, not described previously, were characteristic of patients presenting a severe phenotype. The most frequent missense mutation - p.Thr274Ile, was identified in 9 patients presenting a rather mild phenotype. Three other missense mutations, i.e., p.Ser230Leu, p.Ala111Gly and p.Pro244Leu, were identified in a further 3 SMA3 patients. Mutation p.Pro244Leu, not described so far, was identified in a patient with a mild form of SMA and more distal distribution of muscle weakness. Our results suggest a specific point mutation spectrum in the Polish population. The existence of small deletions not identified thus far could suggest a possible founder effect. In patients with preserved one SMN1 allele without common exon 7 deletion, presenting a mild form of SMA, a special consideration should be given to the p.Thr274Ile mutation.

IBM-type inclusions in a patient with slow-channel syndrome caused by a mutation in the AChR epsilon subunit

We report a patient with a slow-channel congenital myasthenic syndrome who carries a novel slow-channel mutation in the epsilon subunit of the acetylcholine receptor and has tubulofilamentous inclusion bodies, in skeletal muscle of the type observed in hereditary and sporadic inclusion body myositis. Ultrastructural analysis of a muscle specimen obtained at the age of 9 years showed an endplate myopathy typical of the slow-channel syndrome. Twenty years later, a second muscle specimen again showed the endplate myopathy as well numerous nuclear and cytoplasmic tubulofilamentous inclusion bodies. Molecular genetic studies revealed a novel valine to phenylalanine mutation (epsilonV259F) in the M2 domain of the acetylcholine receptor. Coexistence of the slow-channel syndrome with a feature of IBM has not been observed before.

Early-Onset Facioscapulohumeral Muscular Dystrophy Type 1 With Some Atypical Features

Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy).