Dirk Fischer

Neuromuscular imaging in inherited muscle diseases

Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies.

Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporters known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.

Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs

Mutations in the fukutin–related protein (FKRP) have recently been demonstrated to cause limb girdle muscular dystrophy type 2I (LGMD2I), one of the most common forms of the autosomal recessive LGMDs in Europe. We performed a systematic clinical and muscle MRI assessment in 6 LGMD2I patients and compared these findings with those of 14 patients with genetically confirmed diagnosis of other forms of autosomal recessive LGMDs or dystrophinopathies. All LGMD2I patients had a characteristic clinical phenotype with predominant weakness of hip flexion and adduction, knee flexion and ankle dorsiflexion. These findings were also mirrored on MRI of the lower extremities which demonstrated marked signal changes in the adductor muscles, the posterior thigh and posterior calf muscles. This characteristic clinical and MRI phenotype was also seen in LGMD2A. However, in LGMD2A there was a selective involvement of the medial gastrocnemius and soleus muscle in the lower legs which was not seen in LGMD2I. The pattern in LGMD2A and LGMD2I were clearly different from the one seen in alpha–sarcoglycanopathy and dystrophinopathy type Becker which showed marked signal abnormalities in the anterior thigh muscles. Our results indicate that muscular MRI is a powerful tool for differentiating LGMD2I from other forms of autosomal recessive LGMDs and dystrophinopathies.

Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype–phenotype correlation study

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

Consequences of a novel caveolin‐3 mutation in a large German family

Mutations in the human caveolin‐3 gene (cav‐3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC→GAA) in codon 27 of the cav‐3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N‐terminal region of the Cav‐3 protein, which leads to a drastic decrease of Cav‐3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav‐3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav‐3–deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav‐3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav‐3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients. Ann Neurol 2003

Quantitative MRI and loss of free ambulation in Duchenne muscular dystrophy

The purpose of this ethics approved trial was to correlate quantitative MRI with functional abilities in both ambulant and non-ambulant Duchenne muscular dystrophy (DMD). Twenty patients with genetically confirmed DMD were recruited. Physical assessment was performed using the motor function measurement (MFM) scale. Axial 3T MRI scans of the thighs were acquired using T1-weighted in- and opposed-phase images (TRxa0=xa020xa0ms, TE1xa0=xa02.45xa0ms, TE2xa0=xa03.68xa0ms, flip anglexa0=xa015°) to calculate the relative fat fraction according to the two-point Dixon method in the knee extensors, flexors, and adductor muscles. The average MFM was 65.3xa0% and correlated negatively to age (r2xa0=xa00.60). Overall mean fat fraction correlated positively to age (r2xa0=xa00.51–0.64). An average of 5xa0% increase in mean fat fraction per year was calculated. Mean fat fraction of the quadriceps showed a high negative correlation (r2xa0=xa00.93) to the D1 (standing position and transfers) component of the MFM. A cutoff for mean fat fraction of 50xa0% predicted loss of ambulation with a sensitivity of 100xa0% and a specificity of 91xa0%. Therefore, quantitative muscle MRI seems to be a promising endpoint for short clinical trials evaluating the effect of newer treatments on the time of loss of ambulation in DMD.

Quantitative MRI can detect subclinical disease progression in muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant muscular dystrophy with late onset and slow progression. The aim of this study was to compare different methods of quantitative MRI in the follow-up of OPMD to semiquantitative evaluation of MRI images and to functional parameters. We examined 8xa0patients with genetically confirmed OPMD and 5xa0healthy volunteers twice at an interval of 13xa0months. Motor function measurements (MFM) were assessed. Imaging at 1.5xa0T (Siemens Magnetom Avanto) comprised two axial slice groups at the largest diameter of thigh and calf and included T1w TSE, 2-point Dixon for muscular fat fraction (MFF) and a multi-contrast TSE sequence to calculate quantitative T2 values. T1 images were analyzed using Fischer’s semiquantitative 5-point (0–4) scale. MFM and visual scores showed no significant difference over the study period. Overall T2 values increased in patients over the study period from 49.4 to 51.6xa0ms, MFF increased from 19.2 to 20.7%. Neither T2 values nor MFF increased in controls. Changes in T2 correlated with the time interval between examinations (r2xa0=xa00.42). In this small pilot trial, it was shown that quantitative muscle MRI can detect subclinical changes in patients with OPMD. Quantitative MRI might, therefore, be a useful tool for monitoring disease progression in future therapeutic trials.

Muscle Imaging in Congenital Myopathies

Congenital myopathies are a genetically heterogeneous group of early-onset myopathies classified according to the predominant histopathological findings in skeletal muscle. During the past years, considerable overlap between different pathological and genetic forms of congenital myopathies has been discovered. In contrast, the pattern of involved muscles seen on muscle imaging is often more specific, providing useful additional information in the differential diagnosis of these diseases. Therefore, muscle imaging can help to target the most appropriate genetic investigations. The aim of this review is to give a comprehensive up-to-date overview of the muscle imaging findings that have recently been described in different genetic congenital myopathies.

Increased incidence of Guillain–Barré syndrome after surgery

Antecedent surgery has been described to trigger Guillain/x96Barré syndrome (GBS), but its evidence is poor and based on case reports only.

Dynamin 2-related centronuclear myopathy: Clinical, histological and genetic aspects of further patients and review of the literature

Centronuclear myopathy (CNM) is a slowly progressive congenital myopathy with characteristic histopathological findings of chains of centrally located myonuclei in a large number of muscle fibers. Recently, different missense mutations in the dynamin 2 gene (DNM2, 19p13.2) have been shown to cause autosomal dominant CNM. We re-evaluated patients with a histopathological diagnosis of CNM and report on the clinical phenotype, the biopsy findings and the genetic results of these patients and review the current literature. Two of the three patients showed an unusually late disease onset (> 40 years). Interestingly, intramuscular nerve fascicles found in the muscle biopsy of a patient harboring the E368K DNM2 mutation contained nerve fibers with disproportionately thin myelin sheaths. Schwann cells of unmyelinated nerve fibers showed abnormal plasma membrane and basal lamina protrusions, indicating peripheral nerve involvement.